Trova il tuo prossimo libro preferito

Abbonati oggi e leggi gratis per 30 giorni
The Microbiota in Gastrointestinal Pathophysiology: Implications for Human Health, Prebiotics, Probiotics, and Dysbiosis

The Microbiota in Gastrointestinal Pathophysiology: Implications for Human Health, Prebiotics, Probiotics, and Dysbiosis

Leggi anteprima

The Microbiota in Gastrointestinal Pathophysiology: Implications for Human Health, Prebiotics, Probiotics, and Dysbiosis

Lunghezza:
1,631 pagine
153 ore
Pubblicato:
Nov 16, 2016
ISBN:
9780128040621
Formato:
Libro

Descrizione

The Microbiota in Gastrointestinal Pathophysiology: Implications for Human Health, Prebiotics, Probiotics and Dysbiosis is a one-stop reference on the state-of-the-art research on gut microbial ecology in relation to human disease. This important resource starts with an overview of the normal microbiota of the gastrointestinal tract, including the esophagus, stomach, Ileum, and colon.

The book then identifies what a healthy vs. unhealthy microbial community looks like, including methods of identification. Also included is insight into which features and contributions the microbiota make that are essential and useful to host physiology, as is information on how to promote appropriate mutualisms and prevent undesirable dysbioses. Through the power of synthesizing what is known by experienced researchers in the field, current gaps are closed, raising understanding of the role of the microbiome and allowing for further research.

  • Explains how to modify the gut microbiota and how the current strategies used to do this produce their effects
  • Explores the gut microbiota as a therapeutic target
  • Provides the synthesis of existing data from both mainstream and non-mainstream sources through experienced researchers in the field
  • Serves as a ‘one-stop’ shop for a topic that’s currently spread across a number of various journals
Pubblicato:
Nov 16, 2016
ISBN:
9780128040621
Formato:
Libro

Correlato a The Microbiota in Gastrointestinal Pathophysiology

Libri correlati
Articoli correlati

Anteprima del libro

The Microbiota in Gastrointestinal Pathophysiology - Academic Press

The Microbiota in Gastrointestinal Pathophysiology

Implications for Human Health, Prebiotics, Probiotics, and Dysbiosis

Edited by

Martin H. Floch, MD, MACG, FACP, AGAF

Clinical Professor of Medicine

Department of Internal Medicine

Section of Digestive Diseases

Yale University School of Medicine

New Haven, CT

United States

Yehuda Ringel, MD, AGAF, FACG

Department of Gastroenterology

Rabin Medical Center

Petach Tikva, Israel;

Adjunct Professor

Department of Medicine

University of North Carolina

School of Medicine at Chapel Hill

Chapel Hill, NC, United States

W. Allan Walker, MD, AGAF, FACG

Conrad Taff Professor of Nutrition and Professor of Pediatrics

Harvard Medical School

Mucosal Immunology Laboratory

Pediatric Gastroenterology and Nutrition

Massachusetts General Hospital for Children

Boston, MA, United States

Table of Contents

Cover

Title page

Copyright

Dedication

Contributors

About the Editors

Introduction

Part A: The Microbiota of the Gastrointestinal Tract

Chapter 1: The Upper Gastrointestinal Tract—Esophagus and Stomach

Abstract

Introduction

The human microbiome projects

Methods for microbial analysis and advances in sequencing technology

Advances in microbiome research in the proximal versus distal gut

The esophageal microbiome

The microbiome in esophageal diseases

Helicobacter pylori infection and its effect on the esophagus

The gastric microbiome

Impact of Helicobacter pylori infection on the composition of gastric microbiota

Cofactors in the development of Helicobacter pylori-associated gastric adenocarcinoma

Therapeutic interventions and their effect on the gastric physiology and microbiome

Conclusions and perspectives

Acknowledgments

Chapter 2: Characterizing and Functionally Defining the Gut Microbiota: Methodology and Implications

Abstract

Introduction

Microbial niches of the intestines

The 16S rRNA gene

The human microbiota in health and disease

Metagenomics of the human microbiome

Transcriptomics and proteomics of the human microbiome

16S rRNA gene sequencing data analysis

Defining microbiota function through gnotobiotics

Integrating metaomic approaches to assess the efficacy of prebiotic and probiotic interventions

Conclusions

Chapter 3: Microbiota of the Gastrointestinal Tract in Infancy

Abstract

Human microbiota

Conclusions

COI statement

Acknowledgments

Chapter 4: Identification of the Microbiota in the Aging Process

Abstract

Introduction

Gut microbiota, the hidden and forgotten organ

Age-related gastroenterological changes

Gut microbiota in the elderly

Discrepancies in elderly microbiota

Inflamm-aging

Factors influencing changes in GM in the elderly

Special problems of the older adult probably related to GM

Inflammatory bowel disease

Cancers

Alzheimer’s disease

Autoimmune diseases

IBS and gut microbiota

Drug metabolism

Probiotics and prebiotics

Summary, conclusions, projections for the future

Part B: Common Organisms and Probiotics

Chapter 5: Escherichia coli Nissle 1917

Abstract

Introduction—history

Fitness factors and probiotic mechanisms

Clinical indications and applications (Table 5.2)

Conclusions

Chapter 6: Probiotics of the Acidophilus Group: Lactobacillus acidophilus, delbrueckii subsp. bulgaricus and johnsonii

Abstract

Introduction

Lactobacillus acidophilus

Clinical trials of immunomodulation

Clinical trials in digestive diseases

Control of infectious disease

Use in necrotizing enterocolitis

Use in gynecological disorders

Use in hepatic and metabolic disorders

Lactobacillus bulgaricus

Lactobacillus johnsonii

Summary

Chapter 7: Lactobacillus rhamnosus GG

Abstract

History

Bacteriology

Antimicrobial susceptibility

Molecular basis of LGG–host interactions

Gene expression pattern in small bowel

Potential safety concerns

Clinical uses of LGG

Summary

Chapter 8: Lactobacillus reuteri

Abstract

History

Lactobacillus reuteri strains used in human trials, animal models, and in vitro studies

Phylogeny and ecology of Lactobacillus reuteri

Probiotic properties and mechanisms of action

Use of Lactobacillus reuteri as a probiotic for the prevention and treatment of human disease

Future directions and applications for Lactobacillus reuteri

Acknowledgments

Chapter 9: The Use of Lactobacillus casei and Lactobacillus paracasei in Clinical Trials for the Improvement of Human Health

Abstract

Introduction

Clinical trials employing L. casei and L. paracasei to treat digestives diseases

Control of bacterial infections

The effects of probiotics on immunity

Probiotics in the enhancement of lipid metabolism

Probiotics and cancer prevention

Interventions for depressive disorders

Conclusions

Chapter 10: Beneficial Influences of Lactobacillus plantarum on Human Health and Disease

Abstract

Introduction

Trials that report the safety of Lactobacillus plantarum as a probiotic

Lactobacillus plantarum–related trials for irritable bowel syndrome

Metaanalysis of clinical trials

Cardiovascular diseases, pancreatic diseases, and respiratory tract infections

Gynecological and iron absorption influences

Lactobacillus plantarum–induced influences on inflammation

Lactobacillus plantarum–induced influences on metabolism

Lactobacillus plantarum–induced influences on dermatological health

Conclusions

Chapter 11: Use of Bacillus in Human Intestinal Probiotic Applications

Abstract

Introduction

Use of Bacillus in food

Advantages of forming endospores

The rise in respectability of Bacillus probiotics

Transient or inhabitant?

Can an endospore former be metabolically active and be an effective probiotic?

Therapeutic outcomes associated with Bacillus probiotics

Future intestinal uses

Chapter 12: Bifidobacteria as Probiotic Organisms: An Introduction

Abstract

Chapter 13: Bifidobacterium animalis spp. lactis

Abstract

Human studies

Chapter 14: Bifidobacterium bifidum

Abstract

Characterization and laboratory studies

Clinical studies

Safety

Chapter 15: Bifidobacterium breve

Abstract

Characterization and laboratory studies

Clinical studies

Safety

Chapter 16: Bifidobacterium longum

Abstract

Characterization and laboratory studies

Clinical studies

Safety

Chapter 17: Bifidobacterium longum spp. infantis

Abstract

Immunological and physiological effects

Human studies

Conclusions

Chapter 18: Common Organisms and Probiotics: Saccharomyces boulardii

Abstract

Introduction

History

Taxonomy

Mechanisms of action

Pharmacokinetics

Clinical efficacy of Saccharomyces boulardii

Treatment of acute pediatric diarrhea

Antibiotic-associated diarrhea

Helicobacter pylori infections

Other diseases

Inflammatory bowel disease

Irritable bowel syndrome

Acute adult diarrheas

Traveler’s diarrhea

Enteral nutrition-related diarrhea

Necrotizing enterocolitis

Clostridium difficile infections

Giardiasis

Human immunodeficiency virus diarrhea

Sepsis

Acne

Hepatic function

Safety of Saccharomyces boulardii

Conclusions

Acknowledgments

Chapter 19: Common Organisms and Probiotics: Streptococcus thermophilus (Streptococcus salivarius subsp. thermophilus)

Abstract

Introduction

Taxonomy

The shaping of a species by life in milk

The ancestors of Streptococcus thermophilus

Probiotic benefits

The promise of in vitro and animal studies

Chapter 20: Complexities and Pitfalls in the Production of Multispecies Probiotics: The Paradigmatic Case of VSL#3 Formulation and Visbiome

Abstract

Claims for probiotics are product specific

Composition of probiotic products and characterization of their beneficial effects are crucial

Biosimilars—how similar is similar?

Manufacturing changes can alter product characteristics

The lately marketed product versus the original DS formulation of VSL#3—a comparison of selected parameters

Conclusions

Chapter 21: The Viruses of the Gut Microbiota

Abstract

The eukaryotic virome, a component of the gut microbiome

Interplay between gut virome and immune system

Pathogenic viruses of the gut virome: enteropathogenic viruses associated with systemic infections

Gut as a major source of neurotropic viruses, when pathogenesis and shedding is favored by humoral immune deficiency

An uncertain status for diet-derived animal viruses

Part C: Food Substrates Important to the Microbiota

Chapter 22: Dietary Fiber, Soluble and Insoluble, Carbohydrates, Fructose, and Lipids

Abstract

Introduction

High fiber plant-based diets and chronic disease risk

Dietary fiber and undigested carbohydrates

Dietary fiber and carbohydrate fermentation

Gut microbiota and diet link

Plant-based diets and gut microbiota

Gut microbiota and diet-related chronic diseases

Antibiotics, blood lipids, and gut microbiota

Fructose and the gut

Hyposucrasia

Conclusions

Funding statement

Competing interests

Chapter 23: Prebiotics: Inulin and Other Oligosaccharides

Abstract

Introduction

Definitions

Measurements

Types

Candidate Prebiotics

Conclusions

Chapter 24: The Benefits of Yogurt, Cultures, and Fermentation

Abstract

General considerations about yogurt, fermented dairy products, and probiotics

Benefits of yogurt and fermented dairy products

Yogurt and nutrient density

Yogurt and a balanced diet

Yogurt and lactose intolerance

Yogurt and weight management

Yogurt, diabetes, and metabolic health

Yogurt, heart health, blood pressure, and hypertension

Yogurt and immune function

Yogurt and digestive function

Acknowledgments

Disclaimer

Part D: Basic Physiologic Effects of Microbiota

Chapter 25: Dysbiosis

Abstract

Introduction

Dysbiosis

Causes of dysbiosis (Table 25.2)

Perinatal causes of dysbiosis

How do we approach dysbiosis in the context of disease?

Summary and conclusions

Chapter 26: Immunologic Response in the Host

Abstract

Intestinal epithelial cells

Toll-like receptors and intestinal epithelial cells

NOD receptors and intestinal epithelial cells

Immunoregulatory role of intestinal epithelial cells

Transcytosis of immunoglobulin A by intestinal epithelial cells

Antigen presentation in the gut

Role of dendritic cells

Innate lymphoid cells

T cells

Microbial modulation of immune function

Conclusions

Chapter 27: Gastrointestinal Microbiota and the Neural System

Abstract

Intestinal microbiota

Microbiota and the brain

Enteric nervous system

Microbiota and the ENS

Chapter 28: Effect on the Host Metabolism

Abstract

Introduction

Gut microbiota functions in host integrity

Gut microbiota dysbiosis impact on host metabolism

Conclusions

Chapter 29: Relationship Between Gut Microbiota, Energy Metabolism, and Obesity

Abstract

Introduction

The gut microbiota extracts energy from the diet

Regulation of fat storage through production of short-chain fatty acids

Bacterial translocation contributes to obesity and associated disorders through low-grade inflammation

The ANGPTL4 and AMPK pathways are involved in fat storage in germ-free mice

The gut microbiota presents an important hope for future treatment options in obesity

Chapter 30: Taxonomic and Metagenomic Alterations of Microbiota in Bariatric Surgery

Abstract

Introduction

Technology

Obesity and microbiota

Studies on bariatric surgery and the microbiome

Chapter 31: The Influence of Microbiota on Mechanisms of Bariatric Surgery

Abstract

The anatomic and physiologic changes that occur after bariatric surgery and how they alter the gut microbiome

Energy harvest and FXR signaling hypotheses

Lessons learned from bariatric surgery to create nonsurgical weight loss and metabolic treatments

Part E: Management of Disease and Disorders by Prebiotics and Probiotic Therapy

Chapter 32: Allergic and Immunologic Disorders

Abstract

Introduction

Gut microbiota

Microbiota modulation strategies

Clinical efficacy of probiotics/prebiotics

Prevention of allergic diseases

Treatment of allergic diseases

Synbiotics

Type 1 diabetes

Celiac disease

Conclusions

Chapter 33: Probiotics Use in Infectious Disease (Respiratory, Diarrhea, and Antibiotic-Associated Diarrhea)

Abstract

Introduction

Acute respiratory infections

Mechanisms of action

Clinical impact

Acute infectious diarrhea

Antibiotic-associated and Clostridium difficile-associated diarrhea

Necrotizing enterocolitis

Conclusions

Abbreviations

Chapter 34: FMT in Clostridium difficile and Other Potential Uses

Abstract

Introduction

Fecal microbiota transplantation

Donor selection and testing

Preparation of fecal material and delivery

Efficacy of FMT

Mechanism of FMT

Safety of FMT

FMT for other conditions

Conclusions

Chapter 35: Probiotics in the Treatment of Pouchitis

Abstract

Introduction

Probiotics in pouchitis

Conclusions

Chapter 36: Probiotic Treatment in Crohn’s Disease

Abstract

Introduction

Rationale for using probiotics in Crohn’s disease

Probiotic agents in the treatment of Crohn’s disease

Conclusions

Chapter 37: Treatment of Inflammatory Bowel Disease in Ulcerative Colitis

Abstract

Introduction

Probiotics

Active ulcerative colitis

Maintenance of ulcerative colitis

Conclusions

Chapter 38: Treatment of Functional Bowel Disorders With Prebiotics and Probiotics

Abstract

Functional bowel disorders—definitions, epidemiology, and clinical conditions

Conclusions and clinical implications of current data

Abbreviations

Chapter 39: Celiac Disease, the Microbiome, and Probiotics

Abstract

Introduction

Microbiota and celiac disease

Gluten-free diet and microbiome

CD genetics and microbiome

Prebiotics and CD

Probiotics and CD

Conclusions

Chapter 40: Probiotics for the Treatment of Liver Disease

Abstract

Dysbiosis and liver disease

Probiotics and liver disease

Cirrhosis

Conclusion and probiotics in clinical practice

Chapter 41: The Prevention and Treatment of Radiation and Chemotherapy-Induced Intestinal Mucositis

Abstract

Mucositis pathophysiology and the clinical problem

Rationale for using probiotics

Probiotics and intestinal cytoprotection in humans

Limitations of available clinical data and proposals for future studies

Prebiotics and the prevention of GI toxicity in radiotherapy

Chemotherapy and gut microbiota

Influence on probiotics on cancer therapeutics

Summary

Chapter 42: The Role of the Brain–Gut–Microbiome in Mental Health and Mental Disorders

Abstract

Components of the brain–gut axis

Examples of microbiome actions on the superorganism

Examples of human brain effects on the microbiome

Role of the gut–brain axis in specific disease states

Mood disorders

Autism

Schizophrenia

The behavioral effects of toxoplasmosis

Chapter 43: Management of Disease and Disorders by Prebiotics and Probiotic Therapy: Probiotics in Bacterial Vaginosis

Abstract

Introduction

Bacterial vaginosis

Rationale for using probiotics in bacterial vaginosis

Clinical trials on probiotics use in bacterial vaginosis

Formulations of probiotic bacteria for the treatment of bacterial vaginosis

Conclusions

Index

Copyright

Academic Press is an imprint of Elsevier

125 London Wall, London EC2Y 5AS, United Kingdom

525 B Street, Suite 1800, San Diego, CA 92101-4495, United States

50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States

The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom

Copyright © 2017 Elsevier Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library

ISBN: 978-0-12-804024-9

For information on all Academic Press publications visit our website at https://www.elsevier.com/

Publisher: Mica Haley

Acquisition Editor: Stacy Masucci

Editorial Project Manager: Sam Young

Production Project Manager: Julia Haynes

Designer: Greg Harris

Typeset by Thomson Digital

Dedication

We would like to dedicate this book to our wives, Gladys Floch, Tammy Ringel-Kulka, and Ann Sattler-Walker.

We are forever grateful for their guidance, patience, and understanding for the time we spent working on this project.

Contributors

A. Abruzzo PhD,     Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy

A. Alahmadi MBBS,     Department of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada

J.C. Arthur PhD,     Department of Microbiology and Immunology, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

G.J. Bakker MD,     Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

P. Bercik MD,     Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada

R.J. Bertelsen MSc, PhD

Department of Clinical Science, University of Bergen

Department of Occupational Medicine, Haukeland University Hospital, Bergen, Norway

R.A. Britton PhD,     Department of Molecular Virology and Microbiology, Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, United States

J.P. Burton PhD

Division of Urology, Department of Surgery/Department of Microbiology & Immunology, Western University

Lawson Health Research Institute and Canadian Centre for Human Microbiome and Probiotics, London, ON, Canada

J.S. Carr MD,     Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

I.M. Carroll PhD,     Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

R.M. Chanyi PhD

Department of Microbiology & Immunology, Western University

Lawson Health Research Institute, Canadian Centre for Human Microbiome and Probiotics Research, London, ON, Canada

R. Chibbar MD,     Department of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada

M.G. Cifone PhD,     Department of Life, Health & Environmental Sciences, University of L’Aquila, L’Aquila, Italy

B. Cinque PhD,     Department of Life, Health & Environmental Sciences, University of L’Aquila, L’Aquila, Italy

M.A. Ciorba MD,     Division of Gastroenterology, Washington University in Saint Louis, Saint Louis, MO, United States

M. Combs MS,     Department of Nutrition & Scientific Affairs, NBTY, Inc., Ronkonkoma, NY, United States

E.M. Comelli PhD,     Department of Nutritional Sciences and Center for Child Nutrition and Health, University of Toronto, Toronto, ON, Canada

T.M. Darby PhD,     Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States

L.A. Dieleman MD, PhD,     Department of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada

N.S. Ding MBBS (Hons.), FRACP,     Inflammatory Bowel Disease Unit, St Mark’s Hospital, Imperial College London, London, United Kingdom

G. Donelli PhD,     Microbial Biofilm Laboratory, IRCCS Fondazione Santa Lucia, Rome, Italy

S. Doron MD

Department of Medicine, Tufts University School of Medicine

Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA, United States

M. Ellermann PhD

Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC

Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, United States

M. Eloit DVM, PhD

Institut Pasteur, Biology of Infection Unit, Inserm U1117, Laboratory of Pathogen Discovery, Paris

Ecole Nationale Vétérinaire d’Alfort, Maisons-Alfort, France

S. Fine MD, MS,     Department of Gastroenterology, Warren Alpert School of Medicine, Brown University, Providence, RI, United States

M.H. Floch MD, MACG, FACP, AGAF,     Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States

N. Floch MD, FACS,     Department of Surgery, Norwalk Hospital, University of Vermont School of Medicine, and Quinnipiac School of Medicine Fairfield County Bariatrics and Surgical Specialists, P.C, Norwalk, CT, United States

A.A. Fodor PhD,     Department of Bioinformatics and Genomics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

M. Freitas PhD,     Health Affairs, The Dannon Company Inc., White Plains, NY, United States

S. Gorbach MD

Department of Public Health & Medicine, Tufts University School of Medicine

Division of Infectious Diseases, Tufts Medical Center, Boston, MA, United States

P.H.R. Green MD,     Celiac Disease Center, Columbia University, NY, United States

S. Guandalini MD,     Section of Gastroenterology, Hepatology and Nutrition, University of Chicago Medicine—Comer Children’s Hospital, Chicago, IL, United States

M. Guslandi MD,     Clinical Hepato-Gastroenterology Unit, Division of Gastroenterology & Digestive Endoscopy, S. Raffaele University Hospital, Milan, Italy

A. Hart PhD,     Inflammatory Bowel Disease Unit, St Mark’s Hospital, Imperial College London, London, United Kingdom

R.A. Hickman MD,     Department of Pathology, New York University School of Medicine, New York, NY, United States

K. Hod RD, MSc

Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Tel Aviv University

Research Division, Epidemiological Service, Assuta Medical Center, Tel Aviv, Israel

E. Holmes PhD,     Department of Surgery and Cancer, Division of Computational Systems Medicine, Imperial College London, London, United Kingdom

D.J.A. Jenkins MD, PhD

Clinical Nutrition & Risk Factor Modification Center, Li Ka Shing Knowledge Institute and Division of Endocrinology and Metabolism, St. Michael’s Hospital

Departments of Nutritional Sciences and Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

E.T. Jensen MPH, PhD

Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem

Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

R.M. Jones PhD,     Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States

C.R. Kelly MD,     Warren Alpert Medical School of Brown University, Miriam Hospital, and Lifespan Hospital System, Providence, RI, United States

C.W.C. Kendall PhD

Clinical Nutrition & Risk Factor Modification Center, St. Michael’s Hospital

Department of Nutritional Sciences, University of Toronto, Toronto, ON

College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada

A. Khan MD,     Department of Medicine, New York University School of Medicine, New York, NY, United States

S. Krishnareddy MD,     Celiac Disease Center, Columbia University, NY, United States

K.I. Kroeker MD,     Department of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada

C. La Torre PhD,     Department of Life, Health & Environmental Sciences, University of L’Aquila, L’Aquila, Italy

M. Lecuit MD, PhD

Institut Pasteur, Biology of Infection Unit, Inserm U1117, Laboratory of Pathogen Discovery

Paris Descartes University, Sorbonne Paris Cité

Necker-Enfants Malades University Hospital, Division of Infectious Diseases and Tropical Medicine, Paris, France

F. Lombardi PhD,     Department of Life, Health & Environmental Sciences, University of L’Aquila, L’Aquila, Italy

C. Lu MD,     Department of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada

K. Madsen PhD,     Division of Gastroenterology, The Center of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, AB, Canada

F. Magro MD

Department of Medicine, Tufts University School of Medicine

Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA, United States

P. Mastromarino PhD,     Department of Public Health and Infectious Diseases, Sapienza University, Rome, Italy

L.V. McFarland PhD,     Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA, United States

S. Mitmesser PhD,     Department of Nutrition & Scientific Affairs, NBTY, Inc., Ronkonkoma, NY, United States

A.S. Neish MD,     Department of Pathology, Emory University School of Medicine, Atlanta, GA, United States

A.G. Neto MD,     Department of Pathology, New York University School of Medicine, New York, NY, United States

M. Nieuwdorp MD, PhD

Department of Vascular Medicine, Academic Medical Center

Department of Internal Medicine, VUmc Diabetes Center, Free University Medical Center, Amsterdam, The Netherlands

Wallenberg Laboratory, University of Gothenberg, Gothenberg, Sweden

J.C. Noronha HBSc

Department of Nutritional Sciences, University of Toronto

Clinical Nutrition & Risk Factor Modification Center, St. Michael’s Hospital, Toronto, ON, Canada

C. Nossa MD,     Research & Development, Gene By Gene, Ltd., Houston, TX, United States

A. Nowak-Wegrzyn MD,     Pediatrics, Allergy and Immunology, Icahn School of Medicine at Mount Sinai, Jaffe Food Allergy Institute, New York, NY, United States

P. Palumbo PhD,     Department of Life, Health & Environmental Sciences, University of L’Aquila, L’Aquila, Italy

H. Park PhD,     Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada

Z. Pei MD,     Department of Pathology; Department of Medicine; Department of Veterans Affairs New York Harbor Healthcare System, New York University School of Medicine, New York, NY, United States

V. Philip PhD Candidate,     Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada

C.S. Pitchumoni MD,     Saint Peter’s University Hospital, New Brunswick, NJ, United States

C. Punzalan MD,     Lahey Hospital and Medical Center, Burlington, MA, United States

A. Qamar MD

Lahey Hospital and Medical Center, Burlington

Tufts University School of Medicine, Boston, MA, United States

E.M.M. Quigley MD, FRCP, FACP, MACG, FRCPI,     Lynda K and David M Underwood Center for Digestive Disorders, Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX, United States

Y. Ringel MD, AGAF, FACG

Department of Gastroenterology, Rabin Medical Center, Petach Tikva, Israel

Department of Medicine, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, NC, United States

T. Ringel-Kulka MD, MPH,     Department of Maternal and Child Health, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

N. Sansotta MD,     Section of Gastroenterology, Hepatology and Nutrition, University of Chicago Medicine—Comer Children’s Hospital, Chicago, IL, United States

M.H. Sarafian MD,     Department of Surgery and Cancer, Division of Computational Systems Medicine, Imperial College London, London, United Kingdom

A. Sarkar MD,     Rutgers, Robert Wood Johnson Medical School, New Brunswick, NJ, United States

M. Schultz PhD,     Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

J.L. Sievenpiper MD, PhD

Clinical Nutrition & Risk Factor Modification Center, Li Ka Shing Knowledge Institute and Division of Endocrinology and Metabolism, St. Michael’s Hospital

Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada

H. Szajewska MD,     Department of Paediatrics, The Medical University of Warsaw, Warsaw, Poland

G.J. Treisman MD, PhD,     Departments of Psychiatry and Behavioral Sciences and Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States

M.E. van den Rest PhD,     Biovisible, Groningen, The Netherlands

B. Vitali PhD,     Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy

C. Vuotto PhD,     Microbial Biofilm Laboratory, IRCCS Fondazione Santa Lucia, Rome, Italy

W.A. Walker MD, AGAF, FACG,     Harvard Medical School; Mucosal Immunology and Biology Research Center, Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children, Boston, MA, United States

J.M.W. Wong PhD, RD

Clinical Nutrition & Risk Factor Modification Center and Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada

New Balance Obesity Foundation Obesity Prevention Center, Boston Children’s Hospital, Boston, MA, United States

About the Editors

M.H. Floch MD, MACG, FACP, AGAF

Martin Floch is a graduate of New York University, has a Master’s Degree from the University of New Hampshire in Durham and received his MD from New York Medical College. He completed his internal medicine residency at Beth Israel Hospital in New York and his gastroenterology training at the former Seton Hall College of Medicine in South Orange, New Jersey.

He is a Master of the American College of Gastroenterology and holds their Samuel Weiss Award for service to the college. He was Associate Editor for the American Journal of Nutrition before he became Editor for the American College of Gastroenterology. Following that, he became Editor of The Gastroenterologist and is now completing his 16th year as Editor of The Journal of Clinical Gastroenterology.

Dr. Floch was Chairman of the Department of Medicine at Norwalk Hospital, a major affiliate of Yale University, from 1970 to 1994 and also had a consultation practice. He served as Director of the Yale GI clinics for a term of 5 years. While at Yale, Dr. Howard Spiro was his mentor and colleague. Dr. Floch has had several NIH Grants and has done research on Irritable Bowel Syndrome, Diverticulitis, and Probiotics. During the past decade, he has held four international Yale CME Workshop Programs on the Recommendations for Clinical Use of Probiotics, the results of which were published.

W.A. Walker MD

Allan Walker is the Conrad Taff Professor of Nutrition and Professor of Pediatrics at Harvard Medical School. After completing medical school at Washington University of St. Louis, he trained in Pediatrics and Immunology with Dr. Robert Good at the University of Minnesota before coming to Massachusetts General Hospital (Harvard Medical School) to train in Gastroenterology and Nutrition with Dr. Kurt Isselbacher. Dr. Walker joined the faculty of Pediatrics in 1971 and became Professor in 1982. He established the first Pediatric Gastroenterology Unit at Massachusetts General Hospital in 1973 and became Director of a Combined Program in Pediatric Gastroenterology at Boston Children’s Hospital and Massachusetts General Hospital in 1982. He is currently Director of Nutrition at Harvard Medical School and an Investigator in the Mucosal Immunology and Biology Research Center at Massachusetts General Hospital for Children. His research interests include the development of mucosal immune function and the role of breastfeeding, protective nutrients, and initial colonization in the ontogeny of intestinal host defense. He has received numerous honors in recognition of his research including the Shwachman Award from NASPGHAN and the Hugh Butt Award from the AGA for mucosal immunologic research and a R-37 (MERIT) Award from the National Institutes of Health for outstanding investigation in breast milk immunology. Recently, Dr. Walker’s laboratory has defined the cellular mechanism of probiotic protection in necrotizing enterocolitis.

Y. Ringel MD, AGAF, FACG

Yehuda Ringel is an Adjunct Professor of Medicine from the University of North Carolina (UNC) School of Medicine at Chapel Hill. Dr. Ringel earned his medical degree cum laude at The Technion—The Israel Institute of Technology and completed his medical residency and fellowship in Internal Medicine and Gastroenterology at Tel Aviv Medical Center in Israel. Additional training includes a Master in Internal Medicine at Tel Aviv University and a postdoctoral fellowship in functional gastrointestinal (GI) and motility disorders with Drs Douglas Drossman and William Whitehead at UNC—Chapel Hill.

Dr. Ringel has been the Director of the UNC Clinic for Functional GI Disorders and the Associate Director of the UNC Center for Functional GI and Motility Disorders and Chief of GI Division at Rabin Medical Center in Israel. Dr. Ringel has been involved in clinical and translational research for over 20 years. His research focuses on intestinal physiology and functional GI disorders and in the past few years, on the role of the intestinal microbiome and pre- and probiotics in these conditions. He was awarded grants from the National Institute of Health (NIDDK) to examine the role of the intestinal microbiome and immune function in the pathogenesis of GI symptoms. Dr. Ringel’s team has been involved with some of the largest studies characterizing the intestinal microbiota and investigating the effects of interventions targeting the microbiota in patients with functional GI disorders. He is a recipient of several prestigious awards including from the American College of Gastroenterology (ACG), the American Gastroenterology Association (AGA), and the Functional Brain–Gut Research Group (FBG).

Introduction

M.H. Floch*

Y. Ringel**,†

W.A. Walker‡,§

*    Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States

**    Department of Gastroenterology, Rabin Medical Center, Petach Tikva, Israel

†    Department of Medicine, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, NC, United States

‡    Harvard Medical School, Boston, MA, United States

§    Mucosal Immunology Laboratory, Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children, Boston, MA, United States

The modern history of the microbiota of the intestinal/gut microbiome is fascinating. The scientific world did not intensively develop its interest in this world of organisms until the national committee stimulated by Dr. Jeffrey Gordon published the paper Turnbaugh et al. that clearly showed the microbiota of the gastrointestinal tract were numerous at approximately 10¹⁴ and, in effect, were more in number than cells in the human body [1]. With this information, huge interest began to develop and it also stimulated the production and use of probiotics and prebiotics. The supplement industry is approximately $6 billion annually and it continues to grow worldwide throughout North and South America, Europe, and Asia. However, detailed and useful publications on the scientific basis and the clinical use of prebiotics and probiotics are limited. Although many of the prebiotic and probiotic industries market their products, there are few that make recommendations for use in humans. We began the Yale University Workshops which brought together noted scientists who were studying the use of prebiotics and probiotics in human conditions [2–4].

One of us, Floch, was invited by the US Army early in the 1970s to study the anaerobic flora of the gastrointestinal tract [5]. The government was concerned about what would happen, in space, to the organisms. We had laboratories financed at both Norwalk Hospital and Yale University and studied the anaerobes in various physiologic states and diseases [6].

During this period of time, several microbiologists were working in the field. Drs Renee DuBois and Russell Shadler of the Rockefeller were leaders. Drs Moore and Holdeman in Blacksburg, Virginia, developed anaerobic techniques that were used by many [7]. Initial leaders in the field were Sydney Finegold [8], Donald Luckey [9], and many others. Many publications came forth, but early in the 1980s interest decreased. It wasn’t until the 1990s and 2000s that a huge interest developed in using live organisms as probiotics. The probiotic industry became huge and is now an important industry in the world.

This book attempts to bring forward the latest information on the microbiota in humans. It is divided into four parts: (1) the general disposition of the organisms throughout the gut, (2) a detailed description of the most common probiotics organisms used today as described by Andrew Neish, Michael Schultz, Eamonn Quigley, and Sherwood Gorbach, (3) the careful functions of the microbiota and their effect on the immunopathology of the gut and the metabolism of foods by the microbiota and its use of the various nutrients on the host; and finally, (4) is devoted to the recommendations made for use of supplements in patients with possible dysbiosis.

As we noted previously, Martin Floch has worked intensively in identification of the flora. The second Editor, Yehuda Ringel, is a gastrointestinal physiologist who has intensively investigated the interaction between the gut microbiota and the neurobiology and function of the gastrointestinal tract. He also has interest and published extensively on the use of prebiotics and probiotics in patients with functional GI symptoms.

Allan Walker is renowned for his interest and knowledge in the immunologic response of the gut to the microbiota and the effect of all of its nutrients on the host responses. He brings his interest in this field to the editing of the book. He feels that early appropriate colonization when the immune system is developing is important in the expression of chronic disease, later in life.

We are extremely appreciative to the authors who have helped put these chapters together. Most of their work is unique and it adds to science of understanding the microbiome.

We are deeply grateful to the producers of the book, Elsevier, including Samuel Young and Stacy Masucci. We are also very appreciative to the persons who have helped in the administration of the book, particularly Candace Peabody who acted as the coordinator. We hope this book will be helpful as you continue to gain knowledge of the microbiome and its importance.

References

[1] Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature. 2007;449:804–810.

[2] Floch MH, Walker WA, Guandalini S, et al. Recommendations for probiotic use—2008. J Clin Gastroenterol. 2008;42:S104–S108.

[3] Floch MH, Walker WA, Madsen K, et al. Recommendations for probiotic use—2011 update. J Clin Gastroenterol. 2011;45:S168–S171.

[4] Floch MH, Walker WA, Sanders ME, et al. Recommendations for probiotic use—2015 update: proceedings and consensus opinion. J Clin Gastroenterol. 2015;49:S69–S73.

[5] Floch MH, Gorbach SL, Luckey TD. Intestinal microflora. Am J Clin Nutr. 1970;23:1425–1426.

[6] Floch MH, Wolfman M, Doyle R. Fiber and gastrointestinal microecology. J Clin Gastroenterol. 1980;2:175–184.

[7] Moore WEC, Holdeman LV. Human fecal flora: the normal flora of 20 Japanese-Hawaiians. Appl Microbiol. 1974;27:961–979.

[8] Finegold SM, Sutter VL, Sugihara PT, Elder HA, Lehmann SM, Phillips RL. Fecal microbial flora in Seventh Day Adventist population and control subjects. Am J Clin Nutr. 1977;30:1781–1792.

[9] Luckey TD. Introduction to the ecology of the intestinal flora. Am J Clin Nutr. 1970;23:1430–1432.

Part A

The Microbiota of the Gastrointestinal Tract

Chapter 1: The Upper Gastrointestinal Tract—Esophagus and Stomach

Chapter 2: Characterizing and Functionally Defining the Gut Microbiota: Methodology and Implications

Chapter 3: Microbiota of the Gastrointestinal Tract in Infancy

Chapter 4: Identification of the Microbiota in the Aging Process

Chapter 1

The Upper Gastrointestinal Tract—Esophagus and Stomach

A.G. Neto*

R.A. Hickman*

A. Khan**

C. Nossa

Z. Pei*,**,†

*    Department of Pathology, New York University School of Medicine, New York, NY, United States

**    Department of Medicine, New York University School of Medicine, New York, NY, United States

†    Department of Veterans Affairs New York Harbor Healthcare System, New York University School of Medicine, New York, NY, United States

‡    Research & Development, Gene By Gene, Ltd., Houston, TX, United States

Abstract

The human gastrointestinal microbiome represents the collective genomic aggregate of an estimated 10¹⁴ microorganisms that reside within the gut. For some time, microbiota research on the proximal gut was largely eclipsed by that of the distal gut; however, recent studies in the esophagus and stomach have shown that proximal gut dysbioses have significant consequences for disease, notably in cancer pathogenesis.

This chapter discusses the microbiota found in the esophagus and stomach, the dysbioses that can occur at these sites, as well as potential therapeutic avenues for the prevention and treatment of esophagogastric malignancy.

Keywords

microbiome

esophagus

stomach

H. pylori

Barrett’s esophagus

cancer

Introduction

The human body is host to an abundant and diverse population of microbes. Every external and internal surface of the human body that is exposed to the environment is inhabited by its own unique population of microbes. Some parts of the body that are not in direct contact with the environment are also populated with microbes. The role of the human microbiome in both health and disease ranges from negligible to crucial, and much remains undiscovered.

Some microbes inhabiting the human body are true commensals and have no noticeable effect on host physiology. Other members of the human microbiota are beneficial, providing the host with nutrients or defenses against other microbes. For example, beneficial microbes serve as a de facto metabolic organ within the host colon. Conversely, other microbes can be harmful, either by acting as acute pathogens with a range of virulence or by promoting chronic disease. While obligate and opportunistic pathogenic microbes have long been studied for their specific influence on disease, commensal microbes as causative agents of chronic disease have only recently been recognized as an important field of study.

The human microbiome projects

The microbiome had not been a main focus of study until the launch of the human microbiome projects in the last decade, specifically the National Institutes of Health (NIH) Human Microbiome Project and the International Human Microbiome Consortium [1,2]. The primary goals of these initiatives are: to determine a core human microbiome, common to all healthy individuals; to assess how this core microbiome changes during disease; and to establish whether a change in the microbiome, termed dysbiosis, is associated with disease. It was anticipated that the knowledge gained from human microbiome research would offer insight into the etiology and pathogenesis of idiopathic chronic diseases that have a serious impact on human health. Further associated with the overall aim is the characterization of all of the microbial genes within the human body, not only the species constituting the microbiome. Characterization of the human microbial metagenome has the potential to uncover the metabolic processes and pathways of microbes, decipher how they contribute to or perturb normal human health, and ultimately lead to novel treatments and techniques.

After establishing a normal core microbiota, the secondary goal of human microbiome research is to discover correlations between diseases and microbial dysbiosis. Dysbiosis is any perturbation of the normal microbiome content that could disrupt the symbiotic relationship between the host and associated microbes, a disruption that can result in diseases, such as inflammatory bowel disease and other gastrointestinal (GI) disorders, including gastritis, peptic ulcer disease, irritable bowel syndrome, and even gastric and colon cancer [3–6]. The purpose of this research is first to confirm that the correlation between dysbiosis and disease is meaningful in regard to the etiology of disease, and, if so, to then determine the molecular mechanisms of disease causation in order to tailor therapies that target the microbial dysbiosis.

Methods for microbial analysis and advances in sequencing technology

Cultivation-based methods have been the gold standard for bacterial detection, bacterial identification, and disease diagnosis, but these methods are strongly biased toward microbes that can easily be cultured in laboratory settings. The vast majority of microbes are fastidious and therefore invisible to culture-dependent analysis, because they can exist in vivo in a viable but nonculturable state, or as dormant vegetative cells with low metabolic activity [7,8]. While these techniques have advanced tremendously, cultivation-based methods are still inadequate to fully define microbial populations [9]. Cultivation-independent techniques have been developed to attempt to identify both cultivable and fastidious microorganisms by direct sequencing of the microbial DNA and then searching databases of known microbes for genetically similar organisms.

The microbial populations so far defined by cultivation-independent techniques are far more diverse than previously suspected. Thousands of bacterial species have been revealed in specific environments of microbiomes previously assumed to be dominated by a few cultivable species. Currently, most of the research into the gut microbiome focuses on members of the kingdom Eubacteria. This is due to the initial use of the 16S rRNA gene marker using primers that are specifically designed with conserved Eubacteria sequences for phylogenetic analysis. The 16S rRNA subunit sequence was chosen because it not only provides regions that serve as markers all the way down to the species level, but also provides highly conserved regions that serve as primer target regions [10–13]. While 5S and 23S rRNA subunit sequences have been evaluated as possible species-level markers, 16S has proven the most popular bacterial marker [14–16].

Along with the impetus provided by the NIH Human Microbiome Project, the introduction and commercial availability of next-generation sequencing (NGS), namely Roche 454 and Illumina pyrosequencing, contributed to the phenomenal increase in microbiome research. The sequencing capacity and reduced cost of NGS allowed researchers to increase the size and scope of relevant research projects. Previous researchers, constrained by cost, manpower, and logistics, had to limit sample sizes to at most tens of samples; NGS’s massive parallel sequencing allows for the analysis of hundreds to thousands of samples in both less time and at a lower cost. In the past decade, since the inception of the NIH Human Microbiome Project, the capacity of NGS has continued to increase, allowing for in-depth research focusing on microbial identities as well as whole microbial genomic contents. Eventually, the price of sequencing was reduced and capacity increased to the point that specific markers were no longer necessary. It is now cost-effective to sequence the entire metagenome of microbial samples, not only for microbial composition but also for gene pathways and metabolic networks. This is creating a trove of information, allowing for more insight into viral, fungal, and protozoan contributions to the microbiome.

Advances in microbiome research in the proximal versus distal gut

Among the sites within the human microbiome, research focused on the GI tract has been the most successful in uncovering microbiome-associated disease. This is especially true in the distal gut, most likely due to the relatively high biomass present as well as the easy access for sampling. This microbiome has been shown to contribute not only to potential disease, but also to normal human physiologic functioning.

Mouth to colon analyses of the gut microbiome have been published and have established the continuity and progression of the gut microbiota through the GI tract. As the microbiome was characterized from mouth to anus, it was deciphered that there are certain phyla of bacteria common throughout the GI tract, but not necessarily in constant ratios. Species diversity also varies greatly along the gut; from the proximal to the distal gut, there is a marked difference in number and diversity of bacteria [17].

Study of the proximal gut microbiome has been greatly overshadowed by the investigations of the distal gut microbiome, with the exception being the documented consequences of Helicobacter pylori colonization in the stomach. This is due partly to past findings and assumptions regarding the sterility and/or lack of diversity within the proximal gut, as well as the laborious and invasive nature of collecting samples in the esophagus and stomach, which involves endoscopic probing in a specific manner to avoid cross-site contamination. On embryological grounds, the proximal gut comprises the mouth through the esophagus, stomach and extends to the major papillae of the duodenum. The accessory organs that are regarded as being associated with the proximal gut include the liver, gallbladder, and pancreas.

Characterization of the proximal gut microbiome has improved dramatically as the use of culture-independent microbiome analysis has been facilitated by NGS technologies. Although there was already significant research on the oral microbiome, studies involving the microbiome of the esophagus and stomach were sparse; most involved few samples with very shallow characterizations. Recent publications have contributed much more in-depth characterization of the proximal gut microbiome as interest has grown about the nature of the entire human gut microbiome, providing information that is not simply extrapolated from distal gut analysis.

The esophageal and gastric microbiomes share characteristics with the well-described distal gut microbiome and with the gut microbiome as a whole. They also each have their own distinct properties. Currently, associations exist between both the esophageal and the gastric microbiomes and several chronic diseases, some of which are systemic or not localized to the upper GI tract itself. In most cases, it has not yet been determined whether these associations are causative or correlative, as research remains in the discovery phase.

The esophageal microbiome

Early studies of the normal esophageal microflora were undertaken to explore the role of bacteria in postoperative infection [18–20]. Cultivation yielded only a few bacterial species and, in many specimens, researchers were unable to detect any bacteria at all. The few microbes isolated were suspected of having been transiently deposited from either the mouth or stomach rather than being intrinsic to the esophagus [21].

This ambiguity regarding the esophageal microbiome was not sufficiently assessed until two important advances were made in early 2000s: studies of the microbiome by cultivation-independent technology, and visualization of bacteria on the esophageal mucosa using in situ staining. The first broad-range 16S rRNA gene survey revealed the consistent presence of a complex microbiota in the esophagus represented by six major phyla (Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and TM7) and dominated by the genus Streptococcus [22]. Another study successfully detected bacteria in all esophageal specimens obtained from 24 subjects [23]. Furthermore, two studies visually demonstrated the presence of bacteria in the mucosal surface using tissue Gram staining and fluorescence in situ hybridization [22,24]. These findings provided a firm foundation for the existence of a complex bacterial community in the esophagus as well as a logical basis for further exploration of its role in disease.

The recent interest in the esophageal microbiome was largely inspired by the rise in the incidence of esophageal adenocarcinoma (EAC). In the United States and Europe, squamous cell carcinoma of the esophagus comprised the vast majority of esophageal cancers until the 1970s, when the incidence of adenocarcinoma of the esophagus began to gradually increase and ultimately surpass squamous cell carcinoma as the most common esophageal cancer [25,26]. EAC is the end point of a sequence of diseases in the distal esophagus, including reflux esophagitis (RE) and Barrett’s esophagus (BE).

The incidence of EAC has increased sixfold in the United States since the 1970s, parallel to a significant increase in the prevalence of RE. Although specific host factors might predispose to disease risk, the startling increase in EAC incidence suggests a predominantly environmental cause. Our understanding of EAC is mainly derived from studies of epidemiological risk factors [27,28]. Cigarette smoking, obesity, gastroesophageal reflux disorder (GERD), and insufficient consumption of fruits and vegetables account for 39.7, 41.1, 29.7, and 15.3% of EAC, respectively, with a combined population attributable risk of 78.7% [29]. However, these factors cannot consistently explain the recent increase in EAC incidence. For instance, tobacco smoking is unlikely to have a role in more recent increases of EAC in view of the decreasing prevalence of smoking (reduced from 37.1% in 1974 to 20.1% in 2004) [30].

The microbiome in esophageal diseases

Given the lack of a known common causative risk factor for GERDs, it was hypothesized that the esophageal microbiome may be an overlooked contributor to the rise of EAC as well as RE and BE [31]. The esophageal microbiome can be classified into two types (Table 1.1). The type I microbiome, mainly associated with the normal esophagus, is a bacterial community dominated by Gram-positive bacteria from the Firmicutes phylum or Streptococcus at the genus level. The type II microbiome is found more often in patients with RE or BE. In the type II microbiome, there is a shift from Gram-positive species to Gram-negative species, specifically due to the diminishment of Streptococcus species. The decrease in Streptococcus organisms correlates with an increase in the relative abundance of 24 other genera. The most prominent increases involve Veillonella, Prevotella, Haemophilus, Neisseria, Rothia, Granulicatella, Campylobacter, Porphyromonas, Fusobacterium, and Actinomyces, many of which are Gram-negative anaerobes or microaerophiles, and are generally considered to be pathogens for periodontal disease as well. Overall, Gram-negative bacteria constitute 53.4% of the type II microbiome but only 14.9% of the type I microbiome. These observations support the hypothesis that the esophageal microbiome is altered in reflux disorders [31,32].

Table 1.1

Main Difference Between Type I and Type II Esophageal Microbiomes at the Genus Level by Relative Abundancea

a Genera with relative abundance >1% in either type I or type II microbiome are listed [31].

In one study, bacterial quantification was performed by staining specimens from esophageal disease biopsies. It was subsequently found that bacteria were detected more often in BE than in non-BE specimens. It was also discovered that metaplasia and dysplasia were both associated with increasing bacterial stain scores [31,33,34]. Remarkably, Macfarlane et al. found that the esophagus in the majority of patients with BE was colonized with Campylobacter species, specifically Campylobacter concisus and Campylobacter rectus, whereas Campylobacter was not identified in any of the control subjects in their study. Furthermore, this result was confirmed by fluorescence in situ hybridization using specific 16S rRNA oligonucleotide probes, which demonstrated that BE mucosae are colonized by Campylobacter species [24,31]. It has also been documented that C. concisus can cause potentially DNA-damaging nitrosative and oxidative stress, and when coupled with the induction of interleukin-8 (IL-8, which induces natural killer cell activity and apoptosis), this species’ colonization can increase in reflux-related esophageal disease [35]. These results further validated the previous findings by Yang et al. that the esophageal microbiome is altered in reflux disorders, specifically by an increase in Gram-negative bacteria [31]

The type II microbiome, with its larger content of Gram-negative bacteria, may also engage innate immune functions of the epithelial cells differently than the type I microbiome. A relevant explanation is that the type II microbiome produces larger amounts of Gram-negative microbe components, such as lipopolysaccharides and endotoxin [36,37]. The emptying of the stomach after a meal reduces gastric pressure, thus decreasing the opportunity for reflux. In mice treated with lipopolysaccharides, it was found that nearly 80% of food intake remains in the stomach 4 h after a meal; gastric emptying is significantly longer than in untreated mice (25% longer) [38]. The delay in gastric emptying induced by endotoxin can be blocked by pretreatment with either the nonselective cyclooxygenase (COX)-1 and -2 inhibitor indomethacin or selective COX-2 inhibition. Thus, the Gram-negative enriched type II microbiome might contribute to the development of gastroesophageal reflux by an increase in intragastric pressure caused by delayed gastric emptying.

Another factor that determines the development of pathologic reflux is the muscle tone of the lower esophageal sphincter, which serves as a gatekeeper against reflux. In a mouse model, lipopolysaccharides caused a dose-dependent fall in the basal tone. This effect can be prevented by pretreatment with the inducible nitric oxide synthase (iNOS) inhibitor l-canavanine [39]. Thus, it is speculated that the type II microbiome causes an abnormal relaxation of the lower esophageal sphincter and contributes to the etiology of GERD and EAC. The pathway involved in the induction of iNOS and COX-2 expression by Gram-negative bacteria might start with triggering Toll-like receptors (TLRs), which are expressed in human esophageal epithelial cells. TLRs are a class of membrane-spanning proteins that recognize structurally conserved molecules derived from microbes. Activation of TLRs induces nuclear translocation of nuclear factor kappa light-chain-enhancer of activated B cells (NF-κB). This, in turn, leads to the upregulation of expression of its downstream target genes involved in inflammation, including genes for iNOS and COX-2, IL-1b and IL-8, innate immune responses, adaptive immune responses, apoptosis blocking, cell proliferation, and cell differentiation [40].

Helicobacter pylori infection and its effect on the esophagus

Before discussing the effects of H. pylori in gastric conditions, it is imperative to understand its influence on the esophageal mucosa, as microbes from the stomach and esophagus have been implicated in esophageal disease. While bacterial involvement has a potentially important role in inflammation and dysplasia in the esophagus as discussed previously (i.e., Campylobacter involvement), with exposure to bacterial products eliciting inflammation through TLR signaling, gastric acid and bile acids in the reflux contents are considered the primary factors contributing to progressive esophageal inflammation [41].

An inverse association between H. pylori colonization and the risk of EAC and BE has been observed in several studies [34,41]. This has been interpreted as H. pylori having a protective function, with the assumption that the eradication of H. pylori may predispose to EAC [42]. However, an alternative explanation is that the increased use of proton pump inhibitors (PPIs), which are also part of anti-Helicobacter treatment regimens, can modify gastric and/or esophageal microbiota toward a more carcinogenic bacterial community, and the presence or absence of H. pylori is not, in itself, directly implicated in these changes. Ironically, acid-suppressive therapy with PPIs has been effective in healing gastritis and esophagitis, concurrently with the increase in EAC incidence. Gastric acid is a relevant component in the consideration of chemoprevention of EAC because (1) in gastroesophageal reflux, it causes esophageal tissue damage, which is repaired by intestinal metaplasia/dysplasia; (2) acid and bile exposure have also been shown to upregulate COX-2 expression in BE, which has been implicated in esophageal carcinogenesis; and (3) the hostile gastric juice might convert the type I microbiome into the abnormal type II microbiome by killing sensitive bacteria in the esophagus [43–46].

Conversely, complete acid suppression over a period of 6 months, as measured by 24-h pH monitoring, has been shown to decrease markers of epithelial proliferation and increase cell differentiation markers in patients with BE [46]. As well as their acid secretion–suppressive effects in patients with esophagitis and GERD, which may result in gastric bacterial overgrowth and enhanced deconjugation of bile acids, PPIs also have antiinflammatory properties [41,47]. These properties, which are independent of their acid-suppressive effects, may also contribute to their chemopreventive effect against EAC [43–46]. In patients with BE, the formation of esophageal squamous islands may be induced by long-term aggressive PPI therapy and may reduce the length of the BE segment [43–46]. However, clinical studies have been inconclusive as to whether PPIs cause regression of established dysplasia in patients with BE. These studies are limited due to a short duration of PPI therapy (<6 months), small numbers of patients with dysplasia, and short-term follow-up for disease progression [43–46].

In addition to reflux disorders, the microbiome has been examined in other diseases involving the esophagus. In eosinophilic esophagitis, Neisseria and Haemophilus in the phylum Proteobacteria, as well as Corynebacterium in the Actinobacteria phylum are enriched, while Firmicutes organisms are depleted [48,49]. Consumption of highly allergenic foods enriches Granulicatella and Campylobacter in the esophagus, suggesting that microbes may contribute to inflammation in the esophagus [48]. In HIV infection, Firmicutes species are depleted, while Proteobacteria species are enriched. Low CD4 T-cell counts are associated with invasion of the proximal gut, in particular in the stomach and duodenum, by nitrogen-fixing bacteria Burkholderia fungorum and Bradyrhizobium pachyrhizi [50]. Since these bacteria are not detected in normal controls or in HIV-infected patients with normal CD4 counts, it was suggested that the presence of these environmental bacteria reflects a loss of colonization resistance in HIV infection and that compromised immunity could be responsible for the observed invasion by the exogenous microbes.

Although microbiomes may be altered in different esophageal conditions, esophageal pathology across a variety of disease types appears to be associated with common changes in the microbiome: depletion of the dominant phylum Firmicutes and enrichment of the proinflammatory phylum Proteobacteria. To elucidate the etiological impact of these stereotypic changes on disease progression, a potential therapy could be designed to normalize the microbiome in diseased patients by increasing the relative abundance of Streptococcus [34]. Therapeutic manipulation of the altered microbiome could be achieved via the use of TLR inhibitors, probiotics, prebiotics, or antibiotics.

The gastric microbiome

Much like the esophageal microbiome, the gastric microbiome was long considered to be barren. The basic explanation was that a vibrant microbiome would struggle to exist in the hostile, acidic nature of the gastric lumen [51]. Additional factors that were perceived to be adverse to bacterial growth included the retrograde duodenal reflux of bile as well as toxic metabolites that are produced by oral bacteria [52–57]. For these reasons, which were further compounded by practical difficulties in sample collection and a lack of reliable diagnostic tests, this historical dogma persisted for many years.

With the discovery of H. pylori (a spiral shaped, ureolytic Gram-negative bacterium) colonization, it was shown that certain specialized microbes could inhabit the gastric niche. All known gastric Helicobacter species are urease positive and have flagella which provide motility. H. pylori escapes gastric elimination by two principal methods. First, H. pylori produces urease enzyme, which converts urea to ammonia, thereby neutralizing gastric acid and affording an alkaline micromilieu that can allow bacterial survival. Second, the bacterium penetrates the alkaline viscous mucous layer through its urea- and bicarbonate-mediated chemotactic motility. Through these processes, H. pylori can colonize and persist on the surface of the gastric epithelium, inducing a chronic inflammatory response within the gastric mucosa. The presence of H. pylori, which is assumed to be the major constituent of the gastric microbiota in more than half of the human population, has been shown to be important in several disease states, such as peptic ulcer disease, gastric cancer, and esophageal disease, as mentioned previously. With a primarily acidic environment, it was previously assumed that gastric species diversity would be low. However, as research advanced, it became increasingly apparent that although the overall biomass may be relatively small, the gastric microbiome is surprisingly diverse and includes numerous non-Helicobacter organisms. However, the exception is in subjects with active H. pylori colonization, wherein this scenario, most species are outcompeted by the predominant H. pylori bacteria.

Interestingly, non-Helicobacter species were discovered in the gastric lumen prior to the landmark finding of H. pylori by Warren and coworkers [58]. In particular, several acid-resistant strains of bacteria, notably Streptococcus, Neisseria, and Lactobacillus species are now considered to have originated from the oral cavity [59,60]. Currently, it is realized that at least two thirds of phylotypes found within the gastric lumen are also present within the oral cavity. Furthermore, changes in the microbiota of the oral cavity can also result in transient changes in the composition of the gastric microbiome, although the influences of these fleeting changes are generally not perceived to be significant to the host due to insufficient time to colonization within the gastric mucosa, which minimizes interaction with the host [59,61,62].

Impact of Helicobacter pylori infection on the composition of gastric microbiota

The first comprehensive gastric microbiome analysis by cloning and Sanger sequencing of bacterial 16S rRNA genes showed that most of the subjects had H. pylori present, even though not all had clinically tested positive for H. pylori [60]. In subjects who had clinically tested positive for H. pylori, it was the predominant species (72%), while in those testing negative for H. pylori its relative abundance was only 11%. The core phyla of the gastric microbiome identified in this study were Proteobacteria (representing H. pylori; 50%), Firmicutes (30%), Bacteroidetes (10%), Actinobacteria (9%), and Fusobacteria (5%). Later studies showed similar results among the core phyla [51,60]. H. pylori was found to be the most abundant phylotype (42% of all sequences obtained in the first analysis), with the next most dominant genera Prevotella (8%) and Streptococcus (6%), which are also abundant in upstream oral and esophageal microbiomes. In contrast, the healthy human stomach is dominated by Streptococcus, Prevotella, Veillonella, and Rothia followed by Fusobacterium, Haemophilus, Neisseria, Porphyromonas, Pasturellaceae, Propionobacterium, and Lactobacillus [60,63–65]. In another study, H. pylori gastritis was found to be associated with higher abundance of families Bradyrhizobiaceae, Caulobacteraceae, Lactobacillaceae, and Burkholderiaceae [66]. In patients with atrophic gastritis, there is an increased abundance of Streptococcus species and fewer Prevotella species [64]. This implies that H. pylori is the determining factor, and in the absence of it, the core stomach microbiome is more representative of those upstream in the mouth and esophagus [51].

Bacterial diversity within the stomach determined by 16S rRNA gene survey by cloning and Sanger sequencing identified more than 100 bacterial species that reside within the normal stomach [60]. A more complete survey using NGS found 276 phylotypes representing 13 phyla. This included Chlamydiae and Cyanobacteria phyla, in addition to the core phyla stated previously [51,67]. Most of the phyla within the stomach are represented by only one or two genera, which may explain the decrease of species diversity down the GI tract from the mouth. This may constitute a selection of more specialized genera for the more demanding niches found within the GI tract. As bacteria-bearing materials (i.e., food, saliva) pass through the alimentary canal, those species that cannot survive the relatively harsh environments of the esophagus and stomach may perish, while those that have evolved specializations to survive may remain and colonize, outcompeting the less well-equipped commensals [51].

Cofactors in the development of Helicobacter pylori-associated gastric adenocarcinoma

Gastric cancer is a leading cause of infection-associated cancer [68]. Although its mortality has been steadily declining since 1930, gastric cancer continues to be common in Asian countries where nearly 60% of new cases occur [69]. In the United States, its incidence rates are nearly twice in nonwhites, including African Americans, Hispanics, and Asians [70]. Among whites, rates of noncardia gastric cancer are declining in older adults but unexpectedly increasing in persons born since 1952 [71]. Colonization of H. pylori is a major risk factor of intestinal type noncardia gastric adenocarcinoma [72–74]. While nearly all patients diagnosed with gastric adenocarcinoma are infected by H. pylori some time in their life, only less than 1% of H. pylori-infected subjects eventually develop cancer for reasons unclear [75–77]. Potential cofactors include male gender, cigarette smoking, high intake of preserved food, meats, and salty food [69,78–83].

Several factors that mediate carcinogenesis in certain strains of H. pylori infection include the secretion of VacA, type IV cag secretion, and upregulation of beta-catenin within the gastric epithelium [84,85]. Host genetics also

Hai raggiunto la fine di questa anteprima. Registrati per continuare a leggere!
Pagina 1 di 1

Recensioni

Cosa pensano gli utenti di The Microbiota in Gastrointestinal Pathophysiology

0
0 valutazioni / 0 Recensioni
Cosa ne pensi?
Valutazione: 0 su 5 stelle

Recensioni dei lettori