Integrative Gastroenterology (Weil Integrative Medicine Library)

Integrative Gastroenterology

Weil Integrative Medicine Library Published and Forthcoming Volumes series editor andrew weil, md

Donald I. Abrams and Andrew Weil: Integrative Oncology Timothy Culbert and Karen Olness: Integrative Pediatrics Gerard E. Mullin: Integrative Gastroenterology Victoria Maizes and Tieraona Low Dog: Integrative Women’s Health Randy Horwitz and Daniel Muller: Integrative Rheumatology Daniel A. Monti and Bernard Beitman: Integrative Psychiatry Stephen Devries and James Dalen: Integrative Cardiology

Integrative Gastroenterology edited by

Gerard E. Mullin, MD Associate Professor, Medicine Johns Hopkins University School of Medicine The Johns Hopkins Hospital Baltimore, MD

1

1 Published in the United States of America by Oxford University Press, Inc., 198 Madison Avenue, New York, NY, 10016 United States of America Oxford University Press, Inc. publishes works that further Oxford University’s objective of excellence in research, scholarship, and education Oxford is a registered trademark of Oxford University Press in the UK and in certain other countries

© Oxford University Press, Inc. 2011 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, Inc., or as expressly permitted by law, by licence, or under terms agreed with the appropriate reproduction rights organization. Inquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, Inc., at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer ____________________________________________ Library of Congress Cataloging-in-Publication Data Integrative gastroenterology/[edited by] Gerard E. Mullin. p.; cm.—(Weil integrative medicine library) Includes bibliographical references and index. ISBN-13: 978-0-19-537110-9 (alk. paper) ISBN-10: 0-19-537110-0 (alk. paper) 1. Gastrointestinal system—Diseases. 2. Integrative medicine. I. Mullin, Gerard E. II. Series: Weil integrative medicine library. [DNLM: 1. Gastrointestinal Diseases—therapy. 2. Complementary Therapies—methods. WI 140 I605 2010] RC817.I47 2010 616.3’3—dc22 2009023877 978-0-19537110-9 ____________________________________________ 1 3 5 7 9 10 8 6 4 2 Typeset in Minion Pro Regular Printed on acid-free paper Printed in the United States of America This material is not intended to be, and should not be considered, a substitute for medical or other professional advice. Treatment for the conditions described in this material is highly dependent on the individual circumstances. And, while this material is designed to offer accurate information with respect to the subject matter covered and to be current as of the time it was written, research and knowledge about medical and health issues is constantly evolving and dose schedules for medications are being revised continually, with new side effects recognized and accounted for regularly. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulation. The publisher and the authors make no representations or warranties to readers, express or implied, as to the accuracy or completeness of this material. Without limiting the foregoing, the publisher and the authors make no representations or warranties as to the accuracy or efficacy of the drug dosages mentioned in the material. The authors and the publisher do not accept, and expressly disclaim, any responsibility for any liability, loss or risk that may be claimed or incurred as a consequence of the use and/or application of any of the contents of this material.

To the more than 70 million Americans who are known to suffer from digestive disorders. To my loved ones for their unwavering support over the years. To the many who mentored me throughout my career. To Andrew Weil MD for selecting me to edit this textbook. And the beloved memory of my parents.

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FOREWORD

A

few years ago, a leading gastroenterologist in Tucson asked me to meet with him. Over dinner, he expressed the hope that integrative medicine (IM) might have something to offer him. He was frustrated, he said, because, “ninety percent of the patients I see have problems that my training does not enable me to solve.” At that time, the Arizona Center for Integrative Medicine was offering a comprehensive IM fellowship in distributed learning format to physicians and nurse practitioners. We were training family medicine doctors, internists, and surgeons, but had not yet had a GI specialist apply. That disappointed me, because I knew that integrative medicine could greatly enrich the field of gastroenterology, increasing its efficacy and reducing the frustration expressed by my colleague in Tucson and shared by many others. One of the core curricular areas of IM is mind/body medicine. It covers the theory and evidence base for interactions between mental/emotional states and physiology, as well as therapies that take advantage of those interactions. Steven Gurgevich, PhD, a clinical psychologist on the faculty of the American Society of Clinical Hypnosis, helped design the mind/body medicine module. He has said, “Patients with gastrointestinal problems should be seen by hypnotherapists before they go to gastroenterologists,” and over the years, I have referred many patients with GI complaints to him and other mind/body practitioners, with good outcomes. His reasoning is that the organs of the GI system, along with the skin, have the greatest amount of innervation of any organs and, as a result, are the most frequent sites of expression of stressrelated disorders. Michael Gershon, MD, chairman of the Department of vii

viii FOREWORD

Anatomy and Cell Biology at Columbia University Medical Center, in an excellent book on enteric neurology, refers to the gut as the “second brain.” Many common GI disorders arise from disturbed function of the gut—in particular, an imbalance between its intrinsic motility and extrinsic control by the autonomic nervous system (often caused by stress-related overactivity of the sympathetic nerves). Without harmonious coordination, gut motility is abnormal and digestion impaired. In late stages of these disorders, we can visualize or otherwise detect pathological changes, but early on they present as functional complaints. Patients seek relief of GI symptoms; there are few or no measurable correlates of the symptoms. “Functional disorder” is a loaded term in conventional medicine. Often it is used to dismiss complaints of patients without visible pathology; at worst, it is used as a synonym for “imagined disease.” Patients are easily angered by suggestions that their GI problems are all in the mind. Practitioners must be able to help them understand the underlying somatopsychic mechanism that accounts for their very real symptoms. Traditional Chinese medicine (TCM) classifies diseases as “visible” or “invisible” and postulates that all visible disease is preceded by an invisible stage, in which “energy” (chi) circulation through the body is disturbed. TCM practitioners believe that if invisible disease goes untreated (by acupuncture, herbal therapy, dietary adjustment, etc.), it will eventually produce pathological changes in the physical structure of the body. Therefore, TCM prioritizes the diagnosis and treatment of what conventional Western medicine often dismisses as functional disorders. Doctors here tend to minimize the significance of these problems, in part because they find it frustrating to manage them. Their training does not enable them to do so. Because dietary habits and other lifestyle factors can both trigger and aggravate this class of GI disorders, it is not sufficient to send patients to stressmanagement training or hypnotherapy. Physicians must also give them specific recommendations about foods, beverages, physical activity, rest and sleep, and more. And they should know when the pharmaceutical drugs now so widely prescribed for GI problems are really indicated, and for how long patients should be on them. Proton-pump inhibitors for GERD and steroids for inflammatory bowel disease may be useful for short-term suppression of symptoms, but over time the benefit-to-risk ratio changes significantly and unfavorably, and data on the risks are accumulating. Practitioners of integrative medicine are fully trained to diagnose and treat invisible and functional disease before it damages tissues and organs and requires drastic, costly intervention. They work from the premise that the body can heal itself if given a chance, that mind/body interactions are real and often very relevant to issues of health and illness, that all aspects of lifestyle must be

FOREWORD

ix

considered in evaluating patients, and that the doctor/patient relationship is a key factor in the outcome of treatment. In addition, they are familiar with a wide range of therapeutic options other than drugs. In recommending therapies not commonly included in mainstream practice, they pay attention to the evidence that supports them, always working from the principle that the greater the potential of a treatment to cause harm, the stricter the standards of evidence for efficacy it must be held to. A major initiative of the Arizona Center for Integrative Medicine is “Integrative Medicine in Residency” (IMR). We have developed a 200-hour, comprehensive curriculum in IM, much of it taught online, that is currently a required component of eight residency programs around the United States. This is a pilot phase of IMR; the center’s long-range goal is to have this comprehensive curriculum become a required, accredited part of all residency training, including that of specialists and subspecialists. Then all physicians (and surgeons), including gastroenterologists, will know the basics of nutritional medicine, botanical medicine, mind/body medicine, lifestyle influences on health, the indications for and strengths and weaknesses of other systems (like Chinese and Ayurvedic medicine) and of complementary and alternative therapies. I am certain that the resulting transformation of medicine is a prerequisite for building a functional, cost-effective health care system, one that emphasizes disease prevention and health promotion and that uses costly, technology-based interventions (including pharmaceutical drugs) only when they are really indicated, managing common forms of illness with simpler, less expensive interventions. It is my hope that this series of volumes from Oxford University Press will help achieve these goals. I have looked forward to the publication of Integrative Gastroenterology with great anticipation. Not only does it give all clinicians an overview of the subject and specific guidance about the integrative management of common GI problems, it has the potential to hasten the day when integrative gastroenterology will be a vital field of research and practice. The editor, Gerard Mullin, MD, has done a commendable job of assembling expert contributors and informative articles. I have learned much from working with him on the project, and I hope the information in these pages will lessen the frustration of practitioners faced with GI problems that conventional education and training does not enable them to solve. Andrew Weil, MD Series Editor Tucson, Arizona May, 2009

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CONTENTS

Contributors 1. Why Integrative Gastroenterology?

xv 

Gerard E. Mullin

2. The American Digestive Disease Epidemic



Gerard E. Mullin

3. An Overview of Digestive, Sensing, and Immune Functions of the Gut



Patrick J. Hanaway, Laura K. Turnbull, and Gerard E. Mullin

4. The Intestinal Microbiota in Health and Disease: Bystanders, Guardians, or Villains?



Fergus Shanahan

5. Alternative Laboratory Testing for Gastrointestinal Disease



David M. Brady, J. Alexander Bralley, Richard S. Lord, and Gerard E. Mullin

6. New Molecular Techniques Revolutionize Understanding of the Influence of Gut Microbiota on Health and Disease



J. Alexander Bralley

7. Principles of Integrative Gastroenterology: Systemic Signs of Underlying Digestive Dysfunction and Disease



Laura K. Turnbull, Gerard E. Mullin, and Leonard B. Weinstock

8. The Skin and the Gastrointestinal Tract



Andrew G. Franks, Jr.

9. Premenstrual and Menstrual Exacerbation of IBS: An Integrative Medicine Analysis of the Bi-Directional Connection between Female Hormones and Gut Health



Joel M. Evans

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CONTENTS

10. Fibromyalgia and Gastrointestinal Disorders



David M. Brady and Michael J. Schneider

11. Acupuncture for Digestive System



Sanghoon Lee and Ta-Ya Lee

12. Ayurveda and Digestive Health



David Simon and Valencia Porter

13. Osteopathic Medicine



Diane Clawson

14. Gastroenterology and an Integrative Chiropractic Approach



Loren Marks and David M. Durkin

15. Energy Medicine and Gastrointestinal Disorders



Ann Marie Chiasson

16. Guided Imagery and Gastroenterology



Martin L. Rossman

17. Hypnosis and Gastrointestinal Disorders



Anastasia Rowland-Seymour

18. Homeopathy Origins and Therapeutic Principles



Savely Yurkovsky

19. Massage for Digestive Health



Stephanie Porcaro and Gerard E. Mullin

20. Mindfulness Based Stress Reduction for Health and Diseases



Padmini D. Ranasinghe

21. Naturopathic Medicine and Digestion



Joseph Pizzorno

22. Taiji, Qigong, and Digestive Health



Yang Yang and Bob Schlagal

23. Digestive Health and Reiki Energy



Beth Nolan

24. Self-Care Journaling for Digestive Health



Danna M. Park

25. Spirituality



Frederic C. Craigie, Jr.

26. What Patients Want from Their Doctors Donna Jackson Nakazawa



CONTENTS xiii

27. The Value of Support Groups



Pearl L. Lewis and Gerard E. Mullin, with a foreword by Bernie Siegel

28. Overview of Visceral Manipulation for the Integrative Gastroenterologist



Jean-Pierre Barral and Gail Wetzler

29. Probiotics in the Prevention and Treatment of Gastrointestinal Disease



Gerald Friedman

30. The Role of Nutritional Genomics and Functional Medicine in the Management of Crohn’s Disease



Sheila G. Dean and Kathie M. Swift

31. Functional Foods for Digestive Health and Disease



Elizabeth Lipski

32. The Role of Herbal Medicine in Integrative Gastroenterology



Tieraona Low Dog

33. Brief Review of Mind–Body Medicine in Gastroenterology Practice



Miranda A.L. van Tilburg, Stephan R. Weinland, and Olafur S. Palsson

34. Mind–Body Medicine in Digestive Disease



Douglas A. Drossman and William E. Whitehead

35. Yoga and Digestive Health



Sajida Chaudry and Beth Nolan

36. Integrative Approaches to Abdominal Pain



Robert A. Bonakdar and Emily G. Singh

37. Over-the-Counter Remedies for Digestive Health: Potion or Poison?



Jerry Hickey and Gerard E. Mullin

38. Systemic Interactions Between Dental and Gastroenterological Diseases



Philip E. Memoli

39. Upper Gastrointestinal Disorders: Dyspepsia, Heartburn, Peptic Ulcer Disease, and Helicobacter pylori Anil Minocha



xiv

CONTENTS

40. Celiac Disease



S. Devi Rampertab and Peter H.R. Green

41. Food Reactions and Their Implications in the Irritable Bowel Syndrome



Trent W. Nichols, Gerard E. Mullin, and Laura K. Turnbull

42. An Evidence-Based Review of Complementary and Integrative Approaches for Irritable Bowel Syndrome



Octavia Pickett-Blakely, Ashwini S. Davison, and Gerard E. Mullin

43. Nutrition Strategies for the Treatment of IBS and the Prevention of Digestive Complaints



Ashley Koff

44. Alternative Approaches to the Patient with Inflammatory Bowel Disease



Leo Galland, Katarzyna Kines, and Gerard E. Mullin

45. Obesity



Lawrence J. Cheskin and Katrina Seidman

46. Nutrition and Colorectal Health



Mitra Rangarajan and Gerard E. Mullin

47. Liver Disease



Matthew Cave, Naeem Aslam, Christopher Kulisek, Luis S. Marsano, and Craig J. McClain

48. Integrative Approaches to Diseases of the Pancreas and Gallbladder



Vinay Chandrasekhara and Anthony N. Kalloo

49. An Integrative Approach to Gender-Specific Digestive Health Issues



Laura K. Turnbull, Gerard E. Mullin, and Sharon Dudley-Brown

50. Gastrointestinal Disorders and Eating Disorders



Carolyn Coker Ross

51. Ethical Issues in Integrative Gastroenterology



Julie Stone

52. There Is No Alternative to Evidence



Ronald L. Koretz

Index

653

CONTRIBUTORS

Naeem Aslam, MD Fellow, Department of Medicine Division of Gastroenterology and Hepatology University of Louisville School of Medicine Louisville, KY Jean-Pierre Barral, DO Director of the Department of Osteopathic Manipulation University of Paris, School of Medicine Paris, France Robert Alan Bonakdar, MD, FAAFP Director of Pain Management Scripps Center for Integrative Medicine Assistant Clinical Professor Department of Family and Preventative Medicine (Voluntary) University of California, San Diego, School of Medicine San Diego, CA David M. Brady, ND, DC, CCN, DACBN Vice Provost, Health Sciences Division Director, Human Nutrition Institute Associate Professor of Clinical Sciences University of Bridgeport Bridgeport, CT

J. Alexander Bralley, PhD Chief Executive Officer Metametrix Clinical Laboratory Duluth, GA Matthew Cave, MD Assistant Professor of Medicine Division of Gastroenterology/ Hepatology Department of Medicine University of Louisville Louisville, KY Vinay Chandrasekhara, MD Clinical Fellow Division of Gastroenterology & Hepatology Johns Hopkins University School of Medicine Baltimore, MD Sajida Chaudry, MD, MPH Family Medicine and Preventive Medicine Johns Hopkins Community Physicians Odenton, MD

xv

xvi

CONTRIBUTORS

Ann Marie Chiasson, MD, MPH, CCFP Clinical Assistant Professor of Medicine Arizona Center for Integrative Medicine University of Arizona Tucson, AZ Lawrence J. Cheskin, MD, FACP Associate Professor of Health, Behavior & Society Joint Appointment in Medicine (Gastroenterology) Director, Johns Hopkins Weight Management Center Johns Hopkins Bloomberg School of Public Health Johns Hopkins University School of Medicine Baltimore, MD Diane Clawson, DO Attending Physician Department of Psychiatry Department of Pediatrics University of New Mexico Albuquerque, NM Frederic C. Craigie, Jr., PhD Psychologist/Faculty, MaineDartmouth Family Medicine Residency Associate Professor of Community and Family Medicine Dartmouth Medical School Visiting Associate Professor Arizona Center for Integrative Medicine University of Arizona School of Medicine Augusta, Maine

Ashwini S. Davison, MD Senior Resident Department of Internal Medicine Johns Hopkins Hospital Baltimore, MD Sheila G. Dean, DSc, RD, LD, CCN, CDE Integrative Nutrition Solutions Adjunct Professor of Nutrition Science University of Tampa Palm Harbor, FL Douglas A. Drossman, MD Professor of Medicine and Psychiatry Co-Director, UNC Center for Functional GI and Motility Disorders Division of Gastroenterology and Hepatology, Department of Medicine University of North Carolina at Chapel Hill Chapel Hill, NC Sharon Dudley-Brown, PhD, FNP–BC Co-Director, Gastroenterology & Hepatology Nurse Practitioner Fellowship Program Johns Hopkins Hospital Assistant Professor Johns Hopkins University Schools of Medicine & Nursing Baltimore, MD David Durkin, DC Chiropractor Durkin Chiropractic Center Gastonia, NC

CONTRIBUTORS

Joel M. Evans, MD Assistant Clinical Professor Department of Obstetrics, Gynecology, and Women’s Health Albert Einstein College of Medicine Bronx, NY Andrew G. Franks, Jr., MD, FACP Clinical Professor of Dermatology and Medicine (Rheumatology) Director, Skin Lupus, and Connective Tissue Disease New York University School of Medicine New York, NY Gerald Friedman, MD, PhD, MS, FACP, MACG Clinical Professor of Medicine Department of Medicine, Division of Gastroenterology The Mount Sinai School of Medicine New York, NY Leo Galland, MD Director Foundation for Integrated Medicine New York, NY Peter H.R. Green, MD Professor of Clinical Medicine Celiac Disease Center Columbia University College of Physicians and Surgeons New York, NY Patrick Hanaway, MD Chief Medical Officer Genova Diagnostics Asheville, NC

xvii

Jerry Hickey, RPh Scientific Director InVite Health, Inc. New York, NY Anthony N. Kalloo, MD The Moses and Helen Golden Paulson Professor of Gastroenterology Chief, Division of Gastroenterology and Hepatology Johns Hopkins Hospital Baltimore, MD Katarzyna Kines, MS, MA, LDN, CNS, CN Holistic Nutrition Naturally, LLC Contractual Practitioner with Johns Hopkins Integrative Medicine and Digestive Center Green Spring Station, Lutherville, MD Ashley Koff, RD Founder, AshleyKoffApproved.com Ronald L. Koretz, MD Emeritus Professor of Clinical Medicine David Geffen–UCLA School of Medicine Department of Medicine Olive View–UCLA Medical Center Sylmar, CA Christopher Kulisek, MD Resident, Department of Medicine University of Louisville School of Medicine Louisville, KY

xviii CONTRIBUTORS

Sanghoon Lee, OMD, PhD, DiplAc, LAc Associate Professor of Acupuncture & Moxibustion College of Oriental Medicine WHO Collaborating Centre for Traditional Medicine East–West Medical Research Institute Kyung Hee University Seoul, South Korea Ta-Ya Lee, MSN, CRNP, MAc, LAc, MBA, MPH Johns Hopkins Community Physicians Wyman Park Internal Medicine Canton Crossing Integrative Medicine Baltimore, MD Pearl L. Lewis Founder, Maryland Chapter Crohn’s and Colitis Foundation Founder, Maryland Patient Advocacy Group Maryland Renal Advocate National Kidney Foundation of Maryland National Kidney Foundation Malignancy Advisory Board Author, Access to Care for Special Needs Populations (19 states) Ellicott City, MD Liz Lipski, PhD, CCN Director of Doctoral Studies Hawthorn University Founder of Innovative Healing Founder of Access to Health Experts Asheville, NC Richard S. Lord, PhD Chief Science Officer Metametrix Institute Duluth, GA

Tieraona Low Dog, MD Director of the Fellowship Arizona Center for Integrative Medicine Clinical Associate Professor Department of Medicine University of Arizona Tucson, AZ Dan Lukaczer, ND Associate Director of Medical Education Institute for Functional Medicine Gig Harbor, WA Loren Marks, DC, DACBN Diplomate American Clinical Board of Nutrition Integrative Assessment Technique, Founder 200 W 57 St. Ste 1010 NY Luis S. Marsano, MD Professor of Medicine Jewish Hospital Distinguished Professor of Hepatology Division of GI/Hepatology University of Louisville School of Medicine Louisville, KY Craig J. McClain, MD Professor, Departments of Medicine and Pharmacology & Toxicology Associate Vice President for Translational Research Distinguished University Scholar University of Louisville School of Medicine Louisville, KY

CONTRIBUTORS

Philip E. Memoli, DMD, FAGD, CNC Founder, Institute of Systemic Medicine and Dentistry Attending, Overlook Hospital Summit, NJ and Private Practice Berkeley Heights, NJ Anil Minocha, MD Professor of Medicine LSU Health Sciences Center Chief of Gastroenterology VA Medical Center Shreveport, LA Donna Jackson Nakazawa Author and Lecturer The Autoimmune Epidemic www.autoimmuneepidemic.com

Danna Park, MD, FAAP Medical Director Integrative Healthcare Department Mission Hospital Asheville, NC Octavia Pickett-Blakely, MD Post Doctoral Fellow Division of Gastroenterology Johns Hopkins School of Medicine Baltimore, MD Joseph Pizzorno, ND Editor-in-Chief, Integrative Medicine, A Clinician’s Journal Co-Author, Textbook of Natural Medicine President Emeritus, Bastyr University Seattle, WA Stephanie Porcaro, LMT Massage By Stephanie Baltimore, MD

Trent W. Nichols, Jr., MD Center for Digestive Disorders and Nutrition Hanover, PA

Valencia Porter, MD, MPH Director of Women’s Health The Chopra Center for Wellbeing Carlsbad, CA

Beth Nolan, LMT Massage Therapist Life Support Wellness Center Butler, NJ

S. Devi Rampertab, MD Assistant Professor of Medicine Division of Gastroenterology Penn State College of Medicine Hershey Medical Center Hershey, PA

Olafur S. Palsson, PsyD Associate Professor of Medicine Division of Gastroenterology and Hepatology Department of Medicine University of North Carolina at Chapel Hill Chapel Hill, NC

xix

Padmini D. Ranasinghe, MD, MPH Assistant Professor of Medicine Division of General Internal Medicine Johns Hopkins University School of Medicine Baltimore, MD

xx

CONTRIBUTORS

Mitra Rangarajan, MSN, ANP-BC, MPH, CDE, MS, RD Nurse Practitioner, Advanced Therapeutic Endoscopy & GI Motility Division of Gastroenterology & Hepatology Johns Hopkins University School of Medicine Baltimore, MD Carolyn Coker Ross, MD, MPH Clinical Assistant Professor of Medicine University of Arizona, Tucson, AZ Eating Disorder, Addiction Medicine and Integrative Medicine Consultant Denver, CO Martin L. Rossman, MD Clinical Instructor Department of Family and Community Medicine University of California San Francisco Medical School San Francisco, CA Anastasia Rowland-Seymour, MD Assistant Professor of Medicine Division of General Medicine Department of Internal Medicine Johns Hopkins University School of Medicine Baltimore, MD Bob Schlagal, PhD Professor Department of Language, Reading, & Exceptionalities Appalachian State University Boone, NC

Michael J. Schneider, DC, PhD Visiting Assistant Professor School of Health & Rehabilitation Sciences University of Pittsburgh Pittsburgh, PA Katrina B. Seidman, MS, RD, LDN Registered Dietician Johns Hopkins Weight Management Center Department of Health, Behavior and Society Johns Hopkins Bloomberg School of Public Health Baltimore, MD Fergus Shanahan, MD Professor and Chair, Department of Medicine Director, Alimentary Pharmabiotic Centre Cork University Hospital and University College Cork National University of Ireland David Simon, MD Medical Director, Co-Founder The Chopra Center for Wellbeing Carlsbad, CA Emily G. Singh, MD Division of Gastroenterology Scripps Clinic Carmel Valley San Diego, CA Julie Stone, MA, LLB Visiting Professor, Peninsula Medical School Universities of Exeter and Plymouth United Kingdom

CONTRIBUTORS

Kathie Madonna Swift, MS, RD Director, Food As Medicine Center for Mind Body Medicine Washington DC and Lead Nutritionist Kripalu Center for Yoga and Health Stockbridge, MA Laura K. Turnbull, BA, RNc Johns Hopkins University School of Nursing Baltimore, MD Miranda A.L. van Tilburg, PhD Assistant Professor of Medicine University of North Carolina School of Medicine Department of Gastroenterology and Hepatology UNC Center for Functional GI and Motility Disorders Chapel Hill, NC Stephan R. Weinland, PhD Assistant Professor of Medicine University of North Carolina at Chapel Hill Center for Functional GI and Motility Disorders Chapel Hill, NC Leonard B. Weinstock, MD Associate Professor of Clinical Medicine and Surgery Washington University School of Medicine Director, Specialists in Gastroenterology, LLC St. Louis, MO

xxi

Gail Wetzler, PT, EDO, BI–D Director of Physical Therapy Center for Alternative Medicine University of California, Irvine and Director of Curriculum and Program Development Barral Institute and Owner of Wetzler Integrative Physical Therapy Center Newport Beach, CA William E. Whitehead, PhD Professor of Medicine and Adjunct Professor of Obstetrics and Gynecology Co-Director of the Center for Functional GI and Motility Disorders University of North Carolina at Chapel Hill Chapel Hill, NC Yang Yang, PhD Adjunct Faculty Department of Kinesiology and Community Health University of Illinois at UrbanaChampaign and Director Center for Taiji and Qigong Studies New York, NY Savely Yurkovsky, MD Private Practice Chappaqua, NY

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Integrative Gastroenterology

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1 Why Integrative Gastroenterology? GERARD E. MULLIN

key concepts ■

■

■

■

■

■

■

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Digestive diseases encompass more than 40 acute and chronic conditions of the gastrointestinal tract, ranging from common digestive disorders to serious, life-threatening diseases. More than 70 million Americans are afflicted with diseases of the digestive system. Digestive diseases are the second leading cause of disability due to illness in the United States, with more than 2 million Americans impaired to some degree. The annual economic impact on the U.S. economy is more than $141 billion. Westernized diet and lifestyles are the major cases of the digestive disease epidemic. Many of the most common digestive diseases in the United States are also common in Canada and Europe, but are uncommon in Asia and Africa, suggesting that these diseases are preventable through dietary and lifestyle modifications. The escalating prevalence of obesity, anxiety, depression, stress, fast food consumption, and food-borne illnesses, is contributing to the digestive disease epidemic. Adoption of an integrative model by physicians would achieve more effective prevention and treatment of digestive disease. ■

3

Introduction

A

s gastroenterologists, internists, primary-care practitioners, nurse practitioners, or alternative providers, we need to realize that over 50% of patients with digestive disorders incorporate complementary and alternative medicine (CAM) into their treatment regimen. Studies have shown that approximately 72% of patients who utilize alternative strategies are reluctant to disclose this to their providers for fear of being stigmatized. Since our patients seek our guidance and expertise in overseeing their healthcare, it is time for us to realize that consumer demand has driven the present dynamic of patients paying out of pocket to achieve improved health and well-being by “integrating” alternative strategies into their lives. There is a body of experiential and evidence-based literature to support the utilization of these “alternative” strategies in digestive healthcare. Thus, the ongoing utilization of alternative strategies by the public, the evidence supporting its use, and the expanding groups of practitioners achieving improved health outcomes, led Dr. Andrew Weil to commission me to synthesize a comprehensive how-to guide for advising digestive disease patients, aimed at the everyday practitioner. Integrative medicine is a rapidly growing and highly credible field that seeks to integrate the best of Western scientific medicine with a broader understanding of the nature of illness, healing and wellness. Dr. Andrew Weil defines integrative medicine as a “healing-oriented medicine that takes account of the whole person (body, mind and spirit), including all aspects of lifestyle. It emphasizes the therapeutic relationship and makes use of all appropriate therapies, both conventional and alternative.” The Principles of Integrative Medicine by Dr. Andrew Weil: • A partnership between patient and practitioner in the healing process • Appropriate use of conventional and alternative methods to facilitate the body’s innate healing response • Consideration of all factors that influence health, wellness, and disease, including mind, spirit, and community, as well as body • A philosophy that neither rejects conventional medicine nor accepts alternative therapies uncritically • Recognition that good medicine should be based in good science, be inquiry driven, and be open to new paradigms • Use of natural, effective, less invasive interventions whenever possible

Why Integrative Gastroenterology? 5

• Use of the broader concepts of promotion of health and the prevention of illness, as well as the treatment of disease • Training of practitioners to be models of health and healing, committed to the process of self-exploration and self-development.

Integrative medicine aims to transform healthcare by moving the boundaries of the existing field of medicine to include the wisdom inherent in healing the “whole person”—mind, body and spirit.

The Digestive Disease Epidemic Digestive disease is known to affect more than 70 million Americans today. An estimated 70% of Americans have either digestive disease or digestive symptoms over their lifetime. Countless others have migraines, arthritis, fibromyalgia, chronic fatigue, depression, neurological disease, osteoporosis, skin disorders, menstrual irregularities, premenstrual syndrome (PMS), and other conditions that are related to undiagnosed core digestive discord. This emerging epidemic of digestive disease is a social disease that results from a breakdown in the infrastructure of society as we promote stress, meals on the run from fast-food vendors, unhealthy norms in food choices, and exposure to carcinogens and xenobiotics, while producing record rates of mental disorders, social isolation, obesity, and inactivity, which all adversely affect the gut. The end result is a nation in which one in three individuals have a digestive disorder, 63 million either have or show signs of autoimmune disease, and 125 million overall have a chronic disease. This is no accident!

Roots of Integrative Gastroenterology “A person whose basic emotional and physical tendencies are in balance, Whose digestive power is balanced, Whose bodily tissues, elimination functions and activities are in balance, And whose mind, senses and souls are filled with vitality, That person is said to be healthy.” Sushruta Samhita, 2000 B.C.

6 INTEGRATIVE GASTROENTEROLOGY

AYURVEDIC MEDICINE

The human digestive system is our inside track to balanced health and vitality. This principle has been the fundamental basis of health and healing for centuries in Eastern civilization, which comprises most of the world’s population today. Sushruta Samhita is one of the founders of modern Ayurdevic medicine, which is used by healers worldwide to prevent disease and promote health. The driving principle of Ayurveda (translated as the wisdom and science of life) is that disease is the absence of vibrant health, which begins in a breakdown of the spirit, and evolves in definable stages beginning with improper digestion. According to Sushruta Samhita, the Ayurvedic secret to a long, happy, and vital life is predicated upon balanced energetic, metabolic, and protective forces; strong digestion; optimal cellular, tissue and organ function; efficient elimination; and clear senses, joyful mind, and transpersonal connection. For more about Ayurveda and digestive health, see Chapter 12.

TRADITIONAL CHINESE MEDICINE

Traditional Chinese medicine (TCM) was the first formalized system of health and healing in modern civilization. In Eastern philosophy, all life occurs within a circle of nature, with all things in this matrix interconnected and mutually dependent upon each other. Human beings represent a microcosm of nature and are the juncture between heaven and earth. In TCM, health and vitality are predicated upon spiritual connection, balanced living, a vegetable-based diet, proper digestion, and peace of mind. The flow of energy, or chi, is the essence of health and well-being. A blockage in the flow of chi through energy channels called meridians is the beginning of illness, and loss of adaptability is the beginning of disease. In TCM, the foods we eat are not merely nutrients but are vehicles of energy to be dispersed to our body in either a healthy or unhealthy manner, as determined by the outcome of digestion. When the digestive fire is too weak or too strong, the resultant energy imbalances create disharmony and illness. In TCM, chi is centered around the digestive tract in a ball of energy called the don tien. This virtual force field of energy circling our digestive tract is essential to health and well-being. Ayurveda and TCM principles guide the care of billions who are among the world’s healthiest people. These well-proven models of healthy living share in common sound mind, peace, wholeness and harmony, a healthy

Why Integrative Gastroenterology? 7

vegetarian-based diet, spiritual connection, and herbs for early symptoms of illness. In both systems, individuals are the sum of their diet and lifestyle choices. Proper digestion of a healthy diet is the key to a life filled with vibrant health and free of disease.

WESTERN MEDICINE

“Let food be thy medicine and let medicine be thy food.” “Leave your drugs in the chemist’s pot if you can heal the patient with food.” “Above all else, do no harm.” —Hippocrates, 450 B.C. The Western model of healthcare has been traced to Hippocrates, who is considered to be the father of medicine. As physicians, we recite the Hippocratic Oath at our medical school graduation. What I remember most, while reciting a moving self-proclamation of service to mankind by facilitating healing, is Hippocrates, as well as Sushruta Samhita and the early emperors of China, who believed that physicians are healers of the body, mind, and spirit. Th e job of the physician was to provide proper instruction of diet in the prevention and treatment of illness. Hippocrates also strongly believed that the body, mind, and spirit were inseparable in health and disease. “As man thinketh in his head, so shall his life be made.” —Hippocrates, 1450 B.C.

Western Philosophy: The Doctor as Mechanic In the seventeenth century, Rene Descartes and Sir Isaac Newton introduced the principle of “reductionism,” whereby human beings were viewed as the sum of their parts, and the matters of the “spirit” were left to religious organizations. This unfortunate sustained separation of “church and state” excommunicated the very soul of Western medicine, the doctor–patient relationship. People were merely the sum of body parts and molecules. The Cartesian principle of medicine forever transformed the delivery of care to its present-day assembly line of 10-minute office visits, whereby the doctor writes a prescription and barely has time to lay eyes upon his or her patients. Rene Descartes began what managed care has finished—the near extinction of the physician as a healer.

8

INTEGRATIVE GASTROENTEROLOGY

Western medicine is a very sophisticated and advanced form of healthcare for acute illness, emergencies, curable malignancies, sustaining chronic disease, and surgical miracles. When it comes to optimizing health and preventing disease, our results are inferior compared to every country in the industrialized world. For example, the United States is 41st in longevity among industrialized countries—dead last! Despite our poor results, Western-trained physicians still consider the long-standing and highly successful Eastern healing arts to be archaic and quackery, and proudly view our modern system of care to be far superior. As a profession, we perpetuate this reductionist approach more than ever before. Doctors in training are now taught that our health is merely the result of the genes that we inherited from our parents, and that health is all preprogrammed and predetermined. This view excludes the possibility that health also reflects the accumulation of the choices that we make and the circumstances around us. The reality is that our health and well-being are the result of how our environment interacts with our genes. How we were parented, whether we were breastfed, how we connect to spirit, ourselves, and others, what we eat, how we process our food and emotions, and whether our lives are balanced or toxic, all have profound influences on health. Our genes can either become our protectors and partners for wellness, or target practice for pollutants and toxins in producing illness and disease. We do make choices every day that influence the expression of our genes. Table 1.1. Comparison of Conventional, Western-Based Medicine versus Integrative Medicine Aspects of care

Conventional

Integrative

Focus

Disease detection

Disease prevention

Orientation

Doctor-centered

Patient-centered

Treatment

Drugs only

All inclusive

Healing

Drugs only

Self-healing

Empathy

Variable

Loving

Office visits

Rushed, inattentive, prescription-oriented

Open mind, open heart, healing

Doctor–Patient Relationship

Doctor-centered

Partnership

Satisfaction

Low

High

Why Integrative Gastroenterology? 9

Nutritional genomics is an evolving field, started by Nobel Laureate Dr. Linus Pauling and championed by his protégée, Dr. Jeffrey Bland. There has been an explosion of research showing how nutrients derived from food directly influence genetic expression and cellular function. There is more to health and wellness than just the genes that we inherit from our parents.

The Doctor–Patient Relationship: Returning to the Roots of Medicine Digestive disease specialists are fighting to stay afloat financially by severely limiting their allotment of time to perform procedures and see patients for office visits. In the end, patients are being treated as though they are on an assembly line, rather than being present in the nurturing environment of a doctor’s office. Likewise, physicians are speeding through patient care encounters like a “rat race,” constantly fighting an uphill battle. As a measure of the modern doctor–patient relationship that has evolved in the era of Westernized managed care, a study was conducted to determine doctors’ empathy for patients. Previous work suggests that exploration and validation of patients’ concerns is associated with greater patient trust, lower healthcare costs, improved counseling, and more guideline-concordant care. The study by Dr. Ronald Epstein and colleagues included 4,800 patient surveys concerning doctor visits, and 100 covertly recorded visits by actors posing as patients. The results showed that only 15% of the doctors voiced empathy. In the study, published in the Journal of General Internal Medicine, the researchers analyzed the patient surveys and actor visits and characterized the responses by type, frequency, pattern, and communication style, and correlated them with patient satisfaction ratings. Empathy was associated with higher patient ratings of interpersonal care. “The best physicians are empathic. They show neither sympathy nor disdain. Empathy does not develop as naturally as sympathy or disdain. We must nurture this emotion, allowing it to blossom. True empathy greatly helps the doctor–patient relationship.” —Robert M. Centor, 2005 A key element to Dr. Weil’s vision of integrative medicine is for the practitioner to return to the roots of medicine by fostering partnerships with patients. We know that the stronger the doctor–patient relationship, the more powerful the healing response. This is called the placebo response by researchers, but is underutilized in today’s version of “hit and run” medicine. The restoration of

10

INTEGRATIVE GASTROENTEROLOGY

faith and trust in the treating practitioner by the patient is an essential element to healing. At Johns Hopkins, the first physician-in-charge was Sir William Osler (1849–1919), who was the father of modern medicine. In his writings and teachings, Sir William Osler emphasized humanity, compassion, observing and listening to patients with an open mind and heart, and to minimize the use of pharmaceutical medications. Following are some excerpts from many of his famous quotations. “Observe, record, tabulate, and communicate. Use your five senses. Learn to see, learn to hear, learn to feel, learn to smell, and know that by practice alone you can become expert.” “It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has.” “The good physician treats the disease; the great physician treats the patient who has the disease.” “Teach young physicians to care more particularly for the individual patient than for the special features of the disease.” —Sir William Osler (1849–1919) The integrative practitioner should strive to: • Humanize healthcare: Combine old-fashioned caring with superb medical care • Prevent disease and promote health • Listen to and communicate effectively with patients and their families in order to form partnerships • Appreciate and bridge cultural differences, so that care plans are understood by their patients • Share decision making with patients and their families as partners • Emphasize the necessity of a team approach in caring for each patient • Integrate the best medical knowledge into healthcare that is accessible, patient friendly, and high quality • Act as an advocate for patients and the health needs of society • Act as a steadfast guide and source of support to patients, no matter where they choose to seek specialty care • Raise awareness that book-smart doctors can lack emotional intelligence, and appreciate how a disease affects a patient’s daily life

Sir William Osler followed in the footsteps of the ancient Greek physician, Hippocrates (460–377 B.C.). These quotations by Hippocrates reflect his

Why Integrative Gastroenterology? 11

philosophy of the body’s natural healing force and the importance of proper nutrition and exercise to good health. There is also a message to young physicians to guide the patient’s healing, that it is better to do nothing than to harm the patient. “Everyone has a doctor in him or her; we just have to help it in its work. The natural healing force within each one of us is the greatest force in getting well.” “To do nothing is sometimes a good remedy.” “Walking is man’s best medicine.” “If we could give every individual the right amount of nourishment and exercise, not too little and not too much, we would have found the safest way to health.” —Hippocrates

Conclusions Digestive diseases are responsible for a major economic burden in the United States and worldwide. Preventive care, education about the influence of diet and lifestyle on digestive disease development and treatment, and research support, all lag behind in meeting the need to correct the economic burden and to provide future generations of scientists in the digestive sciences. Given the American digestive disease epidemic, there is a need for governments to readdress this shortcoming and to review its methods of support, as well as for physicians to adopt an integrative approach to the prevention and treatment of digestive disease. “The doctor of the future will give no medicine, but will interest her or his patients in the care of the human frame, in a proper diet, and in the cause and prevention of disease.” —Thomas A. Edison, U.S. inventor (1847–1931)

NOTES I. The term iatrogenic is defined as “induced in a patient by a physician’s activity, manner, or therapy. Used especially to pertain to a complication of treatment.” II. Sources: Vital Statistics of the United States—1970, National Center for Health Statistics, Table 1-26, “Deaths from 281 Selected Causes, by Age, Race, and Sex: United States, 1970”; death certificates from 31 states, reported in “Mortality of Dentists, 1968 to 1972,” Bureau of Economic Research and Statistics, Journal of the

12 INTEGRATIVE GASTROENTEROLOGY

American Dental Association, January 1975, pp. 195ff; death reports collected by the American Medical Association, reported in “Suicide by Psychiatrists: A Study of Medical Specialists Among 18,730 Physician Deaths During a Five-Year Period, 1967–72,” Rich et al., Journal of Clinical Psychiatry, August 1980, pp. 261ff.; Vital Statistics of the United States—1990, National Center for Health Statistics, Table 1-27, “Deaths from 282 Selected Causes, by 5-Year Age Groups, Race, and Sex: United States—1990”; National Occupational Mortality Surveillance database, reported in “Mortality Rates and Causes Among U.S. Physicians,” Frank et al., American Journal of Preventive Medicine, Vol. 19, No. 3, 2000.

2 The American Digestive Disease Epidemic GERARD E. MULLIN

key concepts ■ ■

■

■

■

Digestive diseases are highly prevalent in the United States. The age-adjusted increase in the prevalence of digestive diseases between 1998 and 2004 was 35%. The International Foundation of Functional Gastrointestinal Disorders (IFFGD) has projected that the prevalence in America today for gastroesophageal reflux disease (GERD) is 30 to 60 million, and for irritable bowel syndrome (IBS), 30 to 45 million. The annual cost of digestive diseases was estimated to be $142 billion annually in 2004. Proton pump inhibitors (PPIs) have dominated the pharmaceutical market since 2000. Prescriptions for PPIs collectively represent 50.7 percent of total number of prescriptions and 77.3 percent of total cost in 2004. ■

Digestive Disease: The Cold, Hard Facts

I

n 2002, the American Gastroenterology Association (AGA) became the first physician-based organization to address the growing burden of digestive disease on the nation’s healthcare resources. Led by Dr. Robert S. Sandler, the AGA published a special report that outlined the prevalence and economic burden of digestive disease in the United States as of 1998, with financial projections to the year 2000 (Sandler, Everhart, Donowitz et al., 2002). 13

14

INTEGRATIVE GASTROENTEROLOGY

Due to the changes in perceived disease prevalence, and the rising cost of technology, the AGA and the National Institutes of Digestive Diseases, Diabetes and Kidney Diseases (NIDDK) partnered to update the burden of digestive disorders to the U.S. economy, so that effective resources can be allocated and directed to disease prevention (Everhart & Ruhl, 2009a, 2009b, 2009c). In Sandler’s 2002 report, the estimated direct costs for 17 of the most common digestive diseases in 1998 dollars was $85.5 billion for all direct costs, with estimated indirect costs of $22.8 billion, for a total of $108.8 billion. Dr. Everhardt and colleagues reported that in 2004, the total direct cost of digestive disease in the U.S. was $97.8 billion, with estimated indirect costs of $44 billion, for a total of $141.8 billion. The distribution of costs according to disease classification in 2004 is shown in Table 2.2. From 1998, the prevalence of Irritable Bowel Syndrome (IBS) has risen to affect from 30 to 45 million individuals (10%–15% of the U.S. population), according to the International Foundation for Functional Gastrointestinal Disorders (IFFGD).1

THE PREVALENCE OF DIGESTIVE DISEASE IN AMERICA

The NIDDK of the National Institutes of Health (NIH) is a government agency that has collected data from a variety of sources to estimate the burden of digestive disease.2 The overall prevalence of digestive diseases was reported by the NIH in 1996 to be 60 to 70 million. U.S. Government statistics of digestive disease prevalence were updated in a special report on February 02, 2009.(Everhart & Ruhl, 2009a,b,c)

There are numerous studies that analyze the burden of digestive disease in the United States. The past decade has seen a rapid expansion of individuals who suffer from chronic digestive symptoms. The prevalence of digestive disease in America has reached epidemic proportions. Based on the latest available evidence, we collected and summarized data on the prevalence of digestive disease in Tables 2.1 and 2.2. The resulting burden to the U.S economy is shown in Tables 2.3 and 2.4. Since prescription medications represent a great part of this financial burden, the costliest medications to consumers are listed in Table 2.4. 1 2

(www.aboutgerd.org) (http://digestive.niddk.nih.gov/statistics/statistics.htm)

The American Digestive Disease Epidemic 15

Table 2.1. The Burden of Digestive Diseases in America in 2008 Digestive disease

Prevalence

Prevalence

(% U.S. population)

(U.S. population

Year

Reference

4,968,809

1990

NIDDK

255,640

2004

American Cancer Society

24,980,000

2006

Levine & Ahnen (2006); Terhaar et al. (2009)

in millions)

Abdominal wall hernia 1.66 Cancer of digestive system

0.9

Colonic adenomas

30% above age 50

Celiac disease**

1.0

3,000,000

2007

Green (2006)

Clostridium difficle colitis

1.0

3,000,000

2007

Ricciardi, Rothenberger, Madoff, & Baxter (2007)

Chronic liver disease/ cirrhosis

0.15

451,710

2007

NIDDK, populationadjusted

Constipation

1.0

3,100,000

1996

Adams, Hendershot, & Marano (1999)

Diverticulosis

20

60,200,000

1969

Hughes (1969)

Diverticular disease (complicated)

0.9–2.2 4.0

2,500,000– 6,000,000 12,040,000

1996 2006

NIDDK, Duggan (2006)

Gallstones

11–22

30,000,000– 60,000,000

1999

NIDDK

Gastritis; non-ulcer dyspepsia

1.4

37,000,000

1996

Adams, Hendershot, & Marano (1999)

GERD

30–42

90,000,000– 127,000,000

2007

Singh et al. (2007); http:// www.aboutgerd. org

Helicobacter pylori infection

20–52

60,000,000– 157,000

2002

NEJM. 2003; 347:1175–1186 (Continued)

16

INTEGRATIVE GASTROENTEROLOGY

Table 2.1. (Continued) Digestive Disease

Prevalence

Prevalence

(% U.S. Population)

(U.S. Population

Year

Reference

1996

Adams, Hendershot & Marano (1999)

1980– 1998

NIDDK

2007

www.ccfa.org

in Millions)

Hemorrhoids

3.2–4.4

8,500,000

Infectious diarrhea

36.4–44.8

IBD

0.33–0.47

IBS

10–15

30–45,000,000 2007

http://www. aboutibs.org/

Lactose intolerance

10–16.7%

30–50,000,000 1994

Rusynyk & Still (2001)

Non-alcoholic fatty liver disease (NAFLD)

22–33%

Pancreatitis

0.05%

Peptic ulcer disease

135,000,000 1,000,000– 1,400,000

66,250,788– 99,376,182

2003

Angulo (2007); Suzuki & Diehl (2005)

160,000

1995

Everhart (1995)

4.90%

14,500,000

2003

NIDDK

Hepatitis A

31%

93,500,000

1998– 1994

NIDDK, NHANES (2005)

Hepatitis B

0.05–5%

1,500,000– 15,057,000

1998– 2004

NIDDK, McQuillan et al. (1999)

Hepatitis C

1.36–1.8%

4,100,000– 5,420,000

2007

NIDDK, Armstrong et al. (2006)

Hepatitis D

unknown

1990

NIDDK

Viral hepatitis

unknown; 75,000 new cases

* US Population was 301,139,947 as of July 2007. **Only 3% of people with disease are diagnosed, according to Peter HR Green Available at http:// www.ncbi.nlm.nih.gov/pubmed/17593160/pubmed?term=%22Green%20PH%22%5BAuthor% 5D”Green PH Comment on: HYPERLINK “/pubmed/17355413”Am J Gastroenterol. 2007 Jul; 102(7):1454–60

The American Digestive Disease Epidemic 17

Table 2.2. The Prevalence and Costs of Digestive Disease in the United States from 1985 to 2004 Diseases

1985

1998

2004

1985

prevalence

prevalence

prevalence

cost

2004 cost

($millions)

($millions)

Abdominal hernias

4,741,000

4,500,000

4,968,809

2,760

6,078

Constipation

4,458,000

3,100,000

3,100,000

360

1,712

Diverticula

1,900,000

2,500,000

60,200,000

1,550

4,041

Enteric infections*

8,300,00

135,000,000

135,000,000

4,990

7,300

Enteritis (noninfectious)*

5,700,000

75,000,000

75,000,000

820

1,119

Gastritis– dyspepsia,****

2,793,000

3,700,000

3,700,000

1,130

1,269

Gallstones

956,000

20,500,000

30,000,000– 60,000,000

4,710

6,169

GERD**

546,000

53,000,000

90,000,000– 127,000,000

1,100

12,639

GI malignancy

258,000

227,700

255,560

6,080

24,148

10,360,000

8,500,000

8,500,000

830

873

IBD

2,308,000

1,081,200

1,000,000– 1,400,000

820

2,166

IBS

1,379,000

2,100,000

30,000,000– 45,000,000

400

1,007

Liver disease (chronic)**

552,000

21,950,000

108,825,788– 119,928,182

3,250

13,095

Peptic ulcer*

4,491,000

14,500,000

14,500,000

2,520

3,118

All Digestive Disease (Chronic)****

62,000,000

56,140

141,826

Hemorrhoids

60,000,000– ?????????? 70,000,000

* 2008 data based upon NIH/NIDDK statistics from 1996. ** GERD was not included in the 1985 report as a distinct entity, but rather incorporated as “GERD and related esophageal diseases.” *** Chronic Liver Disease includes NAFLD and chronic viral hepatitis (B,C,D). **** Helicobacter pylori infection was not listed for 1985, and was not included for enteric infections or gastritis. **** Prevalence according to NIH/NIDDK; summation by hand shows the true number of digestive disease diagnoses in 1998 to be 345,658,900.

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INTEGRATIVE GASTROENTEROLOGY

Table 2.3. NIH Research Expenditures by Disease in FY 2000 Research

$$$

Diseases

(in millions)

Chronic Liver Disease and Cirrhosis

218.6

Liver Cancer

46.2

Ulcerative Colitis and Crohn’s Disease

27.0

Pancreatic Cancer

20

Gallbladder Disease

14.5

Chronic Hepatitis C

66.5

Irritable Bowel Syndrome

8.2

Peptic Ulcer Disease

12.1

Foodborne Illness

57.5

Colorectal Cancer

205.2

Reprinted with permission from Everhart JE, Ruhl CE. Gastroenterology 2009;136(2):376–386.

Table 2.4. All Digestive Diseases: Costliest Prescriptions Drug

Prescription

Prescription %

Retail Cost

Cost

$3,104,963,208

25.2%

number

Lansoprazole

20,898,993

15.5%

Esomerprazole

19,458,470

14.3

2,845,565,944

23.1

Pantoprazole

11,716,033

8.6

1,408,222,944

11.4

Raberprazole

8,019,431

5.9

1,135,819,908

9.2

Omeprazole

8,582,644

6.3

1,038,622,087

8.4

Mesalamine

2,448,971

1.8

468,426,719

3.8

Ranitidine

13,171,338

9.7

319,418,374

2.6

Tegaserod

1,618,699

1.2

238,030,688

1.9

Ribavirin

221,035

0.2

229,351,616

1.9

Peginterferon alfa-2a

131,001

0.1

191,754,177

1.6

49,378,593

36.4

1,351,443,116

11.0

Other TOTAL

135,735,478

100.0%

$12,331,718,182

100.0%

Reprinted with permission from Everhart JE, Ruhl CE. Gastroenterology 2009;136(4): 1134–1144.

The American Digestive Disease Epidemic 19

The U.S. Congress has been relying on NIH/NIDDK figures in allocating funding initiatives. Thus, the NIH/NIDDK database for the economic impact of digestive disease was updated in 2009in order to properly advocate for and allocate government funding. However, an up to date reviewof the prevalence of digestive disease was not reported. Since individuals can carry more than one digestive disease diagnosis, it may be difficult to know with certainty the actual prevalence.

DIGESTIVE DISEASE AFFLICTS EVERY AMERICAN HOUSEHOLD

Based upon the data in Table 2.1, there were enough digestive disorders in 2007 for each of 301,139,947 Americans to carry at least 2–3 diagnoses each! For example, in one study, 48% of patients diagnosed with IBS had concomitant GERD.(Nastaskin, Mehdikhani, Conklin, Park, & Pimentel, 2006). Likewise, many inflammatory bowel disease IBD patients have IBS diagnosed as well. In other words, many patients suffer from more than one digestive disorder at a time. This is not surprising, since our Westernized diet and sedentary lifestyles have led to many of these digestive illnesses.

DIGESTIVE DISEASE: A GROWING EPIDEMIC IN OUR WESTERN WORLD

An epidemic3 is a classification of a disease that appears as new cases in a given human population, during a given period, at a rate that substantially exceeds what is “expected” based on recent experience. In 1996 the prevalence of digestive diseases was estimated to affect 60 to 70 million Americans. Digestive diseases are a silent epidemic, and the incredible number of Americans with functional digestive disorders may be an underestimate of the true U.S. prevalence. In Olmsted County, Minnesota, the reported prevalence of functional gastrointestinal disease (e.g., IBS, abdominal pain) was shown to be 42.3% in a recent study by the Mayo Clinic. (Halder et al., 2007)

A study by Halder and colleagues showed that two-thirds of studied patients with functional gastrointestinal disorders had chronic symptoms 10 years after

3

(from Greek epi- upon + demos people).

20

INTEGRATIVE GASTROENTEROLOGY

the onset of disease. This study out of the Mayo Clinic was the longest and most comprehensive, population-based, follow-up study of functional gastrointestinal disorder (FGID) patients, and the only long-term U.S. study. Dyspepsia (abdominal discomfort as a separate and additional diagnostic entity) has been recently reported to be present in 11.5% to 14.7% of the population (El-Serag & Talley, 2004).

LOSING THE DIGESTIVE DISEASE BATTLE

There is no doubt that enormous economic resources are being consumed by the burden of digestive disease. Despite the losing battle being fought by many physicians, government funding is funding is inadequately allocated to combat diseases that are affecting easily over 60 million Americans today. In 2000, NIH research expenditures for digestive disease research reached a record $676 million. The NIH spent more than 72.5% of its digestive disease budget for just two groups of conditions—liver disease ($285 million) and colorectal cancer ($205.2 million).

Certainly, colorectal cancer and liver diseases are worthy causes toward which to devote available resources. However, there are more than 40 other known digestive disease conditions that constitute the vast majority of digestive disease prevalence in America, and that deserve proportionate allocation of resources. Despite concerted efforts by the NIH to control the spread of digestive disease, its prevalence is rapidly rising. For example, celiac disease is now reported to affect 3 million Americans and is silent in 97% of those who have the disease, according to Dr. Peter Green in his book, Celiac Disease: A Hidden Epidemic (Green, 2006). The detection rate can be increased 43-fold just by instituting proper screening of all patients who have suggestive symptoms. Other emerging silent epidemics include non-alcoholic fatty liver disease and hepatitis C (Angulo, 2007). Non-alcoholic fatty liver disease (NAFLD) has been estimated to affect from 22% to 33% of Americans and is closely linked to obesity and insulin resistance as the major factors for its rapid emergence (Angulo, 2007; Suzuki & Diehl, 2005). The hepatitis C virus is known to infect 4.1 million Americans and 200 million people worldwide, resulting from person-to-person transmission (Armstrong et al., 2006). Due to the epidemic proportion of hepatitis C in the United States, a special website was established

The American Digestive Disease Epidemic 21

to educate the public and warn about its dangers.4 Both diseases are silent killers. To demonstrate the magnitude of the economic impact of constipation today, a report published in 2007 analyzed the healthcare resource utilization of Medicaid patients in California. Dr. Gurkirpral Singh and colleagues from Stanford University showed that 105,130 patients of the state’s 10 million beneficiaries (1.05%) consumed $18.9 million to treat constipation in a 15-month period of time. The total economic impact of constipation on the U.S. economy was estimated to be $54.4 billion in 2007 (Singh et al., 2007). The total economic impact to the United States economy would be $9.9 billion just to treat constipation for 18.2% of the population on Medicaid assistance.

The Singh et al. study was funded by the Novartis Pharmaceuticals Corporation of East Hanover, New Jersey. Although the report appears credible and highlights the magnitude of the problem of constipation in the United States, there is a self-serving interest for Novartis to fund this study. By showing that constipation produces an untoward economic burden on the U.S. economy, Novartis can make a strong argument to the FDA to reverse its ban on Zelnorm (touted as a magic bullet for constipation). In order to calculate the true total costs of digestive disease in 2007, the actual prevalence of disease would need to be known, along with the actual costs of prescription medications, hospitalizations, procedures, office visits, and mortality, as well as indirect costs of lost wages and productivity. In 2002, an intensive effort by the American Gastroenterology Association estimated the burden of digestive diseases on the U.S. economy (Sandler RS, 2002). Since 1998, the Consumer Price Index (CPI) has risen approximately 4% per year and the economic impact of digestive diseases today must be in excess of 40% higher when compared to 1998 statistics, totaling $141.7 billion ((Everhardt JE. 2008). In 2008, the economic burden of digestive disease appears to be much greater than reported in 1998. (Everhardt JE. 2008)We know from the IFFGD that the prevalence of the irritable bowel syndrome has risen two to three times since 1998.5 In 2003, the estimated annual direct costs for irritable bowel syndrome rose to $1.35 billion, having an estimated impact to the U.S. economy upward of $30 billion annually, excluding prescription and over-the-counter 4 5

(http://www.epidemic.org/theFacts/theEpidemic/ (http://www.aboutgerd.org/site/learning-center/congressional-testimony/2007)

22

INTEGRATIVE GASTROENTEROLOGY

medications (Leong et al., 2003; Inadomi, Fennerty & Bjorkman, 2003; Hulisz, 2004). IBS is second only to hypertension in healthcare costs in the United States annually. (Cash, Sullivan, & Barghout, 2005)

Pancreatitis, an uncommon disorder, causes more than 200,000 hospitalizations and costs between $3.6 to $6.0 billion annually (Draganov & Toskes, 2002). The American Digestive Disease Epidemic (ADDE) is wreaking havoc in the lives of many, and is costing government and industry billions of dollars annually. The most common and costly digestive conditions can be either prevented (e.g. colorectal cancer) or treated (e.g. NAFLD, GERD) with diet, lifestyle modifications, improved self-care, and a more integrative approach to healthcare.

CELIAC DISEASE

Celiac disease is the most common genetic disease in Europe. About 1 in 250 people in Italy and about 1 in 300 people in Ireland have celiac disease. It is rarely diagnosed in African, Chinese, and Japanese people. The prevalence of celiac disease in the United States is similar to that of Europe. This is one example of how our North American and European gene pool renders susceptibility to a diet-induced digestive disorder. : In other words, a combination of genetic susceptibility and environment (Western lifestyle) produce the disease. Celiac disease, by itself, is of epidemic proportions, but only 3% of affected individuals have been diagnosed due to the silent nature of this disease. For example, neuropathy, diabetes, bone disease, anemia and other systemic conditions are caused by celiac disease, but physicians who are unaware of their association fail to connect the dots. As a consequence, physicians are underutilizing available blood tests to screen for celiac disease due to their lack of recognition of its systemic occult manifestations.

DIVERTICULAR DISEASE: A WORLDWIDE OR WESTERN DISEASE?

“Westernized” nations such as the United States have prevalence rates of diverticular disease from 5% to 45%, depending on the method of diagnosis and age of the population. The prevalence of diverticular disease has increased from

The American Digestive Disease Epidemic 23

5%–10% eighty years ago, to 35%–50% in an autopsy series published in 1969 (Hughes, 1969); there are no recent population-based studies. The prevalence of diverticular disease is age-dependent, increasing from less than 5% at age 40, to 30% by age 60, to 65% by age 85. The overall prevalence of diverticular disease in America is estimated to be 20% of the population. The hospital admission rate and surgical rate for diverticular disease has been reported to have increased by 16% for males and by 12%–14% for females in England from 1990–2000 (Kang et al., 2003). Diverticulosis is another example of a disease that has a prevalence in Europe slightly lower, but not significantly different, than in the United States. The relatively high prevalence in Europe is related to Westernization of the European diet. Diverticulosis is rare in Africa and Asia (except in Japan, which has been rapidly become Westernized) and in cultures that consume a highfiber diet (Delvaux, 2003). Diverticular disease is a Western condition due to a poor, low-fiber diet in our fast-food culture.

In contrast to the high prevalence in Western societies, the frequency of diverticulosis in Iran was recently reported to be 1.6% in people above the age of 20, 2.4% in people above the age of 50, and 1.2% in people between the ages of 20 and 50 (Dabestani, Aliabadi, Shah-Rookh, & Borhanmanesh, 1981). The prevalence of diverticula in an aging Western population is relatively high, compared with the low prevalence in developing countries where a highvegetable diet is consumed, because a diet low in plant products is a precipitous factor in the pressure changes needed to produce diverticula. This is the most generally discussed cause of diverticular disease, and provides the basis for much of the advice given to reduce the prevalence of diverticular disease, as well as to manage established disease. Clearly, our unhealthy “Westernized” diets and lifestyles produce these stark differences in digestive diseases in the United States versus other, non-Western civilizations.

COLORECTAL CANCER

Colorectal cancer is another condition in which Western diets high in saturated fat and red meat and low in fiber, compounded by sedentary lifestyles and high obesity rates, portend toward a greater susceptibility. Colorectal cancer is the most common cancer of the digestive organs, accounting for more than 60% of all digestive organ cancers and 25% of all

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cancer mortality in the United States (Boyle & Ferlay, 2005). In 2004, more than 660,000 Europeans were living with a diagnosis of colon cancer. Colorectal cancer is the second most common cancer in Europe and the United States. Like diverticular disease, colon cancer is rare in Africa and Asia (except Japan). In both conditions, a high-fiber diet appears to be protective. A high-fat diet is a risk factor for the development and recurrence of colorectal cancer (Rennert, 2007). The seven Western behavioral risk factors that are associated with an increased risk for colorectal cancer are: smoking; low physical activity; low fruit and vegetable intake; high caloric intake from fat; obesity; high alcohol intake; and low intake of multivitamins (Coups, Manne, Meropol, & Weinberg, 2007).

INFLAMMATORY BOWEL DISEASE

The highest incidence rates and prevalence for ulcerative colitis and Crohn’s disease (inflammatory bowel disease) are reported in North America and northern Europe. The lowest incidence rates are reported in South America, Southeast Asia, Africa (with the exception of South Africa) and Australia. Aside from differences in sanitation, the dietary association between excessive consumption of carbohydrates, and polyunsaturated fats such as corn oil and margarine, correlate with the development of inflammatory bowel disease (Riordan, Ruxton, & Hunter, 1998; Geerling et al., 2000).

GALLSTONE DISEASE

Gallstones are found more commonly in Europe (15.7% prevalence overall) and the UnitedStates, (13.2%), than in Africa (5%–10%) and Asia (3.1%–6.1%). The prevalence of gallstones in Europe is higher for northern countries (e.g., Norway, 19.7%; Germany, 21.7%) when compared to Chianciano (5.9%) and Bari (0.1%), Italy. This is believed to be related to the higher intake of saturated fat in the diet versus the Mediterranean-based diet of the Italian people (Kratzer et al., 1998; Kratzer, Mason, & Kachele, 1999).

IRRITABLE BOWEL SYNDROME

As for IBS, in the United States, Europe, and Canada, the prevalence is 10%–15% with a female to male ratio of 2:1. IBS is less common in Asia and underdeveloped countries, and males and females have equivalent disease prevalence.

The American Digestive Disease Epidemic 25

In China, the history of functional GI disorders (FGID) may be traced back more than 2,500 years, but it was not until 1987 that more attention began to be paid to FGID, especially IBS (Si, Chen, Sun & Dai, 2004). A 1996 randomized sampling study (2,486 subjects randomly chosen from urban, suburban, and rural areas of the United States) showed a point prevalence of IBS of 7.01% (7% of the population at any given time presented with IBS symptoms (Drossman DA et al., 1996) The point prevalence of IBS in the United States doubled to tripled in 2004 when compared to 1998. Figure 2.1 shows the worldwide prevalence of IBS (Gwee, 2005).

GASTROESOPHAGEAL REFLUX DISEASE (GERD)

GERD is common in the United States, Canada, and Europe, and is uncommon in Asia (except Japan) and underdeveloped regions of the world (Wang, Luo, Dong, Gong, & Tong, 2004).Like other diseases we have discussed, diet and lifestyle play a role in disease pathogenesis. The prevalence of GERD and obesity in Japan has approximated that in the United States in recent years, unlike the rest of Asia, possibly due to the Westernization of their society. For example, since the first McDonald’s fast food restaurant opened in Japan on May 1, 1971, there have been 104 franchises opened, which correlate with the growth of obesity and GERD. Western-Based Digestive Diseases Celiac Disease Diverticular Disease Colorectal Cancer Inflammatory Bowel Disease

Gallstone Disease Irritable Bowel Syndrome Gastroesophageal Reflux Disease

Conclusions Despite our affluence and economic world leadership, the United States continues to struggle with suboptimal pay for performance in healthcare outcomes, infant mortality, and life expectancy. America and Western societies continue to be sedentary, obese, consume a nutrition-poor Western-based diet, and rely solely upon pharmaceutical agents to prevent and treat disease— thus, digestive disease prevalence continues to soar. An emerging digestive

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disease epidemic is damaging the physical and economic health of the United States. Lessons should be learned from the low prevalence of digestive disease in countries that adopt more nutritious diets and active lifestyles, and are less avid consumers of pharmaceutical drugs. The remainder of this book is devoted to helping those who have a digestive condition to restore their health, and to those who want to prevent alimentary tract disease and enjoy optimum health.

3 An Overview of Digestive, Sensing, and Immune Functions of the Gut PATRICK J. HANAWAY, LAURA K. TURNBULL , AND GERARD E. MULLIN

key concepts ■

■

■

■

■

■

■

The gastrointestinal tract is a “tube within a tube” that performs a myriad of functions for each individual. We ingest 30–40 tons of nutrients as food in our lifetime. The ability of the gut to properly digest, absorb, and extract the nutrients we need determines which of the essential macronutrients and micronutrients are available for our cells to function properly. The gut is our principal interface with our environment, acting as the barrier and the sorter of information in the form of food and organisms. The concept of “oral tolerance” is the education of our immune system by exposure to phytonutrients and organisms (primarily bacteria) within the gut that arise after we are born. The bacteria, yeast, viruses, and parasites that coexist within our gastrointestinal tract are known as the commensal flora, or gut microflora. We are born with the keys (known as toll-like receptors and pattern-recognition receptors) to relate directly to, learn from, and integrate the messages from our environment (food and flora) directly into our beings via our immune systems. The enteric nervous system, or “second brain,” has more neurotransmitters in the gastrointestinal tract than in the entire brain. ■

27

Introduction

T

his chapter moves beyond the descriptive view of gut function, and serves to illustrate the systems approach to understanding the interrelationship of major gut functions. The evaluation of fundamental processes helps us to understand when, how, and if there is an imbalance within the gut, as well as how to bring it back into balance (i.e., treat it!). Thus, we have organized the chapter according to the five elements of traditional Chinese medicine, the very roots of integrative gastroenterology: • the process of digestion and absorption (EARTH/nurturance) • the selective barrier function that defines our relationship to the “outside” world (WOOD/structure) • the commensal microflora of the gut with which we are interdependent (METAL/interrelationship to the web of life) • the physiologic inflammation that is necessary to activate and maintain the immune surveillance system (FIRE/connection) • the enteric nervous system, which communicates with the rest of the body—based upon all of the above inputs. (WATER/balance).

THE GASTROINTESTINAL TRACT

The gastrointestinal tract, the tube within a tube, connects us to our environment through a dynamic interface that is larger than a doubles tennis court. Over the course of our lifetimes, we will ingest 30–40 tons of macronutrients, micronutrients, chemicals, and toxins, providing the building blocks for everything human. Disturbances in our functional ability to make the most of these nutrients have ramifications on every aspect of our being, and imbalance in the gastrointestinal system has implications that extend far beyond gastrointestinal symptoms. Thus, in nearly every clinical interaction, the clinician must be vigilant to gastrointestinal dysfunction. Classically, the role of digestion and absorption are considered the principal functions of the gastrointestinal epithelium. The quality of discernment that traditional Chinese medicine (TCM) attributes to the “small intestine official” is manifested through its ability to “separate the wheat from the chaff ” (Jarrett, 1999), but is also seen in the intertwined relationship of the innate and adaptive immune system within the gastrointestinal system. The role of diet and nutrients in the balance of the commensal flora, the role of digestion and absorption in providing proper macronutrients and micronutrients,

An Overview of Digestive, Sensing, and Immune Functions of the Gut 29

the appropriate physiologic inflammation, the development of “oral tolerance,” the production of neurochemicals within the “second brain,” and the appropriate excretion of waste, are the functions that must remain within balance to foster health and well-being. Dysfunction within the gastrointestinal system manifests in typical digestive diseases such as: gastroesophageal reflux “disease” (GERD), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD; Sansonetti, 2004), nonalcoholic steatohepatitis (NASH; Angulo, 2002), and even colorectal cancer (CRC; McGarr, Ridlon, & Hylemon, 2005). It is also necessary for us to recognize that gastrointestinal dysfunction can manifest as imbalanced immunologic function, thus creating both atopic illness (Brandtzaeg, 2002), including allergy and asthma, and autoimmune dysfunction (Rook et al., 2004), including rheumatoid arthritis, Type I Diabetes Mellitus, and Hashimoto’s thyroiditis. Other diseases of immune dysregulation and gastrointestinal dysfunction now include the autism spectrum disorders.

The evolution of these diseases begins long before the presentation of symptoms; thus, the opportunity for prevention and early intervention can have tremendous impact on the burden of suffering and disease. Dietary approaches provide the most effective means of returning balance to dysfunction within the gastrointestinal system, and there are many opportunities to bring these tools to patients. However, the profound dietary changes that man has adopted over the past 10,000 years, and that have accelerated over the past 100 years, have created a discord between the nutritional input that our genetic structure has evolved to maximize, and what we are choosing to ingest (Cordain et al., 2005). This discordance creates a much more complex array of clinical opportunities for supporting the whole being to regain balance and optimal function. Diagnostic considerations include, first and foremost, an extensive health history with an exploration of the patient’s dietary inputs, as well as his or her utilization of antibiotics, laxatives, fiber, herbs, etc. In addition, one must elicit the current pattern of bowel movements including frequency, history, abdominal pain, gas, bloating, duration, and relationship of bowel elimination to meals. It is amazing how many patients consider their altered bowel movements to be normal. Western medicine does not have a defined norm of bowel movement frequency, while other forms of healing such as Ayurveda and TCM (see figure 3.1 A) view the regular functioning of the gastrointestinal tract to be a critical barometer of health and well-being, with one well-formed bowel movement per day to be the norm (Svoboda & Lade, 1988). Other diagnostic

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considerations include the evaluation of stool to gather information on parameters of digestion, absorption, inflammation, infection, intestinal permeability, and altered gut flora (known as dysbiosis). Let us look more closely at the specific functional imbalances faced by clinicians, as we examine how they manifest in pathophysiology and how they can be rebalanced to optimize health.

Digestion and Absorption DIGESTION

As simple as it seems, basic evaluation of digestion and absorption are often not part of the initial evaluation of gastrointestinal function in patients with IBS.

Factors that have a negative impact on digestion of food include: inadequate mastication, hypochlorhydria, pancreatic insufficiency, bile insufficiency, and villous atrophy. Mastication is a simple clinical point to make with patients and is often overlooked (see Chapter 38 by Dr. Memoli).

IATROGENIC HYPOCHLORHYDRIA AND GERD

The plethora of advertisements claiming we have too much stomach acid appears to limit the clinical relevance of hypochlorhydria when, in fact, there is no evidence to support this assertion. In actuality, the symptoms associated with gastroesphageal reflux are more likely attributed to our current diets and lifestyle (i.e., obesity), leading to laxity of the gastroesophageal (GE) junction and causing excessive reflux of gastric enzymes, acid, and bile. Measures to block the production of gastric acid do not address the root cause of the pathologies and core imbalances that produce the symptoms of heartburn— mainly, disordered gut motility and impaired lower esophageal sphincter pressure from structural derangements (i.e., hiatal hernia). By overlooking these structural anomalies and, instead, emphasizing pharmaceuticals to reduce stomach acid, we induce a state of hypochlorydria, making patients more susceptible to vitamin and mineral deficiencies, as well as alterations in the normal microbial flora. A more integrative approach to heartburn that addresses these core imbalances is addressed by Dr. Minocha in Chapter 39.

An Overview of Digestive, Sensing, and Immune Functions of the Gut 31

Consequences of suppressing gastric acid production include: vitamin deficiency (folate, B12), mineral deficiencies (calcium, magnesium, zinc, iron, chromium, manganese, and copper), altered bowel flora, dysbiosis, and small bowel bacterial overgrowth.

IATROGENIC HYPOCHLORHYDRIA AND SMALL INTESTINAL BACTERIAL OVERGROWTH (SIBO)

In addition to the important nutrient absorption implications, the role of low stomach acid in IBS is particularly notable in small intestinal bacterial overgrowth (SIBO). Pimentel, Chow, and Lin (2000) demonstrated that 78% of IBS patients tested were positive for SIBO, a condition in which coliform and anaerobic bacteria from the large intestine produce deleterious effects within the delicate environment of the small intestine. The common assay to evaluate for SIBO utilizes the fermentation of sugars, such as lactulose, which stimulates gas production (hydrogen and methane) measurable with a simple breath test. Total gases reflect the quantity of coliform and anaerobic bacteria present in the small intestine. Treatment commonly includes the use of broad-spectrum antibiotics for 7–10 days to eliminate the overgrowth. Pimentel, Chow, and Lin (2000) reported that 48% of patients no longer met the Rome II criteria for IBS when treated with rifaximin. Although antibiotics are the mainstay treatment of conventional medicine, other herbal preparations containing berberine, along with essential oils, will have a similar bacteriocidal effect (see Chapter 7). Lactobacillus acidophilus and Lactobacillus casei help minimize the side effects of antibiotics, and independently decrease the hydrogen gas production (Gaon et al., 2002). While antimicrobial agents are important to eliminate excessive and displaced colonic flora, it is also necessary to address the underlying root causes of SIBO, including antacids, proton pump inhibitors, antihistamines, slowed transit time, maldigestion, lactose intolerance, and excess simple carbohydrates (see Chapter 7).

PANCREATIC INSUFFICIENCY

Pancreatic insufficiency is a common dysfunction that can be evaluated noninvasively. Beyond symptoms of maldigestion (belching, bloating, flatus),

32 INTEGRATIVE GASTROENTEROLOGY

there are relationships between decreased pancreatic function, osteoporosis (Moran et al., 1997), and diabetes (Hardt et al., 2000). Evaluation of pancreatic function can utilize pancreatic enzymes, such as chymotrypsin and elastase, or indirect markers, such as fecal fat. Elastase is the most sensitive marker of pancreatic insufficiency because, unlike chymotrypsin, it is not subject to bacterial degradation as it flows through the gastrointestinal tract. Treatment is simple, with pancreatic enzyme supplementation being a safe and effective therapeutic intervention to improve digestive function.

ABSORPTION

A fundamental source of malabsorption is maldigestion, as evidenced by the example of SIBO. Maldigestion of fermentable starches (i.e., legumes) can cause an overgrowth of bacteria, which injures the gut integrity and results in a subsequent decrease in absorptive capacity. In addition to its critical role in oral tolerance and immune activation, the intestinal mucosa absorbs nutrients while acting as a barrier to toxins and macromolecules.

Barrier Function The ability of the body to be able to discern between friend and foe highlights the critical importance of the single-cell-layer gastrointestinal mucosa. This physical barrier, as large as a high school basketball court, provides the principal interface through which the body communicates with its environment. In addition to this single-cell layer, the gut microflora provide an additional barrier by competing with pathogens and producing a mucopolysaccharide matrix, known as the biofilm. Alterations in barrier function through intestinal permeability [a.k.a. “leaky gut”], changes in the microflora, and alterations in the biofilm layer can lead to immune upregulation. Permeability changes in the gut mucosa can have profound effects on anatomic and immunologic barriers to disease (Figure 3.2) (Baumgart & Dignass, 2002). Intestinal permeability can lead to increased inflammatory cytokine production, and a propagation of inflammation within the intestine (Clayburgh, Shen, & Turner, 2004). In fact, there is a great deal of evidence linking increased intestinal permeability with multiorgan system failure, systemic disease and immune dysfunction (DeMeo et al., 2002).

An Overview of Digestive, Sensing, and Immune Functions of the Gut 33

ALTERED BARRIER FUNCTION: INCREASED INTESTINAL PERMEABILITY

A central theme of this book is that a number of conditions (stress, toxins, inflammation, infection, poor diet, etc.) can alter the barrier function and increase intestinal permeability, thus creating a “leaky gut” (see Chapter 7). Animal models demonstrate that stress significantly increases intestinal permeability (Baumgart & Dignass, 2002), particularly in the cases of trauma and sepsis (Wells, Hess, & Erlandsen, 2004). This process of intestinal permeability is not a disease entity unto itself, but rather a dysfunction that can increase the overall toxic and antigenic burden. When the paracellular junctions are altered, there is an increased antigen presentation to the immune system (Figure 3.3, Table 3.1). Alessio Fasano, one of the world’s leading researchers on celiac disease, proposes that intestinal permeability is also a necessary precursor for many autoimmune diseases, and these processes can be prevented by reestablishing intestinal barrier function (Fasano & Shea-Donohue, 2005). With autoimmune disease, the presentation of an environmental antigen to the gastrointestinal mucosal immune system first requires that the antigen pass from the intestinal lumen into the submucosal layer, then on to the mesenteric lymph nodes and the Peyer’s patches. Immune activation occurs if and when there is a genetic predisposition to respond aberrantly (overactively) to the environmental antigen (Clemente et al., 2003). For example, those patients who are DQ2 and DQ8 positive will have the genetic basis for gliadin’s activation of the inflammatory cytokine pathways. This pathophysiologic process is predicated upon the incompletely digested molecule traversing the intestinal barrier to initiate this sequence of events.

Table 3.1. Diagnoses of Altered Intestinal Permeability Intestinal permeability test interpretation

Mannitol

Lactulose

Suspect

Normal/High

High

Increased Permeability

Low

Low

Malabsorption

Low

High

Increased Permeability & Malabsorption

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Increased permeation of intestinal luminal antigens into the portal circulation leads to an increase in the inflammatory and metabolic stress on the liver. Removal of the initial conditions is necessary to reverse this increase in intestinal permeability. L-glutamine and zinc carnosine have been demonstrated to be important in supporting the healthy growth of enterocytes and microvilli (Zhou et al., 2003). Probiotics have also been shown to reverse increased intestinal permeability in infants, over and above their anti-inflammatory effects (Isolauri, Kirjavainen, & Salminen, 2002).

MALABSORPTION: DECREASED INTESTINAL PERMEABILITY

Absorption of nutrients is impaired when there is chronic inflammation of the small intestine, which injures the villi. The absorption of dipeptides, monosaccharides, and long-chain fatty acids is dependent upon the available surface area of small intestine. Since microvilli increase the absorptive area of the small intestine by a log-order of magnitude, minimal assaults have a tremendous impact upon vitamin and nutrient absorption. Conditions that may produce substantial inflammation and injury to the small intestine include, but are not limited to, Crohn’s disease, celiac disease, and infections. However, iatrogenic injury from medications such as nonsteroidal anti-inflammatories is an overlooked but common cause.

GUT FLORA

The makeup of the community of organisms that comprise the microflora of the gut is principally established during the first one to two years of life, and is maintained throughout our lives. The composition of the gut flora is indicative of our environmental exposures prenatally, intrapartum, and throughout infancy. Factors that influence the succession of gut flora from that time forward include type of delivery (Penders et al., 2006), feeding habits (Harmsen et al., 2000), gestational age, hospitalization (Björkstén, 2004), and infant antibiotic use (Teitelbaum & Walker, 2002). At birth, the digestive tract is sterile but begins to be colonized within the first few days of life. During the subsequent two years of life, the GI tract becomes home to 100 trillion commensal bacteria, fed by milk and other foods. These simple foods that stimulate the growth and maintenance of bowel flora are known as prebiotics. Cordain describes the dietary patterns most common today, and compares them with the characteristics of ancestral diets Cordain et al., 2005).There are significant alterations in glycemic load, fiber content, essential fatty acid

An Overview of Digestive, Sensing, and Immune Functions of the Gut 35

composition, pH balance and macronutrient/micronutrient composition. All of these factors have tremendous effects on the balance of the commensal flora within the gastrointestinal tract. Because nearly 70% of the immune system is localized to the digestive tract, a state of controlled physiologic inflammation, along with environmental contact with commensal bacteria, is essential for proper development of the immune system.

New evidence is evolving that the persistent interactions between host and bacteria taking place in the gut may constantly reshape the immune system (Guarner & Magdelena, 2005). Clinicians see the profound effects of altered commensal flora in the nearly 20% of the population who are affected by the functional GI disorder, irritable bowel syndrome (IBS) (Drossman, Camilleri, & Whitehead, 1997). It is also becoming clear that the immune dysregulation of Crohn’s disease and ulcerative colitis (IBD) is profoundly influenced by the role of gut flora (Shanahan, 2004). Immune balance is maintained as gastrointestinal microflora compete with pathogens to prevent inflammation and intestinal permeability. In addition, metabolic processes facilitate the proper breakdown of foods, thus minimizing gastrointestinal inflammation. Finally, these bacteria help to stimulate growth and epithelial cell differentiation. These processes together provide the importance of gastrointestinal microflora in preventing and treating intestinal permeability.

BIOFILMS

In addition to the role of individual organisms within the gastrointestinal microflora in promoting homeostasis and decreasing intestinal permeability, there is an additional interest in the collective action of these bacteria working together to form unique ecological niches, the biofilm layer. This 30-micronthick layer of “pond scum” acts to protect the intestinal lining, metabolize food remnants (especially carbohydrates), and may communicate with the immune system. In fact, it is postulated that the short-chain fatty acid (SCFA) synthesis that provides energy to the gut epithelium may also be involved in the “crosstalk” that influences the development of humoral and cell-mediated portions of the mucosal immune system. When an inflammatory process is present within the gut, the 30-micron-thick biofilm layer decreases in thickness, and there is a concomitant increase in intestinal permeability (Swidsinski et al., 2007).

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The bacteria growing in these biofilm structures often behave differently from their nonadherent counterparts, with changes in the nature and efficiency of their metabolism (Macfarlane & Macfarlane, 2006). Once the bacteria in the gut achieve a certain concentration, they begin to communicate across species, which changes the fundamental expression and action of the DNA from that of an individual cell to that of a multicelled organism. This phenomenon is known as quorum-sensing, a truly holistic phenomenon in which the “whole is greater than the sum of the parts” (Sifri, 2008).

GUT IMMUNOLOGY

The process of oral tolerance is analogous with the view of traditional Chinese medicine (TCM) regarding the “small intestine meridian.” Note that the channels of “chi” are not limited to physical properties; thus, the “sorter” (as this meridian is also known) is involved in “separating the wheat from the chaff ” through digestion and absorption, but it is also involved in the process of teaching the immune system to determine self from nonself via oral tolerance, as well as all other “sorting” functions throughout body, mind, and spirit. This phenomenon relates, deeper still, to the concept of sorting through information for decision making in which we have a “gut feeling,” and learning to trust that quality of “sorting”—even when it may not make sense. Through the process of evolution, the body has developed a number of methods to identify microbes and modulate the adaptive immune system, based upon the proper timing and presence of the bacterial stimuli. The body responds differentially to bacterial stimuli, and responds to a variety of structural components on each bacterium. The innate immune response stimulates the adaptive immune system and influences the nature of the adaptive response (Figure 3.4; see Abbas & Lichtman, 2003). The process of “oral tolerance” is an important example of this. (Brandtzaeg, 2002). Oral tolerance is mediated by regulatory T cells (Treg), which have antiinflammatory capabilities. Precursor T cells are transformed into Treg cells when antigen-presenting dendritic cells (DCs) of the gut have not been exposed to inflammation. Precursor T cells are transformed into Teffector cells (TH1 or TH2) when the DCs are mature (i.e., activated by inflammatory signals) (McGuirk & Mills, 2002). However, gut flora (like Lactobacillus) can downregulate DC maturation, thus preventing the activation of Teffector cells (Figure 3.5; see Christensen, Frøkiaer, & Pestka, 2002). The gut flora trains the innate immune system to begin to recognize “self.” There are molecules of recognition—pattern recognition receptors (PRR),

An Overview of Digestive, Sensing, and Immune Functions of the Gut 37

toll-like receptors (TLR), and pathogen-associated molecular patterns (PAMP)—that facilitate the mucosal immune system’s awareness of the bacterial environment, and determine its release of stimulating or suppressive cytokines (see figure 3.6). The epithelial mucosa is equipped with PRRs that recognize bacterial DNA from commensal bacteria and effectively modulate immune function (Jijon et al., 2004). Pathogenic bacteria will upregulate the adaptive immune system (via IL-12) within the Peyer’s patches and the mesenteric lymph nodes, inducing NF-kB activation of the inflammatory cascade Figure 3.7). Conversely, the normal gut microflora promotes immune modulation (via IL-10) and has anti-inflammatory properties (Figure 3.8 and 3.9). Disruption of gut flora disrupts oral tolerance by driving the T effector responses in the gut toward a TH1 proinflammatory response. Correction of gut flora improves oral tolerance. Thus, the immune system is dynamically educated by the presence of bacteria at the interface of the intestinal epithelium. The gut flora interacts with our innate immunity, and influences the adaptive immune response, in an important dialogue between the immune system and the environment. Commensal bacteria are also able to modulate expression of host genes involved in important intestinal functions, including nutrient absorption, mucosal stimulation, xenobiotic metabolism, and intestinal maturation (Hooper et al., 2001). Different bacteria induce different immunologic responses. Nonpathogenic bacteria also elicit different cytokine responses from epithelial cells, inducing differential effects on the gut-associated lymphoid tissue GALT and the adaptive immune system (Borruel et al., 2002).Because of this dynamic interplay between the gut flora and the GALT, the immunologic response system can be modified, based upon dietary change (in the form of prebiotics) and beneficial bacteria (in the form of probiotics). Hooper and Gordon (2001) have highlighted the effects of imbalance within this complex ecosystem. Their work has expanded our understanding of the metabolic effects of the microflora by highlighting the metabolic effects that altered gut flora can have on the development (and treatment!) of obesity. The increasing prevalence of allergy and atopy are associated with alterations of intestinal colonization, and decreased tolerance to common food proteins and inhaled allergens. Treatment with probiotics has helped to shift these symptoms back to normal (Kallomaki et al., 2003). Overall, we see that these critical environmental interactions highlight immunologic dysregulation arising from the combination of varied bacterial species (commensal and pathogenic), altered adaptive immune system activation, and multiple antigenic stimuli.

38 INTEGRATIVE GASTROENTEROLOGY

Enteric Nervous System FACTORS INVOLVED IN GUT HOMEOSTASIS

Gastrointestinal homeostasis requires a dynamic balance of the “five elements” of gastrointestinal function (digestion/absorption, intestinal barrier, enteric commensal flora, enteric nervous system, mucosal immunity; see Figure 3.1). Under the guidance of the central nervous system (CNS), the enteric nervous system regulates digestive functions (i.e., digestion, motility) and is crucial to our overall health and well-being. In order to achieve homeostasis, the enteric and central nervous systems communicate via bidirectional signaling. Our ability to adapt to psychological and physical stressors depends upon an optimal functioning of this signaling pathway. In the face of emotional stress, a sympathetic dominant state of nervous system operation diminishes blood flow and motility to the gut, leading to severe impairments in digestive function (Schwetz, Bradesi, & Mayer, 2004). Thus, when there are interferences in Enteric nervous system – central nervous system ENS–CNS coordination in functional bowel disorders such as IBS, consequent disordered modulation of gastrointestinal motility, visceral pain thresholds, barrier defenses, mucosal immune responses, and nutrient processing occur (see Chapter 33).

ROLE OF GUT MICROBIOTA

It has been long thought that disordered regulation of serotonin production played a central role in the pathogenesis of IBS (Sikander, Ranam, & Prasad, 2009). However, emerging evidence suggests that the crosstalk between the enteric nervous system (ENS) and the central nervous system (CNS) is influenced by the interplay between by-products of the gut microbiota and the enteric nerve terminals (ENTs), through the enterochromaffin cells (ECs; see Rhee, Pothoulakis, & Mayer, 2009). Thus, the enteric microbiota can directly influence the relationship between the ENS and the CNS (Figure 3.10 .). Rhee and colleagues have recently reviewed 85 articles that, in totality, suggest that the enteric microbiota maintain gut homeostasis by regulating motility, immune responses, and processing of nutrients (2009).

An Overview of Digestive, Sensing, and Immune Functions of the Gut 39

UNIDIRECTIONAL SIGNALING (BRAIN  ENTERIC)

Altered brain states, such as psychological stress, can modulate the biomass and composition of the enteric microbiota (Bailey, Lubach, & Coe, 2004). Furthermore, the enteric bacterial environment may be directly linked to the increased motility caused by stress states (resulting in shedding of the organisms). The emotional motor system (EMS) of the brain causes changes in the flora in two ways (either alone or in combination) (Holstege, Bandler, & Saper, 1996): • Directly via host enteric microbiota signaling • Indirectly via changes in the floral environment As to which populations of the enteric flora are most influenced by the EMS, reports suggest that the bacteria in biofilms that adhere to the epithelium are actually less vulnerable than luminal populations to the changes in motility and luminal contents. As a consequence, bacteria in biofilms are more involved in bidirectional signaling than luminal populations (Macfarlane & Dillon, 2007).

CNS-Related Changes in the Gut Environment PARASYMPATHETIC TONE

In the state of parasympathetic tone, the vagus nerve of the CNS establishes the rhythmic propagation of gastrointestinal (GI) motility to ensure its “housekeeper” function. Thus, GI motility affects the delivery of nutrients to enteric flora, alters the pH of the luminal environment in both healthy and diseased states, and protects the proximal gut against the buildup of the colonic type of enteric flora (i.e., SIBO; see Van Felius et al., 2007).

SYMPATHETIC NERVOUS SYSTEM, ENTERIC FLORA AND MUCOSAL IMMUNITY

The aforementioned biofilm is the part of the enteric flora that is adherent to the gut epithelium. Or, These bacteria influence mucosal immunity and enteric nerves differently than luminal microbes. The intestinal mucus layer is

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the habitat for the biofilm. In a sympathetic dominant state, unregulated stimulation of the autonomic nervous system (ANS), or insufficient regulation by the parasympathetic nervous system, impairs proper mucus secretion, thus affecting the biofilm (Cooke, 2000). As shown in Figure 3.11 XXX., the sympathetic nervous system can moderate the mucosal immune system’s response to luminal bacteria via degranulation of mast cells, whose by-products (i.e., corticotropin-releasing factor; CRF) increase intestinal permeability, thus allowing even more nonselective antigen presentation to gut macrophages driving the process in a feed-forward manner. Under stress conditions, intestinal barrier function is weakened by a number of different mechanisms other than local release of CRF, and is reviewed elsewhere (Demaude et al., 2006).

BIDIRECTIONAL SIGNALING (BRAIN ENTERIC)

Enteric microbes can affect intestinal motility, which can either assist (especially Bifidobacterium bifidum & Lactobacillus acidophilus, to promote motility) or harm (Escherichia inhibits motility) the host (Mazmanian, Round, & Kasper, 2008). Since the by-products of bacteria within the intestines can influence gut motility by stimulating the enteric nervous system, dysbiosis can, therefore, alter gut motility in the host—which, in turn, affects the balance of enteric microbes. Another key concept that is central to this discussion is that there is an ongoing dialogue between the enteric flora and the intestinal epithelium, as well as crosstalk between different luminal bacterial species themselves (a.k.a., interkingdom signaling; see Figure 3.12 (Hughes & Sperandio, 2008). For example, enteric bacteria can cause the release of norepinephrine into the intestinal lumen, along with an increased expression of adrenergic receptors on the gut epithelium, to influence fluid and electrolyte secretion and local immune function (Valet et al., 1993). As mentioned previously, quorum sensing (Lowery, Dickerson, & Janda, 2008) is a type of decision-making process used by decentralized groups to coordinate behavior. Many species of bacteria use quorum sensing to coordinate their gene expression according to the local density of their population. It is used by bacteria to regulate gene expression by responding to signals from both other bacteria and the host. The signals received by the bacteria (from the host and other bacteria) regulate physiological processes within the bacteria, including pathogenicity, metabolite production, and bacterial motility. Therefore, through interkingdom signaling and quorum sensing, the host’s nervous system can influence microbial behavior (Hughes & Sperandio, 2008).

An Overview of Digestive, Sensing, and Immune Functions of the Gut 41

While this has been demonstrated in pathogenic bacteria, it is likely that it is also the case in commensal flora. Microbial signals can interact with afferent nerve terminals when there is compromised intestinal integrity (as in leaky gut, stress, or inflammation). As intestinal permeability increases, bacterial by-products and inflammatory mediators are able to directly access nerve endings in the mucosa.

Neuroendocrine Immune Signaling The signals released from bacteria interact with receptors on both other bacteria and on host cells, which influence the nervous system via endocrine, immune, and neural signaling mechanisms. The effects on gastrointestinal function of signals released by enteric microbes are widely studied, but the systemic consequences are less well known (Walsh & Mayer, 1993). Enterochromaffin cells (EC cells) produce mediators (i.e., serotonin) that serve as signal transducers to translate bidirectional signals from the enteric microbes to the nerve terminals. EC cells have access to the microbes on the luminal side, and both afferent and efferent nerve terminals on the lamina propria, making them ideal for bidirectional signaling. Enterochromaffin cells secrete signaling-gut-derived peptides such as serotonin, CRF, cholecystokinin and somatostatin, in response to factors elaborated by gut microbes (Figure 3.12; see Wheatcroft et al., 2005). EC cells can affect gut motility via elaboration of the main neurotransmitter of the gut, serotonin, whose production is impaired in IBS (Sikander, Ranam, & Prasad, 2009). Furthermore, the state of the luminal environment is transmitted to the CNS by the vagus nerve, the nerve terminals of which are near EC cells. Thus, signaling from EC cells to the afferent terminals of the vagus nerve could directly connect chemical signaling within the lumen to supraspinal networks.

In unhealthy people where there is increased intestinal permeability, microbe signaling is able to directly access the nerve terminals, which may be a port of entry for the microbes to interact with the CNS (brain). However, in healthy individuals with an intact intestinal barrier, the mechanism by which this microbe–brain communication occurs is principally governed by EC cells.

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Conclusions Proper balance of form and function are required for the human system to be in homeostasis. Nowhere in the body is this more true than in the principal interface we have with our environment—taking in food, digesting and absorbing, defending ourselves from invaders, stimulating the development of our immune system, communicating the “status quo” throughout the body, and living in “right relationship” with the gastrointestinal microflora. Each of these functional components will produce pathophysiologic changes when they are not in balance. The diagnostic and therapeutic approach of integrative (or functional) gastroenterology is to observe the patient through these lenses, rather than the final symptom complex referred to as ICD-9 diagnoses. The functional approach focuses on returning the system to balance, rather than elimination of symptoms, and offers tools that help with gastrointestinal disease but also help with many diseases throughout the body that have their origins within the gastrointestinal tract.

4 The Intestinal Microbiota in Health and Disease: Bystanders, Guardians or Villains? FERGUS SHANAHAN

key concepts

A resurgence of interest in the gut microbiota, enabled by advances in nonculture-based molecular techniques, has shown the importance of host–microbe interactions in gastrointestinal maturation and homeostasis. The microbiota is a health asset, but occasionally a contributor to the pathogenesis of gastrointestinal disease and to certain extra-intestinal disorders. Elements of a modern lifestyle, such as urbanization, domestic hygiene, antibiotic usage, and family size, represent proxy markers of environmental influence on the composition of colonizing microbiota in early life. Comparative studies of germ-free and colonized animals predict the existence of microbial-derived signals which can be mined for bioactives or novel drug discovery. Host–microbe interactions in the gut are bidirectional.

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Introduction

T

here is an ongoing resurgence of interest in the alimentary microbiota (flora). For basic scientists, this is being driven, in part, by improvements in technology, particularly molecular approaches for studying

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44 INTEGRATIVE GASTROENTEROLOGY

the microbiota. For clinicians, the discovery that Helicobacter pylori causes peptic ulcer disease is a continual reminder of the possibility that other chronic diseases may have a microbial basis. Indeed, the most important lesson of that discovery is that the solution to some diseases may never be found if research remains focused on the host, without due attention to the host–environment interface. Furthermore, the contribution of the microbiota to gastrointestinal maturation and maintenance of mucosal homeostasis has stimulated the exploration of host–microbe interactions.

Composition of the Microbiota The complexity and quantity of microbes in the alimentary tract is greatest at the orifices. The oral cavity harbors a relatively large and diverse bacterial population, whereas gastric acid restricts bacterial numbers to fewer than 103 colony-forming units (CFU)/ml of gastric contents. Along the small intestine, bacterial density increases distally with a sharp gradient across the ileocecal valve, with approximately 108 bacteria per gram of ileal contents and up to 1012 per gram of colonic contents, which comprises more than 1,000 different bacterial species (O’Hara & Shanahan, 2006; Turnbaugh et al., 2007). There is also a gradient in the composition of bacteria from mucosa to lumen. Almost all of the culturable bacteria in the ileum and the colon are obligate anaerobes, but the ratios of anaerobes to aerobes are lower at mucosal surfaces. In addition, culture-independent molecular techniques have shown that mucosaassociated bacteria differ from those recovered from feces (Zoetendal et al., 2002). In the proximal small bowel, the resident bacteria are predominantly grampositive facultative bacteria, although enterobacteria and Bacteroides also may be present. Peristalsis is the principal factor restricting bacterial numbers in the small bowel.

In the distal small bowel, the composition of the flora resembles that of the colon, with a preponderance of Gram-negative anaerobes. The most prominently represented genera in the distal bowel include Bacteroides, Clostridium, Lactobacillus, Fusobacterium, Bifidobacterium, Eubacterium, Peptococcus, and Escherichia.

The Intestinal Microbiota in Health and Disease 45

Environmental and Lifestyle Modifiers of the Microbiota Molecular profiling has shown that the microbiota is distinct in different people. Studies of twins suggest that the individuality of the human microbiota may be determined, in part, by host genetics (Zoetendal et al., 2001), but environmental variables including diet, sanitation and other lifestyle factors appear to have profound effects, particularly on early intestinal colonization (Sonnenburg, Angenent, & Gordon, 2004). Indeed, many of the elements of a modern lifestyle such as domestic hygiene, antibiotic usage, urbanization, and family size are proxy markers of microbial exposure during the early stages of life (Bernstein & Shanahan, 2008). Although the numbers and composition of the microbiota are relatively stable after infant weaning, the metabolic activity of the microbiota is continually subject to dietary and other lifestyle variables.

Techniques for Studying the Microbiota Most enteric bacteria cannot be cultured, because of a lack of selective growth media (Marchesi & Shanahan, 2007). Furthermore, because most of the indigenous bacteria are obligate anaerobes, there are logistical difficulties sampling the gut ecosystem. Therefore, molecular strategies have been devised to study bacterial nucleic acid extracted from feces or mucosal biopsy samples (Vaughan et al., 2000). The small ribosomal subunit RNA (16S rRNA in bacteria) contains highly conserved regions of base sequences that reflect an absence of evolutionary change, and that are interspersed with hypervariable regions that contain mutational changes reflecting the evolutionary divergence of different species. Sequencing of 16S rRNA permits identification and phylogenetic classification of intestinal bacteria. For rapid profiling, 16S rRNA can be amplified by polymerase chain reaction (PCR) and a profile of the mixture of hypervariable RNA fragments is achieved by variations in migration distance upon denaturing gradient gel electrophoresis. This reflects the diversity of 16S “species” in the sample. Other molecular techniques for identification of specific bacterial species are now possible because their genomic sequence has become available. Strategies include fluorescence in situ hybridization (FISH), flow cytometry

46 INTEGRATIVE GASTROENTEROLOGY

(FISH-FLOW), and bacterial DNA microarrays. In addition, metagenomic techniques, which involve sequencing genes from mixed microbial populations, will address many of the unresolved questions about the microbiota in health and disease.

Genetic information within the microbiota (microbiome) exceeds that of the host genome by approximately a hundredfold, but the combination of metagenomics with bioinformatics, biochemistry, and traditional bioassays, is yielding important insights into the metabolic capacity of the human gut microbiota. (Turnbaugh et al., 2007)

Life without Bacteria From comparative studies of germ-free and colonized animals, one can deduce that the intestinal microbiota must be a source of positive and negative regulatory signals for the development and function of the intestine. Life without bacteria is associated with reduced digestive enzyme activity and epithelial turnover, rudimentary lymphoid tissue, reduced mucosal cellularity and vascularity, and impaired motility, whereas enterochromaffin cell mass is increased (Midtvedt, 1999). The molecular signals that permit maturation of the gut upon colonization with the microbiota are currently being explored (Hooper et al., 2001). Remarkably, colonization with only a single bacterial strain, Bacteroides thetaiotaomicron, has illustrated the impact of bacteria-derived signaling on the expression of host genes controlling mucosal barrier function, nutrient absorption, angiogenesis, and development of the enteric nervous system.

A diversity of incoming bacterial signals includes: secreted chemoattractants, such as the formylated peptide, fMet-Leu-Phe (fLMP); cell wall constituents, such as lipopolysaccharide (LPS); and peptidoglycans, flagellin, and bacterial nucleic acids (e.g., CpG DNA). Detection of bacterial stimuli by the host, and discrimination of pathogens from commensals, are mediated, in part, by pattern recognition receptors, such as toll-like receptors (TLRs), that are present on epithelial and immune (dendritic) cells. Continual signaling by microbial ligands engaging TLRs is required not only for optimal mucosal and immune development, but also for mucosal homeostasis and responses to injury (Rakoff-Nahoum et al., 2004; Madara, 2004).

The Intestinal Microbiota in Health and Disease 47

Transduction of Bacterial Signals The enteric mucosa is well adapted to sampling the intraluminal microbial community, with its large surface area (approximately 400 m2) and only a single-cell layer separating the internal milieu from the lumen. The surface enterocytes serve an immunosensory role by producing chemokines in response to microbial danger signals, thereby alerting the host immune response to breaches in the mucosal barrier (Artis, 2008). Direct sampling of the lumen across the epithelium is mediated by mucosal dendritic cell processes that extend into the lumen between the surface enterocytes, and by M cells, which transport particulate antigens and intact microbes to underlying lymphoid follicles (Rescigno et al., 2001). After uptake, antigenic material, including intact microbes, is transported by dendritic cells to the mesenteric lymph node (Macpherson & Uhr, 2004). There, local immune responses are generated, and the mesenteric lymph node acts as a gatekeeper by preventing systemic entry by commensal bacteria. The discriminatory function of dendritic cells, depending on whether they are exposed to commensals or pathogens, is facilitated by their plasticity and versatility of responses, and by their tissue-specific specialization within the intestine. Transduction of bacterial signals into host immune responses after engagement of TLRs proceeds along several molecular pathways. The transcription factor, nuclear factor-κB (NF-κB), is the molecular switch for immune responses and is a pivotal regulator of epithelial responses to invasive pathogens. Nonpathogenic bacteria attenuate inflammatory responses by several mechanisms, including delaying the degradation of IκB, which is counterregulatory to NF-κB (Neish et al., 2000), and enhancing the nuclear export of the transcriptionally active subunit (RelA) of NF-κB in a peroxisome proliferator– activated receptor-γ (PPAR-γ)-dependent manner (Kelly et al., 2004).

Host–Microbe Communication is Reciprocal As with many other examples of interkingdom signaling (Hughes & Sperandio, 2008), host–microbe interactions in the gut are bidirectional. The apparent influence of host genetics on the composition of the commensal microbiota is supported by evidence for modulation by the immune system on the microbiota. Mucosal immune defects in different species have been associated with aberrant expansion of certain commensal organisms (Ryu et al., 2008;

48 INTEGRATIVE GASTROENTEROLOGY

Suzuki et al., 2004). In addition, the transcription factor T-bet, which regulates immune development and function, has been shown to have an unexpected influence on commensal populations within the murine intestine. Deletion of T-bet appeared to lead to the emergence of a “colitogenic” microbiota with the capacity to transfer colitis (Garrett et al., 2007).

The Microbiota is a Health Asset and Occasional Contributor to Disease The distinction between a commensal and a pathogen is often one of context. For example, the indigenous microbiota is generally a health asset, but becomes a liability in the setting of bacterial overgrowth syndromes, including C. difficile overgrowth after antibiotics. In other contexts, depending on the genetic susceptibility of the host, some but not all components of the microbiota may become contributors to the pathogenesis of disease, such as inflammatory bowel disease (Sartor, 2008). While a comprehensive review of the microbiota in different diseases is beyond the scope of this chapter, microbial alterations linked with inflammatory bowel disease have attracted particular interest. These include a reduction in fecal lactobacilli and bifidobacteria (Murch, 2001), increased adherent-invasive E. coli (AIEC; see Rhodes, 2007), increased detection of Mycobacterium avium subspec paratuberculosis (MAP; see Feller et al., 2007) and reduced bacterial diversity by metagenomic analysis (Peterson et al., 2008). The latter includes reductions in the anti-inflammatory commensal, Faecalibacterium prausnitzii (Sokol et al., 2008). Whether specific microbiota can be correlated with individual variations in the immune response is unclear, but there is evidence that this may be so (Ivanov et al., 2008).

The Gut Microbiota and Extraintestinal Disorders In addition to its role in gut health, the microbiota has become an important consideration in the context of a variety of other disorders beyond the gut. For example, the impact of the microbiota on immune maturation is not limited to gut-associated lymphoid tissue; peripheral lymphoid structures are also influenced (Mazmanian et al., 2005). As discussed later, the microbiota has been shown to be an environmental regulator of fat storage, and appears to influence the risk of developing obesity and metabolic syndrome (DiBaise et al., 2008). More recent work suggests that microbiota not only influences fat quantity but also fat quality, in terms of bioactive fatty acid composition in adipose and hepatic tissue (Wall et al., 2009).

The Intestinal Microbiota in Health and Disease 49

In addition, the composition of the gut microbiota has been shown to modify the pathogenesis of T-cell mediated destruction of pancreatic islets in murine diabetes. The interaction between the microbiota and the host innate immune system appears to be a critical epigenetic modifying factor, although the relationship between the microbiota and risk of developing diabetes is complex (Wen et al., 2008).

Metabolic Activity of the Microbiota The collective metabolic activity of the enteric microbiota is tantamount to that of a hidden organ (O’Hara & Shanahan, 2006). Coevolution with this inner biomass has several benefits for the host. In addition to the production of regulatory signals for mucosal homeostasis, the microbiota contributes metabolic properties not possessed by the host. These include biotransformation of bile acids, degradation of oxalate, breakdown of otherwise indigestible dietary components, such as plant polysaccharides, and production of shortchain fatty acids—a major energy source for colonic epithelium—from fermentable carbohydrates. Other activities include synthesis of biotin, folate, and vitamin K. Bacterial enzymes, such as azoreductase, have been exploited therapeutically to convert prodrugs, such as sulfasalazine, to active drug metabolites, such as aminosalicylate. Other examples of bacterial action on drug bioavailability include the metabolism of L-dopa to dopamine, and degradation of digoxin. In some instances, the metabolic changes induced by the enteric microbiota may not beneficial to the host. For example, bacteria may promote the production of carcinogens from dietary procarcinogens, although they probably also degrade some carcinogens (Rafter, 2003).

As alluded to earlier, the regulatory effect of the enteric microbiota on fat storage represents a compelling example of the impact of bacterial metabolism on the host (Backhed et al., 2004). Germ-free animals require a higher caloric intake to sustain a body weight similar to that of colonized animals. Thus, the microbiota of the colonized host confers a nutritional benefit. Furthermore, intestinal bacteria promote fat storage by enhancing the bioavailability of dietary monosaccharides for absorption, and also by suppressing epithelialderived, fasting-induced adipocyte factor (FIAF), which in turn releases lipoprotein lipase activity and promotes uptake of fatty acids into adipose tissue. Thus, the composition and activity of the intestinal microbiota should

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be considered as a variable influenced by Western diets that may influence susceptibility to obesity. Gas production is another familiar outcome of bacterial metabolic activity. Of the five gases—N2, O2, CO2, H2, CH4—that comprise 99% of flatus, the latter three are produced by the enteric bacteria, and bacteria are the sole source of hydrogen and methane in the intestine. Hydrogen production by bacterial action on carbohydrates and, to lesser extent, on protein, normally occurs in the colon. The small bowel also becomes a site of H2 production when bacterial overgrowth occurs. Bacterial methanogens occur in the colon and produce methane from H2 and CO2, with detectable excretion in approximately 30% of humans (Levitt & Engel, 1975; Levitt, 1980). While the principal gases produced are odorless, bacterial metabolism also generates various trace and odiferous gases in flatus, such as hydrogen disulfide (Moore, Jessup, & Osborne, 1987; Suarez, Springfield, & Levitt, 1998). Qualitative and quantitative variability in gas production with diet illustrates the fluctuations in bacterial metabolic activity, despite the compositional stability of the microbiota in adulthood.

Mining the Microbiota for Novel Drug Discoveries Several predictions can be made regarding the identity of microbial-derived chemical signals suitable for mining, based on what is already known of the influence of the microbiota on host physiology and pathophysiology (see Table 4.1). Translation of these signaling molecules into bioactives or novel drugs is an exciting prospect for the future (Shanahan & Kiely, 2007). Table 4.1. Examples of Opportunities to Mine the Microbiota for Novel Therapeutics Observation

Opportunity

Isolation of novel Microbe–microbe communication ensures antibiotics (bacteriocins) stability of bacterial numbers in the gut Commensals and probiotics have anti-inflammatory effects on the host

Bacterial components or metabolites for use as anti-inflammatory drugs (e.g., lipoteichoic acid, CpG DNA)

Translation

Reference

Rea et al. Application of lacticin to treatment (2007) of pathogens such as C. difficile Evidence base for this remains to be explored and exploited

Grangette et al. (2005) Obermeie et al. (2003)

The Intestinal Microbiota in Health and Disease 51

Table 4.1. (Continued) Observation

Opportunity

Translation

Reference

Gut microbiota is required for immune maturation

Isolation of bacterialderived molecules as immunomodulatory drugs

Mazmanian Use of cell wall et al. (2005, polysaccharides as immunomodulatory 2008) drugs in IBD

Metabolic signals from the microbiota influence fat storage and composition

Manipulation of the microbiota may alter bioavailability of dietary calories

Use of food-grade organisms to modify composition of the microbiota

Backhed et al. (2004) Wall et al. (2009)

Some but not all commensals or probiotics are beneficial in irritable bowel syndrome

Some components of the microbiota may be suitable for mining for analgesic activities

An intriguing observation that awaits confirmation and exploitation

Rousseaux et al. (2007)

Conclusions The contribution of the microbiota to mucosal homeostasis is such that it is has become essential to study intestinal pathophysiology in the context of the resident bacteria. Lifestyle and environmental influences on the microbiota, and on the developing immune system, may underpin the changing epidemiology of several chronic inflammatory disorders. The molecular basis of microbial-induced gastrointestinal and immune development is beginning to unfold, and may be “mined” for novel therapeutics in the future.

5 Alternative Laboratory Testing for Gastrointestinal Disease1 DAVID M. BRADY, J. ALEXANDER BRALLEY , RICHARD S. LORD , AND GERARD E. MULLIN

key concepts ■

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1

Gastric acid analysis is an important test to consider in patients with recurrent gastrointestinal infections and small intestinal bacterial overgrowth (SIBO). Fecal elastase is a reliable noninvasive stool test for pancreatic insufficiency. Intestinal hyperpermeability indicates ongoing injury to the intestinal epithelium, and is diagnosed using the lactulosemannitol test—a simple, noninvasive and inexpensive test. Lactulose breath hydrogen and methane testing can be used to detect abnormal fermentation in the upper digestive tract, indicative of small intestinal bacterial overgrowth. Microbial analysis of stools using PCR technology may provide valuable information about the colonic flora and guide treatment of digestive conditions. ■

Introduction

H

ealthcare practitioners who manage digestive disorders are oftentimes challenged by the limited testing that is available without referring to specialists who perform invasive procedures. The principal

1

Excerpted and adapted from Richard S. Lord and J. Alexander Bralley (Eds), Chapter 7, Gastrointestinal Function in Laboratory Evaluations for Integrative and Functional Medicine. Metametrix Institute (2008).

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Alternative Laboratory Testing for Gastrointestinal Disease 53

difficulty is that direct sampling of intestinal contents is impractical for nongastroenterologists. Analysis of specimens such as peripheral blood, urine, and feces may give results that indirectly reflect difficulties with digestion and absorption. Due to the critical role of the gastrointestinal tract in nutrient supply, even partial answers can be of great value. Invasive procedures for observation or luminal specimen retrieval can be highly informative when performed in conjunction with noninvasive testing. This chapter will deal mainly with noninvasive laboratory evaluations of gastrointestinal function, as summarized in Table 5.1. Table 5.1. Summary of Laboratory Evaluations for Gastrointestinal Function GI Aspect

Stomach

Function

Testing

Abnormal

Intervention

Heidelberg capsule Direct pH readings

 pH

– Mucosal building protocol – Betaine HCI – Free-form amino acids (see Chapter 4, “Amino Acids”) – B-vitamins – Trace elements (see Chapter 3, “Nutrient and Toxic Elements”)

Gastric acid, Indirect Pepsin indicators

Protease

Fecal chymotrypsin

 Activity

PABA index

 Index

Plasma fatty acids

 PUFA

Fecal fats

 Fat

Fecal fatty acids

 Fatty acids Ox bile, choleretic herbs (milk thistle) and essential fatty acids

Schilling test

 Urinary B12

B12 by injection or ≥ 1,000 μg/d sublingual

LactuloseMannitol challenge

 Urinary mannitol

Mucosal restoration

Pancreas Lipase

Liver/ Gallbladder

Small intestine

Bile acid secretion

Absorption

Multiple  trace elements or amino acids

Fasting plasma Multiple low amino acids values

Pancreatic replacement enzymes (proteolytic, lipolytic and amylytic) and essential fatty acids

Essential amino acid mixtures (Continued)

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Table 5.1. (Continued) GI Aspect

Colon

Immune barrier

Physical barrier

Function

Testing

Abnormal

Intervention

Food-specific IgG

Multiple elevations

Food elimination/Rotation diets

 Butyrate

Increase dietary fiber

Water Fecal butyrate resorption, or other SCFA Microbial containment Glycocalyx antigen binding Allergyantigen elimination

Serum, urinary  Foodor fecal IgA specific IgA  Total IgE Serum IgE

Regulate Serum IgG nutrient admission and restrict toxicant and Lactulosemicrobial Mannitol access challenge Normal: nutrient delivery

Microbial populations Pathogen: toxin production

 Isobutyrate Butyrate enemas

Urinary metabolic markers

HydrogenMethane breath test

Eliminate offending antigens Immune-support nutrients such as Glycerrhiza glabra (licorice) root or l-glutamine 3,000–6,000 mg daily

Many + foods Eliminate + foods by group (Rotation Diet) Add free-form amino acids and glutamine Zinc 50–100 mg/d, Bs 100–200 mg/d  Urinary Lactulose

Eliminate + foods

 Mannitol

Mucosal restoration

 Bacterial markers

Herbal or pharmaceutical antibioitics (e.g., berberine alkaloids, etc.)

 Protozoal markers

Prebiotics and probiotics with antiprotozoals

 Yeast markers

Restrict simple sugars with antifungals

 Expired gases

Herbal or pharmaceutical bacteriostatic agents

Stool microbial  Growth DNA quantititation or culture & sensitivity

Specific antibiotics

Alternative Laboratory Testing for Gastrointestinal Disease 55

The Stomach Standard medical treatments focusing on the gastrointestinal tract most often involve treating digestive symptoms by using proton pump inhibitors, which are among the most frequently prescribed medications with a myriad of potential adverse effects (see Chapter 37 by Hickey and Mullin). Stomach acid secretion is a principal line of defense against infection of the gastrointestinal (GI) tract (Giannella, Broitman, & Zamcheck, 1972). The critical function of low pH in the stomach is required to set up mineral absorption. High levels of ammonia, produced by bacterial action on amino acids, are even more directly associated with inadequate hydrochloric acid. The loss of bactericidal action and the failure to digest protein due to low stomach acid simultaneously leads to higher bacterial populations and greater availability of unassimilated amino acids for bacterial conversion. Simultaneous low levels of iron, zinc, copper, and manganese in serum, erythrocytes, or hair, is often due to gastric acid inadequacy, especially when intake of trace elements is normal.

The proteolytic enzyme activity and low pH in normal gastric secretions kill most of the bacteria and parasites that contaminate food. Chronic hypochlorhydria, whether induced by habitual use of antacids or due to gastric disorders, increases the risk of infection and intestinal microbial overgrowth (Neal et al., 1996).

HEIDELBERG CAPSULE TEST

The Heidelberg capsule test is considered to accurately assess stomach acid, though it is time-consuming for the patient, taking up to 90 minutes to complete (Wright, 1979). This type of test can give definitive answers about the adequacy of gastric acid secretion. The test uses a tiny plastic encapsulated pH probe that is swallowed by the patient. The capsule, small enough to safely pass the circuitous course of the GI tract, contains a miniature radio transmitter that continuously measures gastrointestinal pH and transmits the data to a waistband antenna connected to a bedside receiver. The pH readings are recorded for a permanent record. The capsule can either be tied to a thin string for retrieval, or swallowed untethered. The latter approach allows additional

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measurements of upper intestinal pH to be gathered. After swallowing the capsule, pH readings typically start around 7.0, and then drop toward 1.0 as the capsule settles toward the stomach bottom. The patient then drinks a challenge solution consisting of concentrated sodium bicarbonate (baking soda), which has strong buffering capacity. Within half a minute, the pH will normally rise to approximately 7. If acid secretion is normal, the pH will fall again, returning to between 1.0 and 2.0 within 20 minutes. The challenge solution is given again and repeated up to four times, as long as the pH response time is less than 20 minutes. Hypochlorhydria is indicated for a patient requiring more than 20 minutes to re-acidify. With achlorhydria, the patient’s stomach secretes little acid and the pH will not fall below 4.0, even on the first challenge (Wright, 1979). Experienced technologists must administer this test, because of factors such as the timing of bicarbonate solutions that are critical for accurate, reproducible results.

ENDOSCOPIC SAMPLING

An alternative method to sample stomach acid is to measure gastric pH aspirates during endoscopic procedures, or noninvasively by using a Smartpill analysis. The SmartPill GI Monitoring System is a new, in-office method for assessing gastric motility. The wireless SmartPill capsule collects pH, pressure, and temperature data from throughout the entire gastrointestinal tract (http:// www.smartpill.com).

The Pancreas and Gallbladder Pancreaticobiliary fluid composition can be highly variable. The pancreas contributes to digestion by secreting alkaline bicarbonate and a variety of digestive enzymes. Secretion of pancreatic fluid is controlled in part by vagus nerve stimulation. A more important regulatory mechanism of pancreatic secretion is the control exerted by the hormones secretin and cholecystokinin (CCK). Both are synthesized in the duodenum (upper small intestine) and secreted in response to the presence of acidified chyme in the small intestine. Additionally, CCK stimulates the contraction of the gallbladder, causing the release of bile into the duodenum. Secretin stimulates the flow of bicarbonate-rich pancreatic fluid that serves to raise the pH of normal chyme from below 4 to above 7, allowing trypsin and other pancreatic digestive enzymes to reach their maximal activities.

Alternative Laboratory Testing for Gastrointestinal Disease 57

FECAL CHYMOTRYPSIN TEST

The fecal chymotrypsin test is a useful noninvasive test to determine chronic pancreatic insufficiency (Henry & Steinberg, 1993). False positive results of up to 10% have been reported in normal individuals. Greater reliability for diagnosing chronic pancreatitis can be obtained by performing the fecal chymotrypsin test in combination with the bentiromide (N-benzoyl-L-tyrosyl-p-aminobenzoic acid) test (Kataoka et al., 1997). The bentiromide test measures the amount of p-aminobenzoic acid (PABA) appearing in urine following an oral bentiromide loading, indicating successful chymotrypsin cleavage at the tyrosyl peptide bond. PABA excretion rates are lower in patients with compromised pancreatic function than in healthy control subjects (Gagee et al., 1992).

FECAL PANCREATIC ELASTASE

A newer alternative or companion test to the fecal chymotrypsin assay is fecal pancreatic elastase. Human pancreatic elastase, a member of the acidic elastase family, was first detected by Sziegoleit as a new endoprotease and sterol-binding protein present in both human pancreatic secretions and feces (Chey, 1999; David-Henriau et al., 2005; Domínguez-Muñoz et al., 1995; Stein et al., 1996; Sziegoleit, 1984; Sziegoleit et al., 1989; Sziegoleit & Linder, 1991). Elastase, unlike chymotrypsin, has been found to remain unaffected during intestinal transit, and to be stable in stool samples for up to a week at room temperature (Chey, 1999; Sziegoleit et al., 1989; Sziegoleit & Linder, 1991). Elastase cannot be detected in bovine or porcine pancreatic enzyme preparations. Therefore, unlike chymotrypsin, it is not affected by oral pancreatic enzyme replacement therapy (Chey, 1999; see Figure 5.1).

FECAL FAT

Steatorrhea, defined as the presence of excess fat in the stool, is established by fat-balance studies (Kalivianakis et al., 2000). Normal fecal excretion of fat is less than 6 g/d. However, this test does not distinguish between fat maldigestion and fat malabsorption. Instead, tests for fecal triglycerides and long-chain free fatty acids can help differentiate between the two disorders.

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FECAL FIBERS

Microscopic inspection of stool can reveal the presence of meat and vegetable fibers. The increase in the amount of these fibers that occurs with impaired digestion is an indirect indicator of hypochlorhydria or insufficient output of pancreatic enzymes (Lankisch, 1982; Moore et al., 1971).

Small Intestine INTESTINAL HYPERPERMEABILITY

Patients with intestinal hyperpermeability have more than the normal 2% “leakiness” to large molecules. Degradation of the physical barrier often is due to exposure to toxic substances within the intestinal lumen that can damage the “tight junctions” between intestinal epithelial cells, leading to an increase in passive paracellular absorption (Fink, 1990; Galland, 1996).Common causes of intestinal hyperpermeability are ethanol consumption (Anonymous, 1985), nonsteroidal anti-inflammatory drugs (NSAIDs), and viral, bacterial, yeast, and protozoan infection (Batt et al., 1992; Riordan et al., 1997; Pignata et al., 1990; Serrander, Magnusson, & Sundqvist, 1984). Also, elevated levels of reactive oxygen species coming from a variety of sources, such as bile, food, cytotoxic drugs (Lifschitz & Mahoney, 1989), or inflammatory cells (Grisham et al., 1990; Sundstrom et al., 1998), can increase paracellular permeability. Intestinal hyperpermeability is found in all chronic inflammatory bowel diseases, where it may play an etiologic role, or it may be a secondary consequence due to the vicious cycle involving immune activation, hepatic dysfunction, and pancreatic insufficiency (Galland, 1995). The role of intestinal hyperpermeability in many diseases is often missed. The availability of noninvasive and affordable methods for measuring intestinal hyperpermeability makes it possible for clinicians to diagnose this condition in their patients, and to objectively assess the efficacy of treatment.

LACTULOSE-MANNITOL INTESTINAL PERMEABILITY CHALLENGE TEST

The lactulose-mannitol protocol was developed to measure intestinal hyperpermeability for a wide range of conditions (Andre, 1986), including food sensitivities (Ventura et al., 2006), pancreatitis (Nagpal et al., 2006), Crohn’s

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Table 5.2. The Four “R” Program for Intestinal Health “R”

Object

Amplification

Remove

Microbial overgrowth

Use bacteriostatic or mycostatic agents of sufficient strength to reduce excessive growth rates

Replace

Digestive factors

Support insufficient digestive secretory factors with oral replacements

Reinoculate

Favorable microbes

Employ oral dosing of viable organisms known to help control toxin-producing specie

Repair

Tissue and immune integrity

Support the growth of healthy intestinal mucosal cells, goblet cells and immune cell responses with key nutrients

disease (D’Inca et al., 2006), and cirrhosis (Table 5.2). Lactulose-mannitol is a challenge test in which patients with suspected hyperpermeability ingest the metabolically inert sugars lactulose and mannitol. Mannitol, a monosaccharide, is passively absorbed through the intestinal mucosa. In contrast, lactulose, a disaccharide, is normally not absorbed unless the mucosal barrier is compromised. Since these sugars are not metabolized, any absorbed sugar is fully excreted in the urine within 6 hours. The urine is collected, and concentrations of the two sugars are measured. Percent absorptions are calculated using the following formula: % compound absorption = compound concentration (mg/ml) × urine volume (mL) × 100 Lactulose-Mannitol Testing Protocol • Swallow a solution of 5 g mannitol and 5 g lactulose • Collect urine for 6 hours • Assay for total lactulose and mannitol Calculate recoveriess < 14% Mannitol = Carbohydrate malabsorption > 1% Lactulosee = Disaccharide hyperpermeability In the healthy intestine, the mean absorption of mannitol is 14% of the administered dose, whereas the mean absorption of lactulose is less than 1%. The normal ratio of lactulose-mannitol recovered in urine is < 0.03. An elevated ratio indicates intestinal hyperpermeability. It is best to have the patient perform the lactulose-mannitol test twice—first in the fasting state, then again

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after ingestion of a test meal (Andre et al., 1987). The lactulose-mannitol ratio was found to be an accurate predictor of relapse when measured in patients with Crohn’s disease who were clinically in remission (Wyatt et al., 1993). Recent intake of high carbohydrate meals and prolonged administration of the challenge solutions diminish responses to this test.

Mucosal Inflammation GLUTEN SENSITIVE ENTEROPATHIES

Inherited factors make some individuals sensitive to a protein called gliadin, present in some cereal grains. Gliadin is a part of the total protein, or gluten, in the grains. When undigested gluten reaches the small intestine, gliadin peptides activate autoimmune reactions in susceptible individuals. As many as one in 133 Americans with no previous symptoms or family history of celiac disease may be affected (Fasano et al., 2003). For more information on celiac disease, including testing, see Chapter 40.

POLYMORPHONUCLEAR NEUTROPHIL DISORDERS

Human lactoferrin (Lf), an iron-binding glycoprotein secreted by mucosal membranes, is a major granular component of polymorphonuclear neutrophils. When these cells respond to inflammatory signals, lactoferrin is released as part of the defense mechanism. Fecal Lf is a marker of intestinal inflammation in which leukocytes infiltrate the mucosa, increasing the release of neutrophil lactoferrin. Fecal Lf has been extensively used to differentiate inflammatory bowel disease from irritable bowel syndrome (IBS) and noninflammatory bacterial infections, and it is useful for monitoring IBD treatment efficacy (D’Inca et al., 2006; Logsdon &, Mecsas, 2006; Larsen et al., 2004; Buderus et al., 2004; Kane et al., 2003; Bard et al., 2003; Greenberg et al., 2002; Vaishnavi, Bhasin, & Singh, 2000; Saitoh et al., 2000). Various other neutrophil-derived proteins, such as calprotectin (Cal), polymorphonuclear neutrophil-elastase (PMN-e), α1-antitrypsin, and lysozyme (Lys) have been shown to be reliable indicators of intestinal inflammation, and can aid in the differentiation of organic intestinal disorders (i.e., inflammatory bowel diseases (IBD), ulcerative colitis (UC), Crohn’s disease, infectious gastroenteritis, etc.) from functional intestinal disorders (i.e., IBS; see Larsen et al., 2004; Buderus et al., 2004; Kane et al., 2003; Bard et al., 2003; Gaya et al., 2005; Gearry et al., 2005; Langhorst et al., 2005; Liu et al., 2005;

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Lundberg et al., 2005; Silberer et al., 2005; Tibble & Bjarnason, 2001; van der Sluys Veer A et al., 1999).Fecal levels of these proteins rapidly increase with the influx of leukocytes into the intestinal lumen during inflammation. Among the neutrophil-derived proteins in feces, PMN-e, Cal and Lf represent the most accurate markers of disease activity and severity in patients with ulcerative colitis, with lysozyme being somewhat less useful (Langhorst et al., 2005; Liu et al., 2005).

Secretory IgA Test Secretory IgA status may be evaluated by measurement of salivary or fecal secretory immunoglobulin A (sIgA) levels (Nagao et al., 1995). Salivary sIgA is a predictor of the release of sIgA at intestinal surfaces (Externest et al., 2000). A compromised immune barrier can lead to elevated serum IgA. Fecal sIgA correlates with salivary sIgA, and both may be predictors of partial mucosal sIgA deficiency as defined by serum IgA > 0.05 g/l (Nagao et al., 1994). Many studies on the effects of extreme physical and/or emotional stress in test populations, such as military personnel in basic training and competitive endurance athletes, have demonstrated that levels of sIgA become depressed following such levels of stress, whereas cortisol levels increase (Brenner et al., 2000; Filaire, Bonis, & Lac, 2004; Gomez-Merino et al., 2003; McDowell et al., 1992; Nieman et al., 2002). Stress plays an important role in the compromise of the gastrointestinal mucosal immune response and the development of panallergy to foods and, potentially, the development of autoimmune phenomena via antigen–antibody complex cross-reactivity and molecular mimicry. Combining salivary sIgA with evaluation of cortisol and 5-dehydroepiandrosterone (DHEA) may be beneficial in the overall assessment of the stress response and the management of gut hyperpermeability, food allergy, inflammatory arthritides, immunogenic thyroiditis, autoimmunity, and other chronic diseases (Ansaldi et al., 2003; Gladman, 1991; Marker-Hermann & Schwab, 2000; Martinez-Gonzalez et al., 1994; Mielants, 1990; Petru et al., 1987; Pishak, 1999; Stebbings et al., 2002; Takuno, Sakata, & Miura, 1990; Tiwana et al., 1998; Tomer & Davies, 1993).

Microbial Population Assessment The intestinal flora is a complex ecosystem consisting of over 400 bacterial species that greatly outnumber the total number of cells making up the entire human body (Finegold, Attebery, & Sutter, 1974). These metabolically active

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bacteria reside close to the absorptive mucosal surface, and are capable of a remarkable repertoire of transforming chemical reactions. Any orally taken compound, or a compound entering the intestine through the biliary tract or by secretion directly into the lumen, is a potential substrate for bacterial transformation. Anaerobic bacteria are the predominant microorganisms in the human GI tract, outnumbering aerobes by a factor of 10,000 to 1.

In health, the upper GI tract is sparsely populated with microorganisms. The vast majority of bacteria washed along with saliva from the oral cavity are destroyed in the stomach by gastric juice. The small intestine constitutes a zone of transition between the sparsely populated stomach and the luxuriant bacterial flora of the colon. In the distal ileum, the concentrations of bacteria increase to 106–107 colony-forming units per milliliter (Fuller & Perdigón, 2003). Here, Gram-negative bacteria outnumber the Gram-positive species. Beyond the ileocecal valve, the bacterial concentration increases steeply. Colonic bacteria number between 1011 and 1012 colony-forming units per milliliter of fecal material. Multiple dramatic shifts in populations of species occur between the ileocecal valve and the rectum. By the time they are passed from the body in stools, the large majority of the bacteria are no longer viable.

OPPORTUNISTIC OVERGROWTH AND DISEASE

Overgrowth of any one of the more than 400 microbial species in the healthy human gut can produce adverse clinical effects. Excessive colonization of the gut by undesirable microorganisms alters the metabolic or immunologic status of the host (Van Eldere et al., 1988; Rogers et al., 2006).When this state leads to disease or dysfunction, it has been termed dysbiosis to distinguish it from the correct balance denoted as orthobiosis (Galland & Barrie, 1993). The line between benign opportunistic overgrowth and infectious diseases is difficult to define because apparently benign, small numbers of colony-forming units may be detected for pathogens such as enterohemorrhagic Escherichia coli.

THE TRANSITIONAL GUT

The microbial mass increases from levels around 1 × 105 to counts as high as 1 × 1011 in the region roughly encompassing the mid-ileum to the transverse colon.

Alternative Laboratory Testing for Gastrointestinal Disease 63

This 6-orders-of-magnitude increase represents a fantastically high rate of new cell formation, with associated intense metabolic activity where metabolic products are formed. Thus, it is from this mid- or transitional gut that most of the microbial products found in breath or urine are chiefly derived.

Breath Hydrogen and Methane Test This test offers reasonable sensitivity, and it is very convenient to administer, although it will sometimes give false negative results. For greater predictive value, it is best to also obtain a baseline breath sample from the patient before consumption of the challenge solution. The fasting patient drinks a challenge dose of lactulose (10 g) or glucose (75 g) solution. Breath samples should be collected every 15 minutes for up to 3 hours. If bacteria exist in the small intestine, they will ferment the sugar and release hydrogen and methane, which can be detected in the breath. The typical fasting breath sample contains less than 10 ppm hydrogen or methane; levels higher than 20 ppm indicate a high probability of bacterial overgrowth. Following a lactulose or glucose challenge, a two-phase response may be seen. The first rise in breath hydrogen generally occurs within 30 to 60 minutes, when lactulose contacts the small intestine—the rise may be delayed beyond 60 minutes in those having gastroparesis and small intestinal transit. A second, more pronounced rise occurs about 2–3 hours later, when the sugar enters the large intestine. A rapid and prolonged first-phase response is frequently due to small intestine bacterial overgrowth (Rhodes, Middleton, & Jewell, 1979). Interpretation of results is complicated by the large number of false positive findings, as compared with results obtained from bacterial cultures of intestinal lumen aspirates (Corazza et al., 1990; Riordan et al., 1996).Combining the findings of elevated fasting breath hydrogen (> 20 ppm), and raising the limit for the post-lactulose challenge increase in breath hydrogen and methane to greater than 20 ppm, will reduce the chance of false positive responses (Hamilton, 1992).

URINARY MARKERS OF BACTERIAL OVERGROWTH

Urinary Indican Bacteria in the upper bowel produce the enzymes that catalyze the conversion of tryptophan to indole (Figure 5.2). Absorbed indole is converted in the liver to indoxyl, which is then sulfated to allow urinary excretion as indoxyl sulfate (indican).

64 INTEGRATIVE GASTROENTEROLOGY

Oral, unabsorbed antibiotics reduce indican excretion. Indican excretion is also reduced when the gut is populated with strains of Lactobacillus at levels above 105 organisms/g (Tohyama et al., 1981). Probiotics have been shown to decrease indican levels (Yoshida & Hirayama, 1984). The urine indican test may be performed after oral loading of 5 g tryptophan (Smith, 1982). Reference limits may also be set from data taken under nonloading conditions. Tryptophan loading, which can be monitored by measuring periodic levels of urinary indican, results in neuropsychiatric manifestations due to products of intestinal bacterial conversion of the amino acid (Yoshida & Hirayama, 1984). When elevations of phenol and p-cresol are included with that of indican as criteria of abnormal bacterial colonization of the small intestine, the number of false positives is reduced (Aarbakke & Schjonsby, 1976).

Urinary Phenolic Compounds Dietary polyphenolics are the principal substrates from which products of transitional gut bacterial metabolism are formed. In addition to the use of polyphenol compounds, intestinal bacteria that contain l-amino acid decarboxylase enzymes degrade tyrosine to tyramine. The tyramine is then deaminated and oxidized to p-hydroxyphenylacetate. This product is excreted unchanged and unconjugated in urine. It was used to identify small bowel disease and bacterial overgrowth syndromes in 360 randomly selected, acutely ill infants and children. In this study, no false negative and only 2% false positive results were found (Chalmers, Valman, & Liberman, 1979). Treatment with metronidazole or mepacrine has been shown to eliminate the p-hydroxyphenylacetic aciduria. Although p-hydroxyphenylacetate can be produced in the liver, abnormally high levels in urine are of bacterial origin.

Urinary D-Lactate Another product of bacterial fermentation of sugar is d-lactic acid. d-lactic acidosis is usually a complication of short-bowel syndrome, or of jejunoileal bypass surgery (colonic bacteria being the source of acidosis). Elevated d-lactic acid can be found in cases of overpopulation of the small intestine with L. acidophilus, as a result of low endogenous stomach acid production or the chronic use of acid-reducing medications accompanied by ingestion of large quantities of dietary carbohydrate (Uribarri, Oh, & Carroll, 1998).

Alternative Laboratory Testing for Gastrointestinal Disease 65

URINARY MARKERS OF YEAST OVERGROWTH

D-Arabinitol d-Arabinitol (DA) is a metabolite of most pathogenic Candida species, in vitro as well as in vivo. DA is a five-carbon sugar alcohol that can be assayed by enzymatic analysis. Immunocompromised patients with invasive candidiasis have elevated d-arabinitol/creatinine ratios in urine. Positive DA results have been obtained several days to weeks before positive blood cultures, and the normalization of DA levels has been correlated with therapeutic response in both humans and animals (Roboz, 1994; Christensson, Sigmundsdottir, & Larsson, 1999). Measuring serum DA allows prompt diagnosis of invasive candidiasis (Christensson, Sigmundsdottir, & Larsson, 1999; Tokunaga et al., 1992).

The Colon: Assessing Microbes in Stool The population of the microbiota of the human GI tract is widely diverse and complex, with a high population density. All major groups of microorganisms are represented. Although they are predominately bacteria, a variety of protozoa are also present. In the colon there are over 1011 bacterial cells per gram, and over 400 different species. These bacterial cells outnumber host cells by at least a factor of 10 (Rowland, 1995). This microbial population has important influences on host physiological, nutritional, and immunological processes. In fact, this biomass should more rightly be considered a rapidly adapting, renewable organ, with considerable metabolic activity and significant influence on human health. Consequently, there is renewed and growing interest in identifying the types and activities of these gut microbes (Mackie, Sghir, & Gaskins, 1999). The normal, healthy balance in microbiota provides colonization resistance to pathogens. Since anaerobes comprise over 95% of these organisms, their analysis is of prime importance. Gut microbes might also stimulate immune responses to prevent conditions such as intestinal dysbiosis. Intestinal dysbiosis may be defined as a state of disordered microbial ecology that causes disease (Tamboli et al., 2004). Specifically, the concept of dysbiosis rests on the assumption that patterns of intestinal flora— specifically, overgrowth of some microorganisms found commonly in intestinal flora—have an impact on human health. Symptoms and conditions thought to be caused or complicated

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by dysbiosis include inflammatory bowel diseases, inflammatory or autoimmune disorders, food allergy, atopic eczema, unexplained fatigue, arthritis, mental/emotional disorders in children and adults, malnutrition, and breast and colon cancer (Galland & Barrie, 1993; Hawrelak & Myers, 2004).

DIFFICULTIES IN ASSESSING INTESTINAL MICROBIOTA

Most studies of microbiota in the GI tract have used fecal samples. These do not necessarily represent the populations along the entire GI tract from stomach to rectum. Conditions and species can alter greatly along this tract, and generally run from lower to higher population densities. The stomach and proximal small intestine, with highly acid conditions and rapid flow, contain 103 to 105 bacteria per gram or milliliter of content. These are predominated by acid-tolerant lactobacilli and streptococci bacteria. The distal small intestine to the ileocecal valve usually reaches to 108 bacteria per gram or milliliter of content. The large intestine generates the highest growth, due to longer residence time, and ranges from 1010 to 1011 bacteria per gram or milliliter of content. This region generates a low redox potential, and high amount of short-chain fatty acids. Not only does the microbiota content change throughout the length of the GI tract, but there are also different microenvironments where these organisms can grow. At least four microhabitats exist: the intestinal lumen, the unstirred mucus layer that covers the epithelium, the deeper mucus layer in the crypts between villi, and the glycocalyx of the epithelial cells (Savage, 1977). Given this diverse ecological community, the question arises as to how to sample the various environments to identify populations of microbes, and ultimately understand the host–microbe interactions. This problem is an extremely difficult one, since any intervention to obtain a sample potentially disrupts the population. Fecal sampling has been used for years in microbiota assessment. But it should be understood that this sample most appropriately represents organisms growing in the lumen of the colon. In addition, > 98% of fecal bacteria will not grow in oxygen (Savage, 1977). Therefore, standard culture techniques miss the majority of organisms present.

CONVENTIONAL TECHNIQUES VERSUS NEW TECHNOLOGIES

Conventional Techniques Conventional bacteriological methods such as microscopy, culture, and identification are used for the analysis and/or quantification of the intestinal

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microbiota (O’Sullivan, 1999; Tannock, 1999; Finegold & Rolfe, 1983). Limitations of conventional methods are their low sensitivities (Dutta et al., 2001), their inability to detect noncultivatable bacteria and unknown species, their time-consuming aspects, and their low levels of reproducibility due to the multitude of species to be identified and quantified. In addition, the large differences in growth rates and growth requirements of the different species present in the human gut indicate that quantification by culture is bound to be inaccurate. To overcome the problems of culture, techniques based on 16S ribosomal DNA (rDNA) genes were developed (Amann, Ludwig, & Schleifer, 1995; Wilson & Blitchington, 1996).These include fluorescent in situ hybridization (Franks et al., 1998; Jansen et al., 2000; Langendijk et al., 1995; Muyzer & Smalla, 1998; Welling et al., 1997), denaturing gradient gel electrophoresis (Suau et al., 1999; Simpson et al., 1999), and temperature gradient gel electrophoresis (Zoetendal, Akkermans, & De Vos, 1998). These techniques have high sensitivities, but they are laborious and technically demanding. Another problematic issue with present stool analysis procedures is that of transport. Since analysis is culture dependent, sample collection must be done using nutrient broth containers to maintain microbial viability. This allows continued growth of species during transport and until the sample is actually plated out for culture. This growth allows for a significant change in the balance of microbes present, since some species will more actively grow at the expense of others, especially in the presence of oxygen.

New Technologies DNA analysis eliminates this problem by placing the specimen in vials which contain a fixative for transport. This technique will be discussed in more detail in the next Chapter.

Microbial Metabolic Markers from Stool Testing FECAL β-GLUCURONIDASE

Bacterial β-glucuronidase is an enzyme that can effectively reverse detoxification that has taken place in the liver during the Phase II conjugation reactions. Bacterial flora may express large amounts of glycosidase enzyme activity, the principal glycosidase being β-glucuronidase. A report showing high levels of β-glucuronidase calls attention to the need to restore beneficial bacterial populations, and to the potential for greater enterohepatic circulation that can affect metabolites such as estrogen.

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Glycosides are compounds containing a nonsugar molecule (aglycone) attached to a sugar derivative, such as glucuronic acid, by α- or β-glycoside linkage. Glycosides enter the GI tract through dietary intake, or from the liver through bile secretions. Most dietary glycosides, predominately flavonoids, come from vegetables and fruits. Glycosides coming from the liver include toxic compounds that are inactivated by β-glucuronide formation and subsequently secreted into the bowel by way of the bile. The intestinal flora can hydrolyze the β-glucuronide bond, leading to release of the toxic compound, which may be carcinogenic.

FECAL pH

The colonic microbial mass converts food components into organic acids and amines according to the nature of the substrate passing into the colon, and the type of organisms that predominate. A high rate of organic acid production gives acidic stools, whereas low acid formation with increased amines results in higher pH of stool. One of the most important colonic health practices is regular intake of high-fiber foods, so that beneficial organisms in the colon receive substrate for the production of favorable products such as butyric acid. Direct measurement of fecal pH provides an overall indicator of acid and base balance. Abnormally acidic or alkaline pH of the stool may be an indicator of poor digestive health. There is increasing evidence that fecal pH can serve as a marker for colon cancer (Malhotra, 1982; Kashtan et al., 1990; Walker, Walker, & Walker, 1986; Newmark & Lupton, 1990).High fecal pH, however, is only indirectly associated with the development of colon cancer and, therefore, is a secondary, rather than a primary, measure of cancer risk (Kashtan et al., 1990). High stool pH appears to correlate with low levels of short-chain fatty acids (especially butyric acid; see (Zoran et al., 1997; Segal et al., 1995; Phillips et al., 1995; Folino, McIntyre, & Young, 1995). Alkalinity and low butyric acid levels in the stool appear to signal inadequate intake or digestion of fiber and, possibly, low levels of beneficial colonic flora. Various patterns of simultaneous elevation of multiple bacterial and protozoal by-products in urine are found in putrefactive dysbiosis that is also characterized by lowered ratio of Bifidobacteria to Bacteroides, the major genera of the anaerobic organisms. Fecal pH may be elevated, and β-glucuronidase increases. This scenario has been linked to increased occurrence of colon and breast cancer (possibly due to deconjugation of estrogen-glucuronide complexes) and hepatic encephalopathy (Rowland, 1995).

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FECAL SHORT-CHAIN FATTY ACIDS (SCFAs)

Frequently, disorders of the GI tract are associated with intestinal malabsorption. Many tests are useful in the diagnosis of GI disorders but do not effectively differentiate abnormalities of absorption (mucosal function) from digestion (pancreatic function). The fecal short-chain fatty acid test can be helpful in making a differential diagnosis. Short-chain fatty acids (SCFAs) are formed from bacterial fermentation of dietary carbohydrates and amino acids that escape absorption in the small bowel. An alteration in the proportion of various SCFAs, which stay constant in healthy colons, signifies an impaired state of colonic health (Hoverstad, 1988). Short-chain fatty acids are well absorbed by the colon, and are a significant source of energy for colonic cells. High acetic acid and low butyric acid in relation to total SCFAs in the feces are found in patients with large bowel adenomas and cancer (Latella & Caprilli, 1991). The fecal content of n-butyrate— formed by the bacterial fermentation of fiber—is particularly critical for colonic health, since it is such an important source of energy for the epithelial cells of the colon (McCullough et al., 1998). Research suggests that inadequate amounts of colonic n-butyrate could be a primary factor in the etiology of inflammatory bowel disease, ulcerative colitis, and colon cancer (Royall, Wolever, & Jeejeebhoy, 1990). The SCFA products of bacterial fermentation (or putrefaction), isobutyric, valeric and isovaleric acids, come principally from undigested protein (Rasmussen, Holtug, & Mortensen, 1988; Zarling & Ruchim, 1987).These SCFAs are normally present at low concentrations in the healthy colon. However, maldigestion of protein due to pancreatic enzyme insufficiency can result in excess protein entering the colon. In these cases, fecal isobutyric acid, valeric acid, and isovaleric acid will be elevated. Their presence is more likely due to a pancreatic dysfunction, rather than an inadequacy of mucosal absorption.

FECAPENTAENES

Fecapentaenes are polyunsaturated ether lipids that are derived from human intestinal bacterial plasmalogens that have similar ether linkages (Van Tassell et al., 1989). Fecapentaenes cause DNA damage and mutations in human cells (Plummer et al., 1986; Gupta et al., 1984), and they are found in human feces,

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where they are thought to play a role in the initiation of colorectal cancer (Schiffman et al., 1989; Kingston, Van Tassell, & Wilkins, 1990).The structures of highly mutagenic fecapentaenes have been elucidated (Hirai et al., 1985), and methods for quantification of eight specific fecapentaenes in human feces have been published (de Kok, ten Hoor, & Kleinjans, 1991; Kivits et al., 1990; Kleinjans et al., 1989). Some researchers have proposed that the widely varying ratios of two principal fecapentaenes can be traced to individual differences in intestinal flora (Baptista et al., 1984). Bacteroides have been identified as the source of fecapentaenes in a human autopsy study (Schiffman et al., 1988). With the advent of more broad species identification using 16S DNA identification techniques, there is potential for identifying more closely the organisms in the general population with a capacity for fecapentaene production.

Conclusions Evaluation of gastrointestinal function includes detection of inadequate physical and immune barrier functions, and measures of the digestion and absorption of food. Pathogenic overgrowth of intestinal microbes in the upper gastrointestinal tract can be detected by measuring their unique products in urine. The patterns reflect the type of organisms that are present within broad categories of bacteria, protozoa, or yeast. The information allows discrimination between putrefactive dysbiosis in the colon versus fermentative dysbiosis in the small intestine, or combinations of both. The number of compounds involved, and the degree of elevations found, change in direct proportion to the severity of pathogenic overgrowth and loss of mucosal integrity. Stool profiling yields markers of digestive function and results in direct observation of microbial populations and can suggest specific antimicrobial therapies when necessary.

6 New Molecular Techniques Revolutionize Understanding of the Influence of Gut Microbiota on Health and Disease J. ALEXANDER BRALLEY

key concepts ■

■

■

■

■

The human GI tract contains a diverse and complex ecosystem of microbiota that can exert significant influence on health. New molecular techniques now allow exploration of this ecosystem. Molecular techniques solve many of the problems of traditional culture-based microbiology. Molecular techniques significantly improve sensitivity and specificity in parasitology and bacteriology of fecal samples. Molecular techniques allow for better understanding of microbiota balance, which enhances treatment options and improves outcomes. ■

Introduction

B

acteria in the human gastrointestinal tract increase in concentration from stomach to rectum. There are up to 1012 organisms per gram of fecal material, of which approximately 95% are anaerobic. The gut microbiota cell population outnumbers the host cells by a factor of 10. In fact, the gut microbiota may be looked upon as a metabolically and physiologically adaptable, rapidly renewable organ of the body, whose function is as critical to human health as any other vital organ. 71

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While bacteria predominate, protozoa are commonly found. It has been estimated that more than 400 different bacterial species are present (Macfarlane &. Macfarlane, 2004). This diverse population of bacteria can have a significant impact upon the host environment and health of the individual. Intestinal microbiota have been associated with the pathogenesis and pathophysiology of many diseases, including atopic dermatitis and allergies (Bjorksten et al., 2001; Penders, Stobberingh,van den Brandt, & Thijs, 2007; Penders et al., 2007), chronic inflammatory bowel diseases (Kleessen et al., 2002; Farrell &. LaMont, 2002; Linskens et al., 2001; Roediger & Macfarlane, 2002), ankylosing spondylitis (Blankenberg-Sprenkels et al., 1998; Tiwana et al., 1998; Stebbings et al., 2002), and rheumatoid arthritis (Wilson et al., 1998; Eerola et al., 1994; Peltonen et al., 1994). The positive clinical results of using probiotics (Isolauri, 2001) and prebiotics (Macfarlane, Steed, & Macfarlane, 2008) to control symptoms and improve health underline the critical role intestinal bacteria play in immune defense and general health. While the general makeup of the colonic bacteria population is similar in humans, there can be vast differences in the inter-individual balance on the genus and species levels. Ecological factors such as age, disease, diet, and antibiotic use can adversely affect this balance. Those factors that encourage ecological species diversity support structural stability and metabolic homeostasis in the population. Increased diversity has been associated with improved health, while decreased diversity has been linked to reduced ability to resist pathogens and inflammatory bowel diseases. (Bartosch et al., 2004; Ott, Musfeldt, Wenderoth et al., 2004) The introduction of molecular techniques to assess this microbial population has revealed much about its structure and function. This vastly improves our ability to design therapies that manipulate gut ecology to optimize health. Molecular techniques provide various clinical benefits: an accurate measure of microbiota diversity; insight into genes for drug resistance; more sensitive parasite detection; identification of species subtypes relating to potential pathogenicity; and information regarding microbial balance that influences energy metabolism, insulin resistance, and obesity. This chapter will briefly review the molecular techniques used to identify and measure gut microbial population, and the clinical benefits that result from this quantum leap over culture techniques.

Techniques The major advantage of molecular techniques is that they can quantitatively measure the entire range of microbiota present in the human gastrointestinal tract.

New Molecular Techniques Revolutionize Understanding of the Influence

73

Traditional culture methods cannot grow the vast majority of species present (Eckburg et al., 2005), as only 10% to 20% of bacteria in a habitat are able to be cultured (Wilson & Blitchington, 1996; Nadkarni et al., 2002; Suau et al., 1999). Those that are cultured are usually quantified using relative abundance scores such as +1 to +4 (Dutta et al., 2001; Tannock, 1999). In addition, the large differences in growth rates, growth requirements, and the interdependence of the different species present in the human gut make quantification by culture an inaccurate reflection of the population. To overcome the problems of culture, genomic techniques for bacterial identification have been developed (Wilson & Blitchington, 1996; Welling et al., 1997; Furrie, 2006). The circular bacterial genome possesses multiple copies of a gene that codes for the RNA contained in a ribosome. This ribosomal RNA gene or rDNA gene is made up of several regions referred to by their relative molecular weights. These 16s, 5s and 23s segments are separated by internal transcribed spacer (ITS) regions (Figure 6.1). The rDNA genes have regions that are highly conserved, and are exactly the same in all bacterial species. Other regions are variable, and unique codon sequences for any bacteria can be identified. Since these regions have now been fully sequenced for hundreds of bacteria, unique probes can be designed that select for and identify bacteria by genus or species, and even to the subtype level. By using unique primer sets binding to the variable regions of the 16s or 23s rDNA gene regions, single bacteria or groups of bacteria can be quantified. With the use of general primers and universal probes, polymerase chain reaction (PCR), and hybridization array technology, large populations of bacteria can be defined and quantified in a complex sample such as fecal material (Figure 6.2; see Lyons, Griffen, & Leys, 2000; Ott, Musfeldt, Ullmann, Hampe, & Schreiber, 2004).

Specimen Integrity and Transport Issues The extremely complex fecal microbiota ecosystem relies on anaerobic conditions, pH, adequate nutrients, and temperature, for stability. Consequently, it has been long recognized that a sample in transit can undergo significant changes in microbial balance (Ott, Musfeldt, Timmis et al., 2004). Since traditional analysis is culture dependent, sample collection requires nutrient broth containers to maintain microbial viability. This allows continued growth of species during transport, and until the sample is plated out for culture. This growth results in a significant change in the balance of microbes present, because some species grow more actively at the expense of others. DNA analysis eliminates this problem by placing the specimen in formalin or alcohol vials for transport.

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Recent studies in our laboratory illustrate this situation. One specimen was placed in two vials: one containing formalin, and another containing a nutrient broth commonly used for transport. Both vials were incubated for three days at room temperature, then DNA was extracted. The extract was incubated with three different restriction enzymes, which cleave the DNA at specific base pair sequences (Figure 6.3). The digestate was amplified by PCR, then placed on an agarose gel plate and the DNA fragments were electrophoretically separated. Since restriction enzymes cleave the DNA only at specific base pair sequences, broths with identical populations of microbes would produce the same patterns of banding in the electrophoretic runs. If, however, there were different amounts and types of microbiota in the two tubes, differences would appear in the banding patterns. This was clearly demonstrated in the experiment (Figure 6.4). Another observation from the data is the loss of banding in the nutrient broth vial over time, indicating overgrowth of aerobes at the expense of the anaerobic populations, and consequent loss of diversity. Opportunistic, potentially pathogenic organisms also can overgrow under these conditions. This has been seen in our laboratory. For these reasons, nutrient broth transport vials cannot provide the specimen integrity required for accurate measurement of gut microbes. Clinical laboratory data relying on transport of the specimen to the laboratory for culture are likely erroneous and can lead to inappropriate patient treatment.

Figures 6.5 through 6.7 illustrate the growth response of Bifidobacteria, Candida species and Staphylococcus aureaus in one subject over three days. These results indicate that clinical laboratory data relying on transport of the specimen to the laboratory for culture are likely erroneous, and can lead to inappropriate patient treatment. Candida species overgrowth is particularly notable. As these data indicate, Candida proliferates in nutrient broth transport media. This overgrowth in transport has likely fueled the common belief held by many practitioners, of the deleterious health effects of Candida albicans overgrowth in the gut. This may have resulted in inappropriate prescription of antifungal agents.

Drug Resistance Genes All antibiotic resistance strategies that bacteria develop are encoded in one or more genes. Drug resistance genes are readily shared among and across

New Molecular Techniques Revolutionize Understanding of the Influence 75

species and genera, and even among distantly related bacteria. These genes confer resistance to different classes of drugs, and their sequences are known. Using PCR techniques, they can be readily detected in large populations like those found in fecal material. When considering treatment of a patient for a pathogen, it is important for the clinician to know if a drug resistance gene is present. If a pathogen is detected in stool, an analysis of the presence of antibiotic resistance genes and drug sensitivities can be performed. If the pathogen is found to be sensitive to two antibiotics, for example, but a gene that is resistant to one of the drugs is present in the sample (a very possible scenario), it is imperative that this drug not be used to treat the patient. Otherwise, even though the pathogen is killed, the other organisms that have the gene conferring resistance to the drug would thrive relative to other microbes present. This sets up a potentially dangerous situation where antibiotic resistance is maintained in the population, because that gene can be readily spread to other organisms in the individual and the environment (Bergeron & Ouellette, 1998; Martineau, Picard, Grenier et al., 2000; Martineau, Picard, Lansac et al., 2000). Knowledge of the presence of antibiotic resistance genes in fecal specimens represents a significant advance in patient treatment and maintenance of health.

Parasitology Parasitology is another field of microbiology to benefit greatly from molecular technologies. Parasite infections are a major cause of nonviral diarrhea, even in developed countries. Classically, parasites have been identified by microscopy and enzyme immunoassays (Verweij et al., 2004). In recent studies, molecular techniques have proven to be more sensitive and specific than classic laboratory methods (Verweij et al; Ghosh et al., 2000; Morgan et al., 1998). Because Giardia cysts are shed sporadically, and the number may vary from day to day, laboratories have adopted multiple stool collections to help increase identification rates for all parasite examinations (Ghosh et al.). Even with the advent of antigen detection systems, there has long been uncertainty in diagnosis when no ova or parasites are found. Due to the nearly 100% sensitivity and specificity of DNA analysis, combined with the need for very low amounts of genomic DNA (as low as 2.5 cells per gram (Ghosh et al.), the previously long specimen collection process, laborious and technically challenging microscopy, and resulting delays in reporting have been alleviated. With PCR technology, only one fecal sample is needed for near 100% sensitivity and specificity in parasitology examinations.

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Blastocystis hominis subtypes have been associated with relative pathogenicity in humans (Hussein et al., 2008). Differentiation among pathogenic subtype populations in humans cannot be done using culture based techniques, and is a unique contribution only possible through PCR technology.

Gut Microbiota Influences on Insulin Resistance and Obesity Two predominant bacterial groups in the human GI tract are Bacteroidetes and Firmicutes. These gut microbiota significantly affect energy harvest from the diet, and energy storage in the host. Firmicutes bacteria, which include Bacillus, Clostridia, and Lactobacillus species, are very efficient at metabolizing plant polysaccharides into monosaccharides and short-chain fatty acids. These can then be absorbed by the gut and converted to more complex lipids in the liver. In addition, this group secretes a compound that results in increased activity of lipoprotein lipase in adipocytes, resulting in enhanced storage of these lipids. The Bacteroidetes group, which includes Bacteroides and Provetella species, are not as efficient in this function. While excess caloric intake is a significant factor in obesity, gut populations of microbiota that force an efficient extraction and storage of energy may play a significant role in this growing health problem. The ability to assess the balance of “fat bugs” in humans may prove to be an important advance in understanding and treating diabetes and obesity.

Recent studies have demonstrated another aspect of this intriguing story. Manipulation of the gut microbiota in mice significantly alters their glucose/ insulin response (Membrez et al., 2008). The balance of bacterial populations can actually increase levels of a bacterial lipopolysaccharide endotoxin that dysregulates the inflammatory tone, and triggers body weight gain and diabetes in mice (Cani et al., 2007). These studies demonstrate the possibility in humans that modulation of gut microbiota can ameliorate glucose tolerance by altering the expression of hepatic and intestinal genes involved in inflammation and metabolism, and change the hormonal, inflammatory, and metabolic status of the host. The ability to recognize this aspect of microbiota effects in human health has only become available through the use of molecular techniques.

New Molecular Techniques Revolutionize Understanding of the Influence

77

Ongoing studies are exploring the relationship between gut microbiota and metabolic diseases. The use of specific diets and prebiotic and probiotic therapies may significantly alter microbial balances that affect fat storage. The ability to assess the balance of these “fat bugs” in humans may prove to be an important advance in understanding and treating diabetes and obesity.

Ecosystem Diversity and Dysbiosis Biodiversity in the gut microbiota ecosystem can now be elucidated by molecular techniques. Since traditional clinical microbiological aerobic culture procedures were only able to evaluate less than 5% of organisms present, clinicians were unable to truly assess diversity, or a “dysbiosis” condition commonly associated with ill health (Hawrelak & Myers, 2004). The term dysbiosis was coined to describe an imbalance in the gut microbiota caused by parasitic infection, antibiotic use, or other factors. This dysbiotic condition can contribute to the development of many chronic degenerative diseases. By using molecular techniques, one can examine the major fecal anaerobic genera in comparison to aerobic and fungal organisms, providing a much clearer picture of the diversity and potential dysbiotic structure of the ecosystem. By quantifying all of the major groups of microbiota and potential parasites present in the gut, the concept of dysbiosis can now be much better defined in terms of ecosystem diversity. This concept will be useful for clinicians as they assess how the gut microbiota influence disease processes, and how they might intervene. For example, lack of diversity has been associated with inflammatory bowel diseases (Ott, Musfeldt, Wenderoth et al., 2004). Probiotics and prebiotics influence diversity and, therefore, may significantly impact these diseases (Steed, Macfarlane, & Macfarlane, 2008). Recent research is showing that specific groups of bacteria can be preferentially stimulated to grow relative to other populations. Individually tailored prebiotic compounds may potentially be designed to selectively enhance bowel function through improved microbiota diversity (Macfarlane &. Macfarlane, 2004; Macfarlane, Steed, & Macfarlane, 2008; Macfarlane, & Cummings, 1999; Macfarlane, Furrie, & Macfarlane, 2004; Macfarlane et al., 2005). Evaluating the microbiota diversity balance using molecular techniques, and designing customized prebiotic and probiotic regimens, will be a powerful new tool for the clinician in battling inflammatory bowel diseases and other gut-related disorders.

78 INTEGRATIVE GASTROENTEROLOGY

Table 6.1. Advantages of PCR vs. Culture • Single specimen collection vs. several • Copies a single DNA sequence of a cell over a billion times within 1 to 2 hours, allowing sensitive quantitation • Detects parasites with as few as 5 cells per/g vs. 25,000 cells per/g for microscopic techniques • 5,000 times more sensitive • Ability to ID anaerobes (majority of bacteria—95%) • No growth in transport vs. significant growth in transport • Requires only 5 to 10 bacterial cells for ID vs. 1,000 to 5,000 for culture

Conclusions Molecular techniques using DNA to identify bacterial genus and species are revolutionizing the understanding of how gut microbiota influence human health. Clinical laboratory tests that use these techniques can provide the clinician with practical new interventions targeted to the individual gut ecosystem.

7 Principles of Integrative Gastroenterology: Systemic Signs of Underlying Digestive Dysfunction and Disease LAURA K. TURNBULL, GERARD E. MULLIN , AND LEONARD B. WEINSTOCK

key concepts ■

■

■

■

■

■

Many idiopathic syndromes overlap, and are caused by underlying gut dysfunction. Acute and chronic GI infections trigger chronic systemic diseases by several mechanisms, including small intestinal bacterial overgrowth (SIBO), inflammation, and autoimmune phenomena. SIBO underlies many poorly understood syndromes, including irritable bowel syndrome (IBS), restless legs syndrome (RLS), fibromyalgia syndrome (FMS), rosacea, and interstitial cystitis (IC). Increased intestinal permeability and inflammation are complications of SIBO. Increased intestinal permeability may explain food allergies, and the increased involvement of diseases with eosinophils and mast cells (e.g., asthma). SIBO treatment is effective treatment for IBS and SIBO-related syndromes. ■

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Introduction

G

astrointestinal (GI) dysfunction is defined as abnormal metabolic function, motility, structure, infection, or inflammation, and there are many systemic symptoms and signs (extraintestinal manifestations) that may be an expression of such dysfunction. Classic examples of extraintestinal manifestations include the fever and joint pain that occur during a flare of Crohn’s disease, as well as various skin, eye, and hepatobiliary diseases associated with inflammatory bowel disease (IBD). While these examples are correlated with overt GI illness, the underlying cause of many extraintestinal manifestations can also be attributed to underlying systemic inflammation resulting from asymptomatic gut dysfunction—primarily, intestinal permeability. Two predominant causes of this breach in the integrity of the intestines are small intestinal bacterial overgrowth, and postinfectious enteric illness. Throughout this chapter, we will primarily explore the consequences of SIBO and its relationship to systemic conditions. The prevalence of these disorders, and a review of integrative modalities to their treatment, will be discussed.

Common Extraintestinal Manifestations of GI Dysfunction

Increased Intestinal Permeability There are many barriers and defensive mechanisms by which the intestinal tract mucosa can be exposed to antigens, bacteria, and chemicals, yet still be selective about what is absorbed and secreted. This protection requires an intact immunological and microanatomical defense system—a process in which healthy commensal bacteria play a role. Therefore, bacterial overgrowth and enteric infections are two major insults to the gut that result in increased permeability, as is shown in Figure 7.1.

Genetics, Inflammation and Intestinal Permeability Altered genetic background or phenotype may result in GI dysfunction in several ways. First, specific HLA genome subtypes are found in celiac disease, and

Principles of Integrative Gastroenterology 81

result in predisposition for the disease. Furthermore, a variety of genetic markers have been found in Crohn’s disease patients, as discussed in Chapters 30 and 44 Lastly, in both celiac disease and Crohn’s disease, a genetically determined increased intestinal permeability may be a harbinger of clinical disease. Based on the phenotypic genetic makeup, the impact of various stimuli, including inflammation and dysbiosis, can lead to a variety of diseases or syndromes. Inflammation and infection of the intestinal lining can lead to increased intestinal permeability, by damaging the tight junctions of mucosal cells. The net effects are the stimulation of the inflammatory network, and activation of lymphocytes and mast cells locally and systemically. This stimulation results in the release of various cytokines, which can lead to an increase of corticotropin-releasing hormone, which can in turn affect the central nervous system (CNS), the hypothalamic-pituitary-adrenal (HPA) axis, and the peripheral nervous system. Additionally, translocation of bacteria or the lipopolysaccharides (outer covering of Gram-negative bacteria) into a damaged mucosal lining can alter the HPA axis. The complex dynamics of the emotional motor system (EMS), and the interplay of stress, cytokines, cortisol, neurological, and neuroendocrine responses, are shown in Figure 7.2.

Infections Triggering Digestive Disease and Systemic Illness GI and respiratory viral infections (enterovirus and adenovirus) can trigger a number of gastrointestinal disorders (e.g. celiac disease, Crohn’s disease, IBS) and systemic diseases. There are several good studies that have determined the risk of developing postinfectious irritable bowel syndrome (Pi-IBS). This risk ranges between 7%–34% after a bacterial infection (see Table 7.1). Likewise, an existing GI condition can be worsened by a subsequent viral infection. For example, altered immune mechanisms triggered by an abnormal gene in Crohn’s disease can be a setup for an infection such as intramucosal E. coli, which may exacerbate the disease process (Darfeuille-Michaud, 2002). Histological studies have shown differences in adherence and invasion of bacteria into intestinal mucosa of patients with Crohn’s disease, and this may also be based on altered immunity (Swindsinski et al., 2002). The phenomenon of postenteric infections causing systemic diseases and syndromes is a critical concept because, of the approximately 76 million episodes of food poisoning per year in the United States, many of the diseases and syndromes that are linked to food poisoning are poorly documented

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Table 7.1. Incidence of Postinfectious IBS Follow-Up

Number with acute

% of patients with acute

period(s)

diarrhea

diarrhea who developed IBS

Marshall 2005

2-3 yr

1137

34

Mearin 2005

1 yr

271

10

Okhuysen 2004

6 mo

60

10

Neal 1997 & 2003

6 mo 6yr

357 192

7 7

Thornley 2000

6 mo

93

9

Gwee 1999

3 mo

100

22

McKendrick 1994

1 yr

38

31

Author

(Sobel et al., 2002). The well-publicized tainted food products in the past few years have included beef, cheese, lettuce, peanut butter, spinach, sprouts, tomatoes, and a variety of canned food (Currie et al., 2007; Dechet et al., 2006). Hundreds of thousands of pounds of beef have been recalled because of concerns about E. coli and salmonella. Data from the Centers for Disease Control (CDC) show that foodborne illnesses cause 325,000 hospitalizations and 5,000 deaths per year. However, the subsequent manifestations are not as well publicized. The effects of acute food poisoning can be severe and long-lasting. Of those infected with E. coli O517:H7, 10% develop hemolytic uremic syndrome, which can cause kidney failure and pancreatitis (Garg et al., 2003). After recovery, 25% of these patients will develop chronic renal disease and diabetes (Oakes, Kirkhamm, Nelson, & Siegler, 2008). The incidence of diabetes was determined from a review of 1,139 children from 13 studies (1966–1998, aged 0.2–16 years), and ranged from 0%–15%, with a pooled incidence of 3.2% (Suri et al., 2005). Other systemic illnesses that can result from acute food poisoning include reactive arthritis, which can start 6 months or longer after a bout of Salmonella, Shigella and Yersinia. Eye inflammation and urethritis are part of the classic triad of Reiter’s syndrome. One of the most severe postenteric complications, usually acquired from infected poultry, is camphylobacter-associated GuillainBarré syndrome (Zilbauer, Dorrell, Wren, & Bajaj-Elliott, 2008). Antibodies against camphylobacter create an autoimmune syndrome with ascending paralysis. Subsequent gastrointestinal dysmotilities have been reported, as well (Nakazawa, 2008).

Principles of Integrative Gastroenterology 83

SMALL INTESTINAL BACTERIAL OVERGROWTH (SIBO)

The colon is accustomed to having trillions of coliform bacteria, but complications arise when the coliform count grows in the small intestine. There are several natural protective mechanisms that keep the small bowel bacteria at low colony counts, including the presence of stomach acid, gastrointestinal motility, digestive enzymes, mucosal immunity, and the integrity of the ileocecal valve.

To minimize bacterial counts in the small intestine (SI), one has to: • maintain physiologic gastric acid production to reduce swallowed bacteria; • control the ingestion and have proper digestion of starches (i.e., legumes) to limit the nutrition necessary for bacterial growth; • retain normal small bowel motility (as driven by the migrating motor complex in the fasting state) to sweep the bacteria toward the colon; and • preserve an intact ileocecal valve to act as a physical barrier (between the SI and colon) to prevent the reflux of stool/bacterial contents from the large intestine. These natural defenses are shown in Figure 7.3. SIBO is defined as a disruption or increase of the normal small bowel bacterial population that can result in gas, bloating, flatulence, altered bowel function, and/or malabsorption of nutrients. Bloating, diarrhea, and nutrient deficiencies are induced by excess intraluminal small intestinal bacteria, which results from: (1) fermentation of nutrients producing gas, and (2) bile salt deconjugation by bacteria, leading to fat malabsorption and subsequent steatorrhea and secretory effects, causing diarrhea. Deconjugation of the hydrophilic components decreases absorption from the loss of the water-soluble state, which is involved in fat absorption. The change in bacteria and the effect of undigested starches are shown in Figure 7.4. With chronicity, weakness and weight loss from villous atrophy, and/or malabsorption secondary to the effects of bile salt deconjugation, will become evident. Advanced cases may have peripheral edema from hypoalbuminemia

84 INTEGRATIVE GASTROENTEROLOGY

and pallor from anemia (B12 deficiency, chronic disease, and in some cases iron deficiency, for which achlorhydria is the most common explanation). In advanced stages, cachexia and other changes of vitamin and nutrient deficiency may become evident. Chronic asymptomatic SIBO can result in systemic inflammation (Lin, 2004). Circulating levels of cytokines, such as TNF-α and proinflammatory interleukins, are elevated in SIBO (Dinan et al., 2006). Recent evidence indicates that low-grade SIBO may present with virtually no GI symptoms, but may affect the body in profound ways because of the systemic inflammation it causes. This may explain many syndromes and symptoms associated with chronic fatigue syndrome, rheumatoid arthritis, fibromyalgia, interstitial cystitis, restless legs syndrome, and rosacea (Table 7.3). SIBO may also explain other syndromes due to the presence of systemic low-grade inflammation and increased intestinal permeability.

CAUSES OF SIBO

SIBO occurs when the normal protective mechanisms that maintain bacterial balance are interrupted. The most common causes of SIBO are poor motility of the small intestine, allowing for overgrowth of coliform-type bacteria; pancreatitis, which allows for undigested nutrients to enhance bacterial growth; and gastroparesis.

GASTROINTESTINAL MOTILITY AND SIBO

Neuromuscular disorders of the esophageal body, lower esophageal sphincter, stomach, and small intestine, are important in the pathophysiology of many GI and systemic disorders. Functional disorders such as IBS, GERD, and nonulcer dyspepsia are in part caused by disordered gastrointestinal motility. When small intestinal motility is disturbed, and the ability to “sweep” pathogenic organisms away from the upper gastrointestinal tract is impaired, the risk of SIBO is increased. There is a growing prevalence of SIBO in IBS patients and, as the SIBO resolves the IBS, symptoms improve. Other gastrointestinal motility disorders that can contribute to SIBO are small intestinal pseudo obstruction, scleroderma, and postsurgical states. The latter is among the most well known causes of SIBO, and is due to the decreased motility and achlorhydria after certain gastrointestinal surgical procedures

Principles of Integrative Gastroenterology 85

including, but not limited to, gastric bypass surgery and Whipple’s type surgical procedures. Additionally, gastrointestinal motility disorders, or lack of adequate production of gastric acid with subsequent ingestion of live bacteria, has been commonly recognized as contributing to SIBO (Lewis et al., 2001; Parlesak et al., 2003; Lipski, Kelly, Malhotra, & Mountford, 1992). Other classic examples of SIBO include pancreatic insufficiency, and abnormal small intestinal mucosal disorders, including celiac disease and Crohn’s disease, as shown in Table 7.2. Finally, many systemic diseases and conditions can also cause SIBO—see Tables 7.2 and 7.3 and 7.4.

Table 7.2. Common Causes of SIBO Scleroderma

Achlorhydria

Small intestinal pseudo-obstruction

Diabetes

Pancreatic insufficiency

Radiation enteritis

Jejunal diverticulosis

Immunodeficiency: CLL, IgA deficiency, T-cell deficiency

Post-surgical anatomy: Billroth, Blind-loop, ICV resection, J–pouch

Celiac and Crohn’s diseases

Table 7.3. Lesser Known Causes of SIBO Chronic renal failure

Rheumatoid arthritis

Cirrhosis

Irritable bowel syndrome

Chemotherapy

Fibromyalgia

Acromegaly

Interstitial cystitis

Hypothyroidism

Restless legs syndrome

Chronic fatigue syndrome

Rosacea

SIBO has been reported in as many as 84% of patients meeting diagnostic criteria for IBS. Other studies confirm a relationship of SIBO to IBS, as shown in Table 7.4.

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Table 7.4. Prevalence of Small Intestinal Bacterial Overgrowth in IBS Patients as Determined by a Positive Breath Test for Bacterial Overgrowth Author

Substrate

#

Prevalence

Subjects

(%)

McCallum, 2005

Glucose

143

38.5

Lupascu, 2005

Glucose

65

30.7

Nucera, 2005

Lactulose

98

65

Walters, 2005

Lactulose

39

10

Noddin, 2005

Lactulose

20

10

Nucera, 2004

Lactulose

200

75

Pimentel, 2000–3

Lactulose

313

57, 76, 84

Weinstock, 2006

Lactulose

254

63

INTESTINAL GAS AND THE DIAGNOSIS OF SIBO

The obvious consequence of bacterial fermentation is the production of gas. The variety of gases that develop in the gut expand its diameter, causing abdominal bloating, distention, and discomfort from the triggering of stretch receptors (see Figure 7.5). This bloating is most often caused by excess hydrogen production from bacterial fermentation (King, Elia, & Hunter, 1998). Simple lactose maldigestion is well known to cause hydrogen and lactic acid production, with subsequent bloating and diarrhea. Diagnostic tests for SIBO are either direct invasive studies with bacterial cultures via nasal jejunal tubes, or indirect techniques using breath testing with either glucose or lactulose (Koshini, Dai, Lescano, & Pimentel, 2008). Hydrogen breath testing in particular is useful in identifying patients with IBS who are affected by SIBO, but other exhaled gases may have diagnostic benefit, as well (Koshini, Sun-Chuan, Lezcano, & Pimentel, 2007). Specific characteristics of each gas pose their own hazard. The production of hydrogen sulfide can cause increased nociception, as found in IBS and idiopathic constipation (IC). Excess hydrogen and methane result predominantly in bloating (as seen in IBS), while excess methane also results in altered motility, manifested primarily as constipation. Early studies of the association of methane production and altered motility looked at orocecal and whole gut transit, and found that each was significantly delayed if methane excretion occurred early on in the lactulose

Principles of Integrative Gastroenterology 87

breath test (LBT). As a result, abnormal methane production was shown to be strongly associated with constipation-predominant IBS (Pimentel et al., 2003). Methane was detected in 50 (17%) of 296 patients with IBS, compared with 2 (3%) of 78 patients with IBD (P < .01). Subsequently, a study of 87 patients showed that, of the 20 that had methane production, severity of constipation was double that of non-methane-producing IBS subjects (Chatterjee et al., 2007). A correlation was found between the degree of methane production on the breath test and the severity of constipation. Infusion of methane into the small intestine has shown that gut transit can be reduced by up to 70% (Pimentel et al., 2006). Thus, methane as a by-product of fermentation can itself slow intestinal transit.

THERAPY FOR SMALL INTESTINAL BACTERIAL OVERGROWTH

The basis for SIBO treatment is the understanding that most cases of SIBO are caused by poor motility of the small intestine, which then allows for bacterial overgrowth and subsequent damage to the intestinal lining. Antibiotic treatment is the mainstay of treatment, and requires a broad-spectrum antibiotic to be effective. Treatment with quinolones, amoxicillin, tetracycline, and metronidazole, is somewhat effective, but can cause bacterial resistance and antibiotic-associated diarrhea.

RIFAXIMIN THERAPY FOR SIBO

Rifaximin offers a unique profile for SIBO, with its broad-spectrum activity, non-absorbable moiety, bile solvency (thus increasing activity in the small intestine), and low likelihood of long-term resistance (Su, Aberra, & Lichtenstein, 2006). It has been shown to be effective in patients with SIBO, IBS with SIBO, and scleroderma (Lauritano et al., 2005; Pimentel, Park, Mirocha, Kane, & Kong, 2006; Parodi et al., 2008). The efficacy of Rifaximin in the treatment of SIBO, IBS, and functional bowel syndrome has been evaluated in several studies, as summarized in Table 7.5 (Di Stefano, Malservisi, Veneto, Ferrieri, & Corazza, 2000). Nucera et al. (2005) looked at a large group of patients who were treated with weekly courses of combination antibiotics every month for 4 months. There was a significant improvement in the breath tests using lactulose, lactose and fructose. Laurentino et al. (2005) showed that increasing the dose of rifaximin from 800 mg/day/week to 1,200 mg/day/week resulted in double the improvement in reversing the breath test. The UCLA group has subsequently

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Table 7.5. Rifaximin Therapy for IBS-SIBO Author

Yr

Patients

Type

Efficacy

Nucera

‘04

IBS-SIBO (n=200)

Open label; Rfx 87-100% effective in + paramomycin treating SI BO by reversing 3 sugar BT’s

Lauritano

‘05

IBS-SIBO (n=90)

Dose-ranging

Dose response with Rfx

Lupascu

‘05

IBS-SIBO (n=80)

Abx comparison; open label

1 wk of Rfx vs. metro/ levoquin 12/20 vs. 14/20 H2 BT normalized

Pimentel

‘05

IBS-SIBO (n=87)

R/DB/PC

Statistical sig. vs. placebo; duration of response over 2 months for 10-day Rx

Sharara

‘06

IBS (n=70)

R/DB/PC

Statistically sig. vs. placebo

Sharara

‘06

Fx-SIBO (n=54)

R/DB/PC

Numerically diff. vs. placebo

Weinstock

‘06

IBS-SIBO (n=254)

Observational

60% mod-greatly improved

Weinstock

‘06

Fx-SIBO (n=85)

Observational

63% mod-greatly improved

reported that reversing the breath test is critical in symptom resolution (Pimentel, Chow, & Lin, 2003). Pimentel, Park, Murocha et al.’s 2006 study showed that a 10-day course of 1,200 mg/day of rifaximin resulted in 10 weeks of improvement of IBS symptoms. Patients experienced a 36% mean improvement from baseline in the severity of IBS symptoms at 10 weeks post-treatment, compared with a mean improvement of 21% among 44 patients who received placebo (P = .02). The dose of rifaximin in Sharara et al.’s study (2006) was 800 mg/day for 10 days; global symptomatic response was achieved in 41% of 37 patients, compared with 6 (18%) of 33 patients who received placebo (P = .04). After 10 days posttreatment, 10 (27%) of 37 patients in the rifaximin group maintained their symptomatic response, compared with 3 (9%) of 33 patients in the placebo group (p=0.05). In an open-label, observational study, a 10-day course of rifaximin 1,200 mg/day, as part of a comprehensive treatment regimen including tegaserod and probiotic therapy, improved IBS symptoms in 60% of 81 patients (Weinstock et al., 2006;110:A1123). Our own experience shows that effective

Principles of Integrative Gastroenterology 89

antibiotic therapy, (LBW) along with high doses of Coenzyme Q10, reduces the severity of fatigue in IBS patients with SIBO. Studies have also been done comparing the effectiveness of other antibiotics used in the treatment of SIBO compared to Rifaximin. A retrospective chart review of 98 patients with IBS who received antibiotic therapy (Yang J, Lee HR, Low K et al., 2008) showed that 58 (69%) of 84 patients who received at least one course of rifaximin experienced clinical response, compared with 9 (38%) of 24 patients who received neomycin (p<0.01) and 27 (44%) of 61 patients who received other antibiotics (e.g. amoxicillin clavulanate and doxycycline; P < .01).

COMBINATION PROMOTILITY ANTIBIOTIC THERAPY FOR SIBO

Given that disturbances in gastrointestinal motility are key to the development of SIBO (via impaired “sweeping” of bacteria in the upper digestive tract), treatment with promotility agents are paramount to the therapy of this condition. In the past, long-term tegaserod (a serotonin agonist) was given in an attempt to improve the Phase III abnormality of the migrating motor complex found in patients with IBS who have SIBO (Spiller et al., 2000). A review of IBS-SIBO patients who were treated with antibiotics and then were given tegaserod (no longer available in the United States) versus low-dose erythromycin (50mg dose acts as a stimulant to the migrating motor complex) showed that tegaserod decreased recurrence of IBS-SIBO symptoms at a rate twice that of erythromycin, and four times that of no medication after rifaximin alone (Yang J, Lee HR, Low K et al., 2008). The problems with erythromycin include the potential for abdominal cramps, interference with birth control pills, and other drug interactions including an increased risk of muscle damage when used concurrently with statin medications. Low-dose naltrexone may be used as an alternative to erythromycin. This anti-opioid can stimulate the intestine, and some emerging data suggests that it has anti-inflammatory properties, which might help repair the intestinal lining. The problems with naltrexone include general CNS stimulation (potential for jittery feelings, insomnia, and unusual dreams). It is contraindicated for people who take chronic opioids. The following are possible alternative treatments for SIBO: • Probiotics can reduce inflammation and improve permeability problems (Spiller, 2005; Resta-Lenert & Barrett, 2006; Ait-Belgnaoui et al., 2006). Specifically, bifidobacteria-based probiotics may repair small

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intestinal permeability and immune defects characteristic of SIBO, IBS, and postinfectious IBS (Spiller et al., 2000; Dunlap, Hebden, & Campbell, 2006; Plaza, 2001). • Zinc can theoretically help reverse defects in small intestinal permeability (Spiller, Jenkins, Thornley et al., 2000). Experimental evidence shows that zinc supplementation improves intestinal permeability in toxin-induced colitis (Sturniolo, Fries, Mazzon et al., YEAR). Zinc carnosine (ZnC) stimulated migration and proliferation of cells in vitro, in a dose-dependent manner, and decreased gastric and smallintestinal injury (50% reduction in villous shortening at 40 mg/ml; both p<0.01; see Mahmood et al., 2007). In volunteers, indomethacin caused a threefold increase in gut permeability in the control arm, while no significant increase in permeability was seen when ZnC was co-administered. • Medical foods containing glutamine or aloe (either individually or in combination) are used by many practitioners to facilitate intestinal permeability resolution after therapy of SIBO. • Antimicrobial herbal preparations have been used by the author (G. Mullin) to resolve SIBO that is refractory to rifaximin and triple antibiotics (clindamycin, neomycin, metronidazole. Examples of products used by the author with success include: ° Dysbiocide (Biotics Research Laboratories) ° FC Cidal (Biotics Research Laboratories) ° ADP (Biotics Research Laboratories) • The role of diet therapy during the treatment of SIBO cannot be emphasized enough. Individuals need to be counseled to avoid fructose, fructans, and poorly digestible starches, such as beans (see Appendix A). • Since immune GI dysfunction plays a role in IBS, there are additional alternative approaches to SIBO treatment, including: ° Probiotics administered post-treatment, once SIBO is resolved ° Elimination diet to avoid allergens that can trigger immune and inflammatory responses Avoiding food products (i.e., indigestible starches) that can fer° ment in the small intestine and facilitate the growth of the gut microbiota ° Hypnotherapy to downregulate the stress response on the immune system and the gut lining

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° Acupuncture to facilitate GI motility via resetting the migrating motor complex to sweep intestinal bacteria in an antegrade manner ° Immune enhancers such as:  Arabinogalactans (raises mucosal sIgA levels)  Saccharomyces boulardii (raises mucosal sIgA levels)  IgG2000 (raises mucosal sIgA levels)  Colostrum (rich in preformed antibodies) ° Behavioral therapy to attenuate the stress response, reset pain thresholds, and lower neuroendocrine and inflammatory markers.

Systemic Consequences of SIBO-Induced Gut Injury CHRONIC FATIGUE SYNDROME

Chronic fatigue syndrome (CFS) is an idiopathic complex illness characterized by heightened reactive oxygen metabolites, along with mitochondrial defects that lead to aberrant fatty acid and energy metabolism. Research also indicates that CFS patients are under increased oxidative stress, have a Type 2 helper-cell-dominant cytokine profile, frequently report allergies, have altered essential fatty acid (EFA) status, and may have malabsorption of certain micronutrients (Logan, Venket Rao, & Irani, 2003). Gastrointestinal links to chronic fatigue syndrome include marked alterations in microbial flora, including lowered levels of bifidobacteria, and SIBO Lactic acid bacteria (LAB) found in probiotics have the potential to influence the immune system in CFS patients by supporting T-helper-cell-1-driven cellular immunity, and may decrease allergies. Systemic inflammation induced by SIBO could be responsible for alterations in the hypothalamic pituitary adrenal axis, causing the fatigue found in the irritable bowel syndrome. Interestingly, IBS has also been associated with CFS and SIBO independently (Figure 7.2; see Cleare, Miell, Heap et al., 2001; Gaab, Rohleder, Heitz et al., 2005; Hamilton, Gallagher, Thomas, & White, 2009). Preliminary data by Pimentel et al. (2000) showed that SIBO was common in CFS (77% of 31 patients), and there was improvement in tender points and depression (but not in fatigue scores) when antibiotics improved SIBO.

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RESTLESS LEGS SYNDROME (RLS)

The prevalence of RLS is estimated at 10% of the general population, and it results in sleep disorders and a poor quality of life (Allen, Walters, Montplaisir et al., 2005) from the compelling urge to move the legs at night, often with discomfort. RLS is a central nervous system disorder that is either idiopathic (primary) or secondary to a number of conditions, including GI dysfunction. Possible mechanisms of action in RLS include iron deficiency, inflammation, and/or SIBO. In virtually all forms of RLS (primary, familial, and secondary), there is central nervous system iron deficiency (Berger, Von Eckardstein, Trenkwalder et al., 2002; Allen, 2004). Additionally, RLS patients often have varying degrees of asymptomatic peripheral iron deficiency (Aul, Davis, & Rodnitzky, 1998; Rama, Aul, Davis, & Rodnitzky, 1998). A chronic inflammatory state caused by SIBO (Lin, 2004) could be related to RLS by affecting hepcidin production directly (Kemna, Pickkers, Nemeth et al., 2005) and indirectly (Liu Z, Li, & Neu, 2005), decreasing peripheral and central nervous system iron uptake and transportation (Earley, Connor, Beard et al., 2000; Clardy, Earley, Allen et al., 2006). There is limited recognition that iron deficiency is an integral part of the pathophysiology of RLS. The growing understanding of iron metabolism and the role of SIBO and systemic inflammation in RLS is exciting. The role for modulation of dysbiosis will be determined with double-blind, placebocontrolled studies, which are in progress.

THEORY FOR SIBO CAUSING RLS AND CENTRAL IRON DEFICIENCY

Factors that are associated with secondary RLS include elderly status, diabetes, end-stage renal disease, fibromyalgia, rheumatoid arthritis, and Parkinson’s syndrome. Furthermore, all of these conditions have also been associated with SIBO. Secondary RLS has also been associated with gastrointestinal conditions, such as gastric resection, chronic liver disease, IBS associated with SIBO, celiac disease, and Crohn’s disease (Banerji & Hurwitz, 1970; Franco, Ashwathnarayan, Deshpandee et al., 2008; Weinstock, Fern, & Duntley, 2008; Weinstock, Bosworth, Scherl et al., 2008). Patients with scleroderma also have a reported increased incidence of RLS, although in this single study the patients did not have symptoms of end-stage SIBO (Prado, Allen, Trevisani et al., 2002).

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TREATMENT OF SECONDARY RLS

Medical trials for RLS have been recently reviewed extensively, and are summarized in Table 7.6 (Trenkwalker, Hening, Montagna et al., 2008). Magnesium, folic acid, and exercise are frequently used in practice, but are considered to be investigational. The efficacy of oral iron is also considered investigational; however, its efficacy appears to depend on the iron status of subjects. Intravenous iron is likely efficacious for the treatment of RLS secondary to end-stage renal disease, but investigational in RLS subjects with normal renal function (Earley, Heckler, & Allen, 2005). Most physicians who treat RLS feel that the first approach after iron treatment is to initiate dopamine agonists (Comella, 2002). Ropinirole is marginally better than placebo augmentation, and a wide array of side effects of dopamine agonists have led to interest in finding therapeutic alternatives (García-Borreguero, Allen, Kohnen et al., 2007).

ANTIBIOTICS FOR RLS

Two pilot studies have evaluated the effect of rifaximin for the treatment of RLS. The first prospective clinical trial of 13 IBS patients with both SIBO and RLS reported that 77% of patients (10/13) had ≥80% long-lasting improvement of RLS symptoms following open-label treatment with rifaximin 1,200 mg/day

Table 7.6. Medical Therapy for Restless Legs Syndrome Dopaminergic agents Neuroleptics Anti-seizure medications Narcotics Benzodiazepines Iron Investigational Rifaximin antibiotic therapy Magnesium Acupuncture Botox injections

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for 10 days, followed by motility and probiotic therapy (Weinstock, Fern, & Duntley, 2008). The next study included patients with primary RLS who had a positive lactulose breath test for SIBO. The mean baseline IRLS score was 23.1 (Weinstock, Fern, & Duntley, 2008). Open-label treatment with rifaximin 1,200 mg/day/10 days, followed by 400 mg/every other day/20 days, resulted in a decrease in the IRLS score by 10.7 in 9 of 14 patients. Two of the five RLS nonresponders had improvement with a second course of rifaximin when combined with metronidazole, and a third patient improved when she was later diagnosed with celiac disease and placed on a gluten-free diet and iron supplementation.

ALTERNATIVE THERAPIES FOR RLS

The common approaches used for many conditions include herbs, vitamins and/or minerals, acupuncture, botulinum toxin, hyperbaric therapy∗ and chelation therapy∗. Small studies have suggested improvement from magnesium, although scientific studies of magnesium in RLS have been nonsupportive (Hornyak, Voderholzer, Hohagen et al., 1998; Bartell & Zallek, 2006; Walters, Elin, Cohen et al., 2007). Acupuncture has been studied in 14 studies, but only 2 were judged worthy of comment based on the design, and there is insufficient evidence to support the use of acupuncture in RLS (Cui, Wang, & Liu, 2008). Intramuscular botulinum injections have shown success in 3 patients (Rotenberg, Canard, & Difazio, 2006). Finally, pneumatic sequential compression devices on RLS symptoms showed success in 6 of 10 patients (Eliasson & Lettieri, 2007). Small, open-label studies with RLS are problematic, since the placebo response is so high.

RESTLESS LEGS SYNDROME (RLS), CELIAC, AND CROHN’S DISEASE

• The relationship between restless legs syndrome (RLS) and celiac disease has recently been reported (Weinstock, Bosworth, Scherl et al., 2008). • RLS was found to be a frequently associated condition in 85 celiac patients: the incidence was 35.5% and the prevalence was 24.7%, compared with spouse control group of 9.5%. • Neurologic complications have only recently been reported in Crohn’s disease. ∗

Have not been reported in the literature.

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• The incidence of RLS was 42.7% in a large number of Crohn’s disease patients from three academic centers and one large community practice (Weinstock, Bosworth, Scherl et al., 2008). • The prevalence of RLS in Crohn’s disease was 30.2%, compared to a prevalence of 8.4% in the sex-matched spouse control group.

Interstitial Cystitis (IC) Interstitial cystitis (also known as painful bladder syndrome) is an idiopathic syndrome characterized by symptoms of urinary frequency, urinary urgency, pain with bladder filling, pelvic pain, and dyspareunia. There is a significant overlap of interstitial cystitis (IC) with food allergies, autoimmune disease, and IBS. GI dysfunction may play a role in IC, since food triggers, mast cells, neural crosstalk, and SIBO have been implicated in the pathophysiology. A connection to SIBO has been proposed, and a positive therapeutic study using SIBO open-label antibiotic therapy was reported (Lin, 2004; Weinstock, Klutke, & Lin, 2007). The potential interactions of mast cells, inflammatory mediators, and the peripheral nervous system are shown in Figure 7.7.

Possible Role of SIBO and IC Pathophysiology ROLE OF FOOD ALLERGIES

Shorter et al. (2007) determined the prevalence of the effect of food substances on painful bladder syndrome/interstitial cystitis symptoms. Of the surveyed patients with IC, 90.2% indicated that the consumption of certain foods or beverages caused symptom exacerbation. Patients who reported that specific foods worsened symptoms tended to have more severe IC symptom scores. The most frequently reported foods causing symptom exacerbations were coffee, tea, soda, alcoholic beverages, citrus fruits and juices, artificial sweeteners, and hot pepper.

Gut Permeability, Inflammation, and Pelvic Pain The link between chronic pelvic pain, dyspareunia, and functional digestive diseases (i.e., IBS) has been long established (Vercellini, Somigliana, Viganò et al., 2009). Since SIBO, chronic inflammation, altered HPA axis, and systemic

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proinflammatory cytokines are implicated in the pathogenesis of IBS, an experimental study was undertaken to investigate the mechanism of development of pelvic pain (Rudick, Chen, Mongiu, & Klumpp, 2007). One study explored, in an animal model of IBS, whether pelvic pain could develop remotely from the original site of inflammation. These investigators confirmed that there is organ crosstalk (between the intestine and vagina), as well as modulation of pain responses by visceral inputs distinct from the inflamed site. Thus, SIBO/IBS can manifest in other organ systems distant from the site of pathology, via the common mucosal immune system (see Chapter 3).

Rosacea Systemic inflammation caused by GI dysfunction may be an explanation for rosacea, which is a common idiopathic disease that presents with transient or persistent facial erythema, telangiectasia, edema, papules, and pustules, usually confined to the central portion of the face (Buechner, 2005). In the past, genetic, environmental, vascular and inflammatory factors, and microorganisms such as skin bacteria, including Demodex folliculorum, and gastric infections with Helicobacter pylori have been considered as etiologic factors.

ROSACEA AND DIGESTIVE DISORDERS Rosacea has been associated with gastritis and hypochlorhydria; many people have nonspecific gastrointestinal symptoms.

Helicobacter pylori The role of Helicobacter pylori has often been a subject of investigation, with studies showing conflicting results. A small study investigated ocular rosacea, and clinical and serological evidence of H. pylori infection showed significant improvement of rosacea symptoms, with ocular disease responding better than cutaneous rosacea (Daković, Vesić, Vuković et al., 2007). An older study from Poland on the treatment of H. pylori infection, in 60 patients with rosacea having erythema and flushing on the face with visible papules and pustules, was compared to 60 age and gender matched patients without any skin diseases (Szlachcic, 2002). The effect of treatment on plasma interleukin (IL-8) and tumor necrosis factor alpha (TNF-α) was also determined after 1 week of

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omeprazole 20 mg, clarithromycin 500 mg, and metronidazole 500 mg, all twice daily. The H. pylori prevalence in rosacea patients was about 88%, compared to 65% in control patients. There was twice the incidence among rosacea patients of a more virulent form of H. pylori (cytotoxin-associated gene A [CagA] positive). After antibiotics, 51 out of 53 treated rosacea patients became Hp negative. Within 2 to 4 weeks, the symptoms of rosacea disappeared in 51 patients, markedly declined in one, and remained unchanged in one other subject. Plasma TNF-α and IL-8 were reduced significantly after the therapy in both groups of patients (72% and 65%, respectively).

Rosacea could be considered as one of the major extragastric symptoms of H. pylori infection cytotoxins and cytokines.

SIBO

Italian investigators recently discovered the link between rosacea and small intestinal bacterial overgrowth (Parodi, Paolino, Greco et al., 2008). Of 113 consecutive rosacea patients, 52 had a positive breath test (versus 3 of 60 controls). After SIBO eradication by rifaximin, as determined by reversal of the breath test, cutaneous lesions cleared in 20 of 28, and greatly improved in 6 of 28 patients, whereas patients treated with placebo remained unchanged (18/20) or worsened (2/20) (P<0.001) (Figure 7.8). The patients who were given placebo were subsequently switched to rifaximin. In these patients, SIBO was eradicated in 17 of 20 cases. Fifteen of these patients had a complete resolution of rosacea. Thirteen of 16 patients with negative breath tests for SIBO remained unchanged, and this result differed from SIBO-positive cases (P<0.001). Eradication of SIBO induced an almost complete regression of their cutaneous lesions for at least 9 months. The authors of the study suggested that chronic systemic inflammation causes inflammation of the skin. Figure 7.8 shows the clinical outcome in SIBO-positive and SIBO-negative rosacea patients treated with rifaximin. 1. Myth: Syndromes are all “in your head” and are due to “stress.” 2. Restless legs syndrome is caused by central nervous system iron deficiency and altered dopamine interactions. Evidence is growing for the role of small intestinal bacterial overgrowth. 3. The real name for “leaky gut” is increased intestinal permeability.

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Summary 1. Integrity of the gut mucosa is essential for good health. 2. Imbalance of bacteria plays a role in many disorders. 3. A shift of colonic type bacteria into the small intestine results in inflammation as well as fermentation, with subsequent gas production. 4. Treatment with special antibiotics, motility medicine, and probiotics may provide benefits to those suffering from “syndromes.” 5. Syndromes do not exist in a vacuum. The high prevalence of these idiopathic conditions in the population, and the overlapping of symptoms from one condition to another, suggest that a central cause could be a significant factor (Figure 7.9).

8 The Skin and the Gastrointestinal Tract ANDREW G. FRANKS , JR.

key concepts ■

■

■

■

The neutrophilic dermatoses are a spectrum encompassing four distinct diseases characterized by sterile neutrophilic cutaneous infiltrates, and include erythema elevatum diutinum, pyoderma gangrenosum, Sneddon-Wilkinson syndrome, and Sweet’s syndrome. Bowel stasis, which promotes bacterial overgrowth, with either disease or surgically induced blind loops, can cause a bowelassociated dermatosis-arthritis syndrome. Acanthosis nigricans is arguably also the most well-recognized cutaneous sign of internal malignancy. Peutz-Jeghers syndrome is a dominantly inherited polyposis syndrome, characterized by hamartomatous polyps of the gastrointestinal tract, and mucocutaneous pigmentation and melanin spots. ■

Introduction

T

he skin and the gastrointestinal tract are both covered or lined by epithelium, and both communicate with the external environment. Therefore, it is not surprising that diseases that primarily affect the gastrointestinal tract often have cutaneous manifestations as well. These cutaneous

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findings frequently provide clues to the diagnosis of the underlying gastrointestinal disease (Gregory & Ho, 1992a, 1992b). There are a vast number of associations, from extremely rare genetic disorders to more common illnesses, both benign and malignant. These more common associations, which are most likely to be encountered in clinical practice, are the focus of this review. Of the benign disorders, the following will be reviewed: • • • • • • • •

IBD and the neutrophilic dermatoses Bowel bypass syndrome Erythema nodosum Acrodermatitis enteropathica Dermatitis herpetiformis Pancreatic panniculitis Hepatitis C Helicobacter pylori

Of the malignancy-associated disorders, examples of the following will also be reviewed: • • • • • • •

Glucagonoma syndrome Bazex’s syndrome Palmar-plantar hyperkeratosis Acanthosis nigricans Gardner’s syndrome Peutz-Jeghers syndrome Cowden disease

The Neutrophilic Dermatoses and Other Benign Disorders The neutrophilic dermatoses are a spectrum encompassing four distinct diseases characterized by sterile neutrophilic cutaneous infiltrates. The etiology of these disorders is not well understood, but is thought to be related to deposition of immune complexes in dermal vessels, resulting in complement fixation and leukocytoclastic vasculitis, as well as altered neutrophilic chemotaxis. The neutrophilic dermatoses include erythema elevatum diutinum, pyoderma gangrenosum, Sneddon-Wilkinson syndrome and Sweet’s syndrome.

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ERYTHEMA ELEVATUM DIUTINUM

Erythema elevatum diutinum (EED) is characterized by multiple symmetric papules, plaques, nodules, vesicles, or bullae on the extensor surface of joints, particularly the elbows, knees, hands, and feet. The lesions usually are initially red to purple in color, some becoming yellowish-brown. Many patients are asymptomatic, but pruritus, tenderness, and pain may occur. They may be cold-induced, and also demonstrate Koebnerization. Constitutional symptoms may include arthralgias and fever. The course of the disease is chronic and frequently relapsing, though it may spontaneously remit. Lesions heal with residual atrophic patches, with loss of collagen in the dermis. EED has been associated with a variety of underlying autoimmune, gastrointestinal, and hematopoietic disorders, including Crohn’s disease (Evans et al., 1999; Walker & Badame, 1990). Skin biopsy is not specific, and usually reveals a dense perivascular neutrophilic infiltrate involving the superficial and mid dermis, with leukocytoclastic vasculitis, fibrin deposition, and endothelial swelling. An interstitial infiltrate of lymphocytes, neutrophils, eosinophils, plasma cells, and histiocytes may be observed. Features of older lesions include perivascular fibrosis, intracellular lipid deposition, and capillary proliferation.

PYODERMA GANGRENOSUM

Pyoderma gangrenosum (PG) usually begins as painful papules/pustules, which rapidly expand into painful burrowing ulcers with undermined borders and/or raised violaceous rims. The pretibial areas of the legs are the most frequent site, but any location may be involved. Different clinical presentations of PG include: ulceration with rapidly evolving purulent wound; discrete pustules, commonly associated with inflammatory bowel disease; superficial bullae with development of ulcerations; and vegetative erosions and superficial ulcers. An oral form of the disease, known as pyostomatitis vegetans, occurs primarily in patients with inflammatory bowel disease (Yasuda et al., 2008). Often the lesions heal, leaving a cribriform-shaped scar. Ulcerations of pyoderma gangrenosum may occur after trauma or any injury to the skin, and the term pathergy is used to describe the process. PG occurs most often in association with inflammatory bowel disease (Crowson et al., 2003), but also with any of the connective tissue diseases, Monoclonal gammopathy of undetermined significance (MGUS), myeloma, myelodysplastic syndrome

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(MDS) leukemia and lymphoma. Culture-negative pulmonary infiltrates are the most common extracutaneous manifestation. Histopathologic changes vary where the biopsy is taken in relation to the lesion. Lymphocytic vasculitis is found in the area of erythema peripheral to the central ulceration, whereas neutrophilic infiltrates and abscess formation are identified more centrally.

SNEDDON-WILKINSON SYNDROME

Sneddon-Wilkinson syndrome, or subcorneal pustular dermatosis, is a recurrent pustular disorder that may mimic pustular psoriasis, and presents with bilateral crops of lesions on the flanks, trunk, and proximal extremities with a flexural tendency. The primary lesions are pea-sized sterile pustules and papulovesicles, often described as half-pustular (bottom) and half-clear (top), or “half & half blister.” Sometimes, burning, pain, and tenderness of the affected areas of the skin may occur. Subsequently, the lesions may coalesce and form annular polycyclic rings, which eventually crust and erode. The histopathology reveals a subcorneal pustule filled with polymorphonuclear leukocytes, with only occasional eosinophils, and absence of spongiosis and acantholysis. Constitutional features may not be prominent, but generalized arthralgias and arthritis may occur. It is frequently associated with an MGUS, particularly IgA, less commonly IgG. Multiple myeloma and other lymphoproliferative disorders are sometimes found, and an association with pyoderma gangrenosum and inflammatory bowel disease has been noted (Delaporte et al., 1992; Garcia-Salces et al., 2008).

SWEET’S SYNDROME

The combination of high fever, leukocytosis, boggy, red, painful papules and plaques with dense neutrophilic dermal infiltrates, without evidence of vasculitis on skin biopsy, is characteristic of Sweet’s syndrome, or acute febrile neutrophilic dermatosis. Soft, pea-sized papules and papulovesicles grouped within boggy violaceous plaques are very suggestive of the diagnosis. If the plaque is squeezed between the thumb and forefinger, a grey-yellow coloration may be noted within the papules. Lesions tend to occur on the extremities more so than the trunk. Sweet’s syndrome may be associated with hematological malignancy, especially acute myelogenous leukemia, as well as inflammatory bowel disease, particularly Crohn’s disease (Burrows, 1995; Mustafa & Lavizzo, 2008). The initial episode is often thought to be cellulitis or erysipelas. Patients are placed on antibiotics empirically and, as spontaneous remission

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occurs, this reinforces the misdiagnosis. Patients may become secondarily infected, further causing confusion.

Bowel Bypass Syndrome Bowel bypass syndrome refers to a constellation of cutaneous and arthritic symptoms related to, but not exclusively associated with, bypass surgery. Although this procedure is not routinely performed today, patients with its complications are still seen by physicians. Interestingly, a similar clinicopathological syndrome has been reported in patients without surgery but with other bowel conditions, particularly inflammatory bowel disease. Therefore, the term bowel-associated dermatosis-arthritis syndrome has been proposed, to include patients without bowel bypass surgery for obesity. The common risk factor appears to be bowel stasis, which promotes bacterial overgrowth with either disease, or surgically induced blind loops. The bowel bypass syndrome consists clinically of a characteristic, intermittent neutrophilic dermatosis, often associated with polyarthritis, tenosynovitis, malaise, and fever. Cryoglobulinemia is commonly found. The syndrome often mimics gonococcal sepsis. Skin manifestations consist of characteristic lesions that are erythematous macules, oval in shape, ranging from 3 mm to 10 mm in diameter. The skin lesions consist of sweeps of neutrophils, very much like Sweet’s syndrome. The formation of vesicles become pustular, and may appear similar to disseminated gonococcal disease. They may become painful, and last for up to a week but remain sterile on culture.

Erythema Nodosum Erythema nodosum accompanied by gastrointestinal complaints includes inflammatory bowel disease, Behcet’s disease, bacterial gastroenteritides, pancreatitis, celiac disease, and Whipple’s disease (Schwartz & Nervi, 2007). Erythema nodosum is the most common form of septal panniculitis, and the most frequent skin manifestation associated with inflammatory bowel disease. Since the development of erythema nodosum is closely related with a variety of disorders and conditions, it can serve as an important early sign of systemic disease. Aphthous stomatitis and pyoderma gangrenosum, along with erythema nodosum, are the most common skin disorders related to inflammatory bowel disease (Farhi et al., 2008). Erythema nodosum clinically presents as multiple, bilateral, painful, non-ulcerating, subcutaneous nodules that undergo characteristic color changes commencing with bright erythema, and ending in

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bruise-like areas. It occurs most commonly on the extensor surface of the shins, and is less common on the thighs and arms. It usually subsides in 3 to 6 weeks without scarring or atrophy, but may be chronic.

Acrodermatitis Enteropathica Acrodermatitis enteropathica is most often a hereditable disease of infancy or childhood, related to the malabsorption of zinc (Maverakis et al., 2007). Zinc deficiency can be an acquired condition in adults as a result of inflammatory bowel disease, or as a result of nutritional deprivation of zinc. Eczematous, psoriasiform, and vesicular lesions have been described, most of which occur in acral locations and, sometimes, on the face as well. The same process may be associated in adults with niacin deficiency and the glucagonoma syndrome (Teixeira, Nico, & Ghideti, 2008).

Dermatitis Herpetiformis Dermatitis herpetiformis (DH) is an autoimmune blistering skin disease associated with a gluten-sensitive enteropathy. Gluten sensitivity usually presents as celiac disease in infancy and childhood, and DH later in life. It is associated with IgA antibody formation and gluten-sensitive enteropathy, but 90% if patients have no gastrointestinal symptoms (Oxentenko & Murray, 2003). Skin lesions are extremely itchy groups of vesicles, most often found on extensor surfaces. There is burning, stinging, and intense pruritus. Erythematous vesicles are symmetrical over the extensor surfaces, including elbows, knees, buttocks, shoulders, and neck. There may be associated crusts and erosions. Patients often complain of stinging or burning of the skin before the appearance of new lesions (Nicolas et al., 2003). The oral mucosa is usually not involved, nor are the palms or soles. Biopsy is required for diagnosis. Light microscopy alone is often inadequate, and direct immunofluorescence is usually necessary to confirm the diagnosis. Granular IgA deposits in dermal papillae of perilesional skin, observed by direct immunofluorescence, are diagnostic (Kárpáti, 2004).

Pancreatic Panniculitis Pancreatic panniculitis is an uncommon cutaneous eruption that is associated with disorders of the pancreas, both benign and malignant (García-Romero & Vanaclocha, 2008). The most common disorders associated with pancreatic

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panniculitis are acute or chronic pancreatitis, especially the alcohol-related types, and pancreatic carcinoma. Although the underlying pancreatic pathologic conditions vary, the clinical features of pancreatic panniculitis are similar (Sagi et al., 2008.). The legs are the most commonly affected area, but the lesions can also occur on the arms, thighs, and trunk. They begin as erythematous or red-brown subcutaneous nodules, with a tendency to central softening. In the mild form, they may involute within weeks and leave an atrophic hyperpigmented scar. If the fat necrosis is severe, individual nodules may break down and ulcerate (Shehan & Kalaaji, 2005).

Hepatitis C Hepatitis C may be associated with a number of cutaneous disorders, but classically with mixed cryoglobulinemia (Agnello & Romain, 1996). Cryoglobulins are abnormal immunoglobulins that form complexes and precipitate out of serum at low temperatures, and redissolve upon warming or returning to room temperature. Cryoglobulins are made up of monoclonal antibodies of IgM or IgG, rarely IgA. Types II and III cryoglobulinemia (mixed cryoglobulinemia) contain rheumatoid factors (RFs), which are usually IgM and, rarely, IgG or IgA. These RFs form complexes with the Fc portion of polyclonal IgG. The actual RF may be monoclonal (in Type II cryoglobulinemia) or polyclonal (in Type III cryoglobulinemia) immunoglobulin. Types II and III cryoglobulinemia represent 80% of all cryoglobulins. The cryoglobulin concentration is usually low, just above 1mg/ml. Types II and III are called mixed cryoglobulinemias, and are associated with chronic inflammatory states, such as systemic lupus erythematosus (SLE), Sjögren’s syndrome, and viral infections, particularly HCV (Della Rossa et al., 2001). Cutaneous vasculitis associated with cryoglobulinemia and hypocomplementemia is not uncommon in the course of chronic active hepatitis C infection. The triad of necrotizing vasculitis, chronic hepatitis C infection, and cryoglobulinemia, occurs late after initial infection with hepatitis C (La Civita et al., 1996). In these disorders, the IgG fraction is always polyclonal, with either monoclonal (Type II) or polyclonal (Type III) IgM (rarely IgA or IgG), and RF activity. Cutaneous findings in cryoglobulinemia include erythematous to purpuric macules, papules and urticarial plaques, livedo, acral necrotic infarction, hemorrhagic erosions, painful distal ulcers, and extensive postinflammatory hyperpigmentation. Skin biopsy most often reveals small-vessel leukocytoclastic vasculitis and, less frequently, inflammatory or noninflammatory purpura, noninflammatory hyaline thrombosis, and postinflammatory sequelae. HCV virus has also been identified in vessel walls (Schott, Hartmann, & Ramadori, 2001).

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Helicobacter pylori There is increasing evidence for systemic effects of gastric H. pylori infection, which may result in extragastrointestinal disorders (Rojo-García et al., 2000). There is some evidence for a potential link of H. pylori infection and chronic urticaria, although the data are still conflicting. Thus, the search for H. pylori should be included in the diagnostic management of chronic urticaria. With regard to other skin diseases such as rosacea, a higher prevalence of H. pylori infection in rosacea patients than in healthy controls has been reported, and may be worth evaluation (Buechner, 2005).

Malignancy-Associated Disorders GLUCAGONOMA SYNDROME

Glucagonoma syndrome is a paraneoplastic phenomenon characterized by an islet alpha-cell pancreatic tumor, necrolytic migratory erythema on the skin, diabetes mellitus, weight loss, anemia, stomatitis, thromboembolism, and gastrointestinal and neuropsychiatric disturbances. These clinical findings, in association with hyperglucagonemia and demonstrable pancreatic tumor, establish the diagnosis. Glucagon itself is responsible for most of the observed signs and symptoms, and its induction of hypoaminoacidemia is thought to lead to necrolytic migratory erythema. Liver disease, and fatty acid and zinc deficiency states, may also contribute to the pathogenesis of the eruption in some cases (Chastain, 2001). At diagnosis, most glucagonomas are malignant and often metastatic (Chen et al., 2005). The diagnostic features of necrolytic migratory erythema include a chronic migratory cutaneous eruption with advancing borders, which often contain vesicopustules. Patients also usually have glossitis, angular cheilitis, blepharitis, weight loss, and abnormal glucose tolerance.

BAZEX’S SYNDROME

Acrokeratosis paraneoplastica (Bazex’s syndrome) is a rare paraneoplastic dermatosis characterized by psoriasiform and erythematous plaques, typically affecting hands, feet, nose, and earlobes. The condition almost exclusively affects Caucasian men older than 40 years. It is usually associated with primary

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malignant neoplasms of the upper digestive tract, especially esophageal carcinoma, as well as cervical lymph node metastases from an unknown primary tumor. Other rare associations include adenocarcinoma of the stomach or uterus, anaplastic small-cell carcinoma of the lung, Hodgkin’s lymphoma transitional-cell carcinoma of the bladder, adenocarcinoma of the colon, and squamous cell carcinoma of the lower leg (Rao & Shenoi, 2004). In most cases, the skin changes precede the clinical manifestation of the underlying neoplasm. The dermatosis can be cured only by removal of the underlying carcinoma (Sator, Breier, & Gschnait, 2006).

PALMOPLANTAR KERATODERMAS

Palmoplantar keratodermas are a heterogeneous group of disorders characterized by diffuse, abnormal thickening of the palms and soles, with autosomal recessive and dominant, X-linked, and acquired forms, all having been described. Some hereditary types, as well as some acquired forms, have been associated with pancreatic carcinoma, as well as other carcinomas (Kaur, Sarkar, & Kanwar, 2002).

ACANTHOSIS NIGRICANS

Although acanthosis nigricans is a skin condition that occurs most often with insulin resistance associated with obesity, particularly with Cushing’s syndrome or Type 2 diabetes, it is arguably also the most well-recognized cutaneous sign of internal malignancy. Acanthosis nigricans is characterized by hyperpigmentation, velvety cutaneous thickening, and intensified skin markings, often with the development of verrucous or skin-tag-like excrescences typically involving the intertriginous areas, but may also be found on the lips and within the mouth (Kaminska-Winciorek et al., 2007). It has been reported with many kinds of cancer, but the most common underlying malignancy is an adenocarcinoma of gastrointestinal origin, usually a gastric adenocarcinoma (Bohm, Luger, & Metze, 1999).

GARDNER’S SYNDROME

Gardner’s syndrome is the association of multiple colonic and rectal polyps with sebaceous cysts and jaw osteomas (Parks, Caldemeyer, & Mirowski, 2001). The significance of this dominantly inherited condition is that the

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polyps usually undergo malignant change by the fourth decade, and the extraintestinal lesions may be apparent before those in the bowel. Therefore, early detection of multiple jaw osteomas and/or multiple sebaceous cysts, particularly on the scalp, may lead to appropriate further investigation and treatment prior to malignant transformation (Basaran & Erkan, 2008). Gardner described the occurrence of familial adenomatous polyposis, with the extracolonic manifestations of desmoids, osteomas, and epidermoid cysts in the skin and the gastrointestinal tract. The number of polyps can range from no detectable polyps at colonoscopy, to more than 7,000 seen on resected specimens of bowel. The polyposis predominantly affects the left colon (Bilkay et al., 2004).

PEUTZ-JEGHERS SYNDROME

Peutz-Jeghers syndrome is a dominantly inherited polyposis syndrome characterized by hamartomatous polyps of the gastrointestinal tract, and mucocutaneous pigmentation and melanin spots. They appear as small, flat, brown or dark blue spots with the appearance of freckles, most commonly in the perioral area. They may be present on the fingers and the toes, on the hands and the feet, and around the anus and genitalia. Of note, the lesions may fade considerably after puberty (Giardiello & Trimbath, 2006). Since its description, much debate has centered on the true malignancy risk of Peutz-Jeghers syndrome, including malignancy within and outside the gastrointestinal tract. Although the intestinal lesions are hamartomas, patients with Peutz-Jeghers syndrome are generally considered to have a 15-fold increased risk of developing intestinal cancer compared to that of the general population (Homan, Strazar, & Orel, 2005). Rare tumors such as adenoma malignum of the cervix occur in Peutz-Jeghers syndrome. Likewise, more common cancers occur at younger ages. Children may manifest symptoms of this disease, including gastrointestinal complications and malignancy (Brichard et al., 2005).

COWDEN SYNDROME

Cowden syndrome is an autosomal dominant disorder characterized by multiple hamartomas and a high risk of development of breast, thyroid, endometrial, and other cancers (Schrager et al., 1998). The classic features of the disease include mucocutaneous papillomatous papules and trichilemmomas on the malar area of the face (Kovich & Cohen, 2004). Most affected people develop these characteristic lesions by their early twenties. At least one of four types of skin lesions is present in nearly all cases. Facial papules are flesh-colored,

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flat-topped, dry or warty 1mm to 5mm papules around the mouth, nostrils, and eyes. Oral lesions are numerous 1mm–3mm smooth white spots on the gums and palate that create a cobblestone appearance known as papillomatosis (Jornayvaz & Philippe, 2008). Acral keratoses are flesh-colored or slightly pigmented smooth or warty papules on the upper surface of hands and feet. Palmoplantar keratoses are scaly spots on the palms and soles that also may occur. Noncancerous breast and thyroid diseases are also common.

Conclusions Integrative practitioners should become aware of the various systemic manifestations of gastrointestinal disease. Dermatological conditions can precede, coincide, or occur after the underlying digestive disorder. Early recognition of dermatoses that underlie digestive health problems can lead to early diagnosis and treatment.

9 Premenstrual and Menstrual Exacerbation of IBS: An Integrative Medicine Analysis of the Bi-Directional Connection between Female Hormones and Gut Health JOEL M. EVANS

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IBS symptoms often have premenstrual and menstrual exacerbations. Progesterone dominance in the second half of the menstrual cycle explains the observation that constipation as an IBS symptom is more frequent in reproductive-aged women than in men. Stress is proinflammatory and known to exacerbate IBS. The perimenstrual release of proinflammatory cytokines contributes to the observed increase in IBS symptoms during menstruation. Healthy gut flora and overall gut health have a direct relationship to female hormonal health. An integrative treatment plan for IBS includes normalizing hormone levels, as well as reducing stress and inflammation. ■

Introduction

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omen have long been aware of the relationship of their menstrual cycle to nongynecologic health complaints. However, because up to 75% of women experience some recurrent premenstrual

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symptoms, there has been disagreement among medical authorities on whether to classify these nongynecologic health complaints as normal (physiologic) or abnormal. The premenstrual symptoms germane to IBS are the changes in bowel habits (abdominal pain, bloating, diarrhea and constipation) described by many healthy women, as well as those diagnosed with IBS.

Background: Menstrual Symptoms and IBS In 1990, the medical literature began to address the connection between the menstrual cycle and IBS symptoms, when Whitehead et al. (1990) reported an increase in flatulence, diarrhea, and constipation during menstruation. These findings were confirmed by Heitkemper and Jarrett (1992) two years later. In 1998, Kane, Sable and Hanauer found that a high percentage of healthy women have a premenstrual change in many bowel symptoms, but this change is more pronounced in women with IBS. Interestingly, the authors also found that patients with IBS have more extraintestinal premenstrual and menstrual complaints than controls. This is an important finding when discussing possible emotional (neurochemical) factors underlying the physiologic mechanisms for the premenstrual worsening of IBS, including changes in serotonin levels, progesterone levels, and prostaglandin production. Women with an IBS diagnosis also report a fluctuation in symptoms related to their menstrual cycle (Heitkemper & Jarrett, 2008).

EMOTIONAL FACTORS

Like PMS, the extent of the contribution of emotional factors to IBS has also been the subject of debate, with some authors even describing IBS as part of the spectrum of purely depressive disorders (Kovacs & Kovacs, 2007). In fact, stress is well known to both exacerbate symptoms of IBS in humans, and cause increased intestinal permeability in rodents (Gareau et al., 2008). Stress itself can cause increased intestinal permeability.

However, even though stress itself increases inflammation (Miller et al., 2002), when describing the premenstrual and menstrual exacerbations of IBS it is most accurate to classify stress and emotions as contributing factors, rather than the predominant factor, to the other, more significant underlying mechanisms mentioned earlier. These mechanisms will now be discussed in further

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detail, to better understand the basis for an integrative approach to premenstruation- and menstruation-exacerbated IBS.

HORMONES AND IBS

The second half, or luteal phase, of the menstrual cycle is associated with progesterone dominance relative to estrogen, with a sharp decrease of both hormones at the end of the luteal phase causing a destabilization of the endometrial lining, ending in menstruation. Because progesterone is known to have the effect of decreasing gut motility (Gonne et al., 2006), the hormonal milieu of progesterone dominance explains the clinical observation that women with IBS, as opposed to men, frequently present with constipation as the dominant IBS complaint (IBS-C).

It also explains why symptoms associated with increased motility occur immediately before and during menstruation, when progesterone levels are at their nadir. In addition, as women go through the age-related spectrum of hormonal transition of reproductive age to menopause, the hormonal shift that occurs first is a drop in luteal phase progesterone levels (Lipson et al., 1992). The gynecologic literature is filled with research attempting to explain the hormonal imbalances associated with premenstrual syndrome (PMS), and a recent Cochrane literature review on the subject (Ford et al., 2006a), found some evidence for relief with progesterone administration. This would help support the progesterone hypothesis, which states that decreasing levels of progesterone are responsible for the myriad symptoms associated with PMS. However, the trials referenced in the Cochrane review differed in route of administration, dose, and duration of treatment, as well as selection of participants. Although still a theory at this point, the progesterone hypothesis is a plausible explanation for the observed worsening of IBS symptoms seen in women with PMS (Altman et al., 2006).

INFLAMMATION AND IBS

The final mechanism to explain menstrual exacerbation of IBS is the proinflammatory state associated with menses. While all clinicians are familiar with

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the therapeutic efficacy of antiprostaglandin medications in the treatment of dysmenorrhea, further research (Wander et al., 2008) has shown that menstruation is associated with a 17% increase in C-reactive protein, a biomarker of inflammation. This shows that menstruation induces a systemic inflammatory state. Additionally, there is a documented local and systemic inflammatory cytokine release that is associated with both the tissue breakdown and progesterone withdrawal that accompanies menstruation (Critchley et al., 2001). The systemic increase in proinflammatory cytokines serves as a further explanation for the observed increase in IBS symptoms during menstruation (O’Mahony et al., 2005).

Gynecological Manifestations of IBS So far, the discussion has centered on the exacerbations of IBS that accompany the premenstrual and menstrual phases of a woman’s hormonal cycle. However, practitioners that are active in caring for women are likely to note that their patients suffering from endometriosis, chronic pelvic pain, and dysmenorrhea are more likely to also have IBS symptoms or an IBS diagnosis. In fact, one out of three women with chronic pelvic pain has IBS symptoms (Zondervan et al., 2001).

Anti-Inflammatory Therapeutic Options to Improve Gynecological Health The common underlying pathophysiologic mechanism of inflammation is the link between all of these conditions, and serves as the basis for using a broad anti-inflammatory approach (supplementing with fish oil, hops, rosemary, bromelain, turmeric, quercetin) to address both menstrual and gut symptoms (De Giorgio & Barbara, 2008). In addition, treating the underlying abnormalities in the gut—for example, by avoiding foods that create an inflammatory reaction, and supplementing with anti-inflammatory probiotics (such as Lactobacillus plantarum 299v, Lactobacillus acidophilus NCFM®, and Bifidobacterium lactis), in order to decrease gut induced inflammation—will often dramatically decrease the severity of gynecologic symptoms.

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The Gut–Gynecological Axis of Health All of the preceding relationships can be summarized as showing that hormonal changes affect gut function, both directly (progesterone mediated effects) and indirectly (inflammation mediated effects). However, the relationship between the gut and female hormonal milieus is really bidirectional. In other words, it is not just that hormonal health affects gut health, but also that gut health influences hormonal health. It is crucial for practitioners treating bowel dysfunction to be aware of this bidirectionality, because by ensuring optimal gut health in their female patients, they are not only helping them lead more comfortable lives but also helping prevent and treat common estrogenrelated disorders (endometriosis, fibroid tumors, breast cancer).

The Gut and Gynecological Hormonal Health The connection between gut health and hormonal health has its basis in the way estrogen is eliminated by the body. All of a woman’s circulating estrogen that does not bind to an estrogen receptor in estrogen-sensitive tissue (such as breast and endometrium) must be eliminated through the liver via the Phase I and Phase II detoxification pathways. It is then secreted into the bile, and dumped into the gut for elimination via stool.

Any process that impairs Phase I or Phase II detoxification, whether genetic (CYP 450 polymorphisms), environmental (increased toxic burden), or nutritional (decreased micronutrient or protein intake), will decrease estrogen elimination.

Nutritional Interventions to Improve Gynecological and Gut Health Phase II detoxification of estrogen involves the attachment, or conjugation, of other compounds to enable the estrogen molecule to be excreted in the bile and then into the gut for elimination. The most important conjugation reaction for estrogen elimination is glucuronidation, whereby a glucuronide molecule is attached to estrogen to form an estrogen glucuronide. This relates to

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gut health, in that the most common reason for impaired glucuronidation (and, therefore, reduced estrogen elimination) occurs when abnormal or unhealthy gut florae are present, as they secrete an enzyme called betaglucuronidase. This enzyme cleaves the glucuronide molecule from the estrogen-glucuronide that was sent to the gut through the bile, leaving free estrogen to be reabsorbed systemically via enterohepatic recirculation. Interventions that have been shown to improve glucuronidation include a low-animal-fat diet, and supplementation with probiotics and calcium-D-glucarate (Walaszek et al., 1997). Thus, eliminating constipation and ensuring regular bowel movements in patients with IBS now has a whole new level of importance.

Conclusions In summary, the physiological mechanisms described in this chapter associated with the luteal phase of the menstrual cycle, PMS, and menstruation, explain the observed phenomenon of IBS exacerbation during those periods. The systemic inflammation associated with chronic pelvic pain and other gynecologic disorders explains the observation of increased in IBS in those patients. Lastly, the connection between gut health and estrogen elimination demonstrates the importance that gut health has in estrogen related disorders. Therefore, a truly integrative approach to managing IBS in women, in addition to therapies targeting the gut, addresses all of these additional factors. Helping women with IBS assess and normalize hormone levels, reduce systemic and gastrointestinal inflammation, ensure healthy gut flora, and identify their stressors and resolve their interpersonal conflicts, will not only improve their IBS but will also help decrease the symptoms and incidence of the disorders associated with excess estrogen, allowing women to experience healthier and happier lives. This is the true definition of a holistic approach, and is exactly what brings joy and fulfillment to the busy lives of integrative practitioners.

10 Fibromyalgia and Gastrointestinal Disorders DAVID M. BRADY AND MICHAEL J. SCHNEIDER

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Fibromyalgia syndrome (FMS) does not appear to be a disorder of peripheral tissues, including muscle, but a dysfunction within the central nervous system (CNS) that involves the processing of sensory stimuli. Dysfunction of CNS processing of pain, and overactivity of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetics, are likely the root causes of classic FMS. 5-hydroxytryptophan, a serotonin precursor, is effective in improving the symptoms of FMS. Many studies have demonstrated a common association (comorbidity) between IBS and FMS, ranging from 30% to more than 80%. Patients with FMS frequently have nonspecific bowel complaints similar to those with small intestinal bacterial overgrowth (SIBO). Significant improvement in IBS symptoms has been reported after antibiotic treatment, including rifaximin, typically used to treat SIBO. ■

Introduction

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ibromyalgia syndrome (FMS) remains an elusive condition of unknown etiology, with a strong prevalence of overdiagnosis, in which patients report chronic widespread pain (allodynia or hyperalgesia) and a variety of