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MICROBIAL ECOLOGY
IN STATES OF HEALTH
AND DISEASE

WORKSHOP SUMMARY

Eileen R. Choffnes, LeighAnne Olsen, and Alison Mack,
Rapporteurs

Forum on Microbial Threats

Board on Global Health

INSTITUTE OF MEDICINE
              OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.

www.nap.edu



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Eileen R. Choffnes, LeighAnne Olsen, and Alison Mack, Rapporteurs Forum on Microbial Threats Board on Global Health

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THE NATIONAL ACADEMIES PRESS  500 Fifth Street, NW  Washington, DC 20001 NOTICE: The workshop that is the subject of this workshop summary was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. Financial support for this activity was provided by the U.S. Department of Health and H ­ uman Services: National Institutes of Health, National Institute of Allergy and Infec- tious Diseases, Centers for Disease Control and Prevention, Food and Drug Administra- tion, and the Fogarty International Center; U.S. Department of Defense: Armed Forces Health Surveillance Center, Defense Threat Reduction Agency, and Medical Research and M ­ ateriel Command; U.S. Department of Justice: Federal Bureau of Investigation; U.S. Department of Veterans Affairs; U.S. Department of Homeland Security; U.S. Agency for International Development; Uniformed Services University of the Health Sciences; Alfred P. Sloan Foundation; American Society for Microbiology; Burroughs Wellcome Fund; ­ laxoSmithKline; Infectious Diseases Society of America; Johnson & Johnson; G Merck Company Foundation; and sanofi pasteur. The views presented in this publication do not necessarily reflect the views of the organizations or agencies that provided support for this activity. International Standard Book Number-13: 978-0-309-29062-3 International Standard Book Number-10: 0-309-29062-7 Additional copies of this workshop summary are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2014 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Cover images: (Front, upper) Medical illustration of methicillin-resistant Staphylococcus aureus (MRSA); (Front, lower) Medical Illustration of Clostridium difficile; (Back) Medi- cal illustration of Streptococcus pneumoniae. Photo Credits: All photos courtesy of the Centers for Disease Control and Prevention, www.cdc.gov. Suggested citation: IOM (Institute of Medicine). 2014. Microbial ecology in states of health and disease: Workshop summary. Washington, DC: The National Academies Press.

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“Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe Advising the Nation. Improving Health.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. C. D. Mote, Jr., is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examina- tion of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the ­ ational N Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. C. D. Mote, Jr., are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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PLANNING COMMITTEE FOR A WORKSHOP ON MICROBIAL ECOLOGY IN STATES OF HEALTH AND DISEASE1 ARTURO CASADEVALL, Albert Einstein College of Medicine, Bronx, New York EDUARDO GOTUZZO, Instituto de Medicina Tropical–Alexander von Humboldt, Universidad Peruaña Cayetano Heredia, Lima, Peru JO HANDELSMAN, Yale University, New Haven, Connecticut JAMES M. HUGHES, Emory University, Atlanta, Georgia DAVID A. RELMAN, Stanford University and Veterans Affairs Palo Alto Health Care System, Palo Alto, California P. FREDERICK SPARLING, University of North Carolina, Chapel Hill, North Carolina 1  Institute of Medicine planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests solely with the workshop rapporteurs and the institution. v

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FORUM ON MICROBIAL THREATS1 DAVID A. RELMAN (Chair), Stanford University, and Veterans Affairs Palo Alto Health Care System, Palo Alto, California JAMES M. HUGHES (Vice-Chair), Global Infectious Diseases Program, Emory University, Atlanta, Georgia LONNIE J. KING (Vice-Chair), Ohio State University, Columbus, Ohio KEVIN ANDERSON, Biological and Chemical Defense Division, Science and Technology Directorate, Department of Homeland Security, Washington, DC ENRIQUETA C. BOND, Burroughs Wellcome Fund (Emeritus), QE Philanthropic Advisors, Marshall, Virginia ROGER G. BREEZE, Lawrence Livermore National Laboratory, Livermore, California JOHN E. BURRIS,2 Burroughs Wellcome Fund, Research Triangle Park, North Carolina ARTURO CASADEVALL, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York ANDREW CLEMENTS, U.S. Agency for International Development, Washington, DC PETER DASZAK, EcoHealth Alliance, New York, New York JEFFREY S. DUCHIN, Public Health–Seattle and King County, Seattle, Washington JONATHAN EISEN, Genome Center, University of California, Davis, California RALPH L. ERICKSON,3 Walter Reed Army Institute of Research, Silver Spring, Maryland MARK B. FEINBERG, Merck Vaccine Division, Merck & Co., Inc., West Point, Pennsylvania JACQUELINE FLETCHER, Oklahoma State University, Stillwater, Oklahoma CLAIRE FRASER, Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland JESSE L. GOODMAN, Food and Drug Administration, Rockville, Maryland EDUARDO GOTUZZO, Instituto de Medicina Tropical–Alexander von Humboldt, Universidad Peruaña Cayetano Heredia, Lima, Peru CAROLE A. HEILMAN, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland DAVID L. HEYMANN, Public Health England, London, United Kingdom 1   Institute of Medicine forums and roundtables do not issue, review, or approve individual docu- ments. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. 2   Forum member until October 18, 2013. 3   Forum member until June 30, 2013. vi

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ZHI HONG,4 GlaxoSmithKline, Research Triangle Park, North Carolina PHILIP HOSBACH, sanofi pasteur, Swiftwater, Pennsylvania STEPHEN ALBERT JOHNSTON, Arizona BioDesign Institute, Arizona State University, Tempe, Arizona KENT KESTER,5 Uniformed Services University of the Health Sciences, Bethesda, Maryland GERALD T. KEUSCH, Boston University School of Medicine and Boston University School of Public Health, Boston, Massachusetts RIMA F. KHABBAZ, Centers for Disease Control and Prevention, Atlanta, Georgia MARK KORTEPETER,6 Uniformed Services University of the Health Sciences, Bethesda, Maryland STANLEY M. LEMON, University of North Carolina, Chapel Hill, North Carolina MARGARET J. McFALL-NGAI, University of Wisconsin, Madison, Wisconsin EDWARD McSWEEGAN, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland PAULA J. OLSIEWSKI, Alfred P. Sloan Foundation, New York, New York JULIE PAVLIN, Armed Forces Health Surveillance Center, Silver Spring, Maryland GEORGE POSTE, Complex Adaptive Systems Initiative, Arizona State University, SkySong, Scottsdale, Arizona DAVID RIZZO, University of California, Davis, California GARY A. ROSELLE, Veterans Health Administration, Department of Veterans Affairs, Cincinnati, Ohio KEVIN RUSSELL, Armed Forces Health Surveillance Center, Silver Spring, Maryland JANET SHOEMAKER, American Society for Microbiology, Washington, DC JAY P. SIEGEL,7 Johnson & Johnson, Radnor, Pennsylvania P. FREDERICK SPARLING, University of North Carolina, Chapel Hill, North Carolina MARY E. WILSON, Harvard School of Public Health, Harvard University, Boston, Massachusetts EDWARD H. YOU,8 Federal Bureau of Investigation, Washington, DC 4  Forum member until October 18, 2013. 5  Retired as of December 31, 2013. 6  Forum member since January 15, 2014. 7  Forum member since January 15, 2014. 8  Forum member since July 1, 2013. vii

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IOM Staff EILEEN CHOFFNES, Scholar and Director LEIGHANNE OLSEN,9 Program Officer KATHERINE McCLURE, Associate Program Officer REBEKAH HUTTON, Research Associate CHARLEE ALEXANDER,10 Senior Program Assistant JOANNA ROBERTS,11 Senior Program Assistant (Temp) 9  Staff member until August 15, 2013. 10   Staff member from April 1 to November 15, 2013. 11   Staff member since November 1, 2013.  viii

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BOARD ON GLOBAL HEALTH1 THOMAS C. QUINN (Chair), Associate Director for International Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Professor of Medicine, International Health, Epidemiology, and Molecular Biology and Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland JO IVEY BOUFFORD (IOM Foreign Secretary), President, New York Academy of Medicine, New York CLAIRE V. BROOME, Adjunct Professor, Division of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia JACQUELYN C. CAMPBELL, Anna D. Wolf Chair, and Professor, Johns Hopkins University School of Nursing, Baltimore, Maryland THOMAS J. COATES, Michael and Sue Steinberg Professor of Global AIDS, Research Co-Director, UC Global Health Institute, David Geffen School of Medicine, University of California, Los Angeles, California GARY DARMSTADT, Director, Family Health Division, Global Health Program, Bill & Melinda Gates Foundation, Seattle, Washington VALENTIN FUSTER, Director, Wiener Cardiovascular Institute, Kravis Cardiovascular Health Center, Professor of Cardiology, Mount Sinai School of Medicine, Mount Sinai Medical Center, New York, New York JACOB A. GAYLE, Vice President, Community Affairs, Executive Director, Medtronic Foundation, Minneapolis, Minnesota GLENDA E. GRAY, Executive Director, Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, University of the Witwatersrand, Diepkloof, South Africa STEPHEN W. HARGARTEN, Associate Dean, Global Health Program, Medical College of Wisconsin, Milwaukee, Wisconsin PETER J. HOTEZ, Professor of Pediatrics and Molecular Virology and Microbiology, Texas Children’s Hospital Endowed Chair of Tropical Pediatrics, President, Sabin Vaccine Institute and Texas Children’s Center for Vaccine Development, Dean, National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas CLARION JOHNSON, Consultant, Exxon Mobil, Fairfax, Virginia FITZHUGH MULLAN, Professor, Department of Health Policy, The George Washington University, Washington, DC OLUFUNMILAYO F. OLOPADE, Walter L. Palmer Distinguished Service Professor of Medicine, The University of Chicago, Chicago, Illinois 1  Institute of Medicine boards do not review or approve individual workshop summaries. The responsibility for the content of the workshop summary rests with the workshop rapporteurs and the institution. ix

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GUY PALMER, Regents Professor of Pathology and Infectious Diseases, Director of the School for Global Animal Health, Washington State University, Pullman, Washington IOM Staff PATRICK KELLEY, Director ANGELA CHRISTIAN, Program Associate x

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Reviewers This workshop summary has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Com- mittee. The purpose of this independent review is to provide candid and criti- cal comments that will assist the institution in making its published workshop summary as sound as possible and to ensure that the workshop summary meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the process. We wish to thank the following individuals for their review of this workshop summary: Jeffrey L. Dangl, University of North Carolina, Chapel Hill, North Carolina Maria Dominguez-Bello, New York University Langone Medical Center, New York, New York Jesse L. Goodman, Food and Drug Administration, Rockville, Maryland Margaret J. McFall-Ngai, University of Wisconsin, Madison, Wisconsin Although the reviewers listed above have provided many constructive com- ments and suggestions, they did not see the final draft of the workshop summary before its release. The review of this workshop summary was overseen by Melvin Worth. Appointed by the Institute of Medicine, he was responsible for making certain that an independent examination of this workshop summary was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this workshop summary rests entirely with the rapporteurs and the institution. xi

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xvi CONTENTS A6  Seasonal Restructuring of the Ground Squirrel Gut Microbiota Over the Annual Hibernation Cycle, 184 Hannah V. Carey, William A. Walters, and Rob Knight A7 Lessons from Studying Insect Symbioses, 207 Angela E. Douglas A8 A New Vision of Immunity: Homeostasis of the Superorganism, 224 Gérard Eberl A9 Host Defense and Immunomodulation of Mucosal Candidiasis, 249 Paul J. Fidel, Jr., and Mairi C. Noverr A10 Microbiota-Targeted Therapies: An Ecological Perspective, 273  Katherine P. Lemon, Gary C. Armitage, David A. Relman, and Michael Fischbach A11 Community Ecology and the Vaginal Microbiome, 292 Larry J. Forney and Jacques Ravel A12 Investigating Bacterial-Animal Symbioses with Light Sheet Microscopy, 323  Michael J. Taormina, Matthew Jemielita, W. Zac Stephens, Adam R. Burns, Joshua V. Troll, Raghuveer Parthasarathy, and Karen Guillemin A13 Clinical Application of Fecal Microbiota Transplantation in ­ lostridium difficile Infection and Beyond, 347 C Josbert J. Keller and Els van Nood A14 Consumption of Human Milk Glycoconjugates by Infant-Associated Bifidobacteria: Mechanisms and Implications, 356 Daniel Garrido, David C. Dallas, and David A. Mills A15 Bacteriophage Adhering to Mucus Provide a Non–Host-Derived Immunity, 383  Jeremy J. Barr, Rita Auro, Mike Furlan, Katrine L. Whiteson, Marcella L. Erb, Joe Pogliano, Aleksandr Stotland, Roland ­ olkowicz, Andrew S. Cutting, Kelly S. Doran, W Peter Salamon, Merry Youle, and Forest Rohwer A16 Topographic Diversity of Fungal and Bacterial Communities in ­ uman Skin, 401 H  Keisha Findley, Julia Oh, Joy Yang, Sean Conlan, Clayton Deming, Jennifer A. Meyer, Deborah Schoenfeld, Effie Nomicos, Morgan Park, NIH Intramural Sequencing Center Comparative Sequencing Program, Heidi H. Kong, and Julia A. Segre

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CONTENTS xvii A17 Distinct Microbial Communities Within the Endosphere and Rhizosphere of Populus deltoides Roots Across Contrasting Soil Types, 412  Neil R. Gottel, Hector F. Castro, Marilyn Kerley, Zamin Yang, Dale A. Pelletier, Mircea Podar, Tatiana Karpinets, Ed Uberbacher, Gerald A. Tuskan, Rytas Vilgalys, Mitchel J. Doktycz, and Christopher W. Schadt A18 Interactions Between Commensal Fungi and the C-Type Lectin Receptor Dectin-1 Influence Colitis, 435  Iliyan D. Iliev, Vincent A. Funari, Kent D. Taylor, Quoclinh Nguyen, Christopher N. Reyes, Samuel P. Strom, Jordan Brown, Courtney A. Becker, Phillip R. Fleshner, Marla Dubinsky, Jerome I. Rotter, Hanlin L. Wang, Dermot P. B. McGovern, Gordon D. Brown, and David M. Underhill A19 Metagenomics and Personalized Medicine, 445 Herbert W. Virgin and John A. Todd A20 From Genetics of Inflammatory Bowel Disease Towards Mechanistic Insights, 471 Daniel B. Graham and Ramnik J. Xavier A21 Antimicrobial Peptides and the Microbiome, 489 Michael Zasloff B Agenda 497 C Acronyms 501 D Glossary 503 E Speaker Biographies 513

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Tables, Figures, and Boxes TABLES WO-1 Microbial Ecology Definitions, 6 WO-2 Changes in Human Ecology That Might Affect Microbiota Composition, 79 A2-1 Changes in Human Ecology That Might Affect Microbiota Composition, 116 A3-1 Metabolic Consequences of Specified Host and Dietary Interactions with the Microbiome, 138 A6-1 Ground Squirrel Body Mass, Cecal Tissue Mass, Body Temperature, and Torpor Characteristics, 188 A6-2 Short-Chain Fatty Acid and Ammonia Concentrations and Molar Proportions of SCFA in Ground Squirrel Cecal Contents, 196 A6-3 Correlations Between SCFA Levels and Microbial Taxa in Squirrel Cecal Contents, 197 A11-1 Median Vaginal pH by Community State Types Within Ethnic Background, 302 A12-1 List of Key Parts for the Author’s Light Sheet Microscope, 330 A13-1 Donor Screening, 351 xix

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xx TABLES, FIGURES, AND BOXES A17-1 Selected Tree Dendrometric Measurements and Soil Physicochemical Characteristics for Bottomland and Upland Sites, 414 A20-1 Candidate IBD Genes, 479 Figures WO-1 Model for early colonization, 8 WO-2 Illustration of the chemical communication that exists between plant roots and other organisms in the complex rhizosphere, 10 WO-3 Host–microbe systems biology, 11 WO-4 Monoassociation with zebrafish gut bacterial isolates elicits a wide range of neutrophil influx, 12 WO-5 The gut microbial community composition changes over developmental time, 14 WO-6 Positive and negative selection of colonizing microbial species in the gut, 14 WO-7 The dynamic interfaces that exist between plants, microbes, and the environment, 16 WO-8 Constructed communities based on functional diversity, 18 WO-9 The ancestry of humans reflected in the genomic signature, 19 WO-10 The metabolic network of Buchnera aphidicola APS1, illustrating the flow of carbon from the main precursors to essential amino acids, 21 WO-11 Annual cycles of body temperature, gut morphology, and feeding behavior, 22 WO-12 Compositional differences in the microbiota by anatomical site, 24 WO-13 The development of the microbiota from the first inoculum as an infant through continued change, modified by diet, genetics, and environment, throughout life, 28 WO-14 The continuum of microbial states and immune responses: a dynamic equilibrium, 32 WO-15 The intestinal mucosa in states of health and disease, 34 WO-16 Physiological differences observed between the ancient (H. pylori– colonized) stomach and the postmodern (H. pylori–free) stomach, 36 WO-17 Bacterial diversity increases with age in populations from distinct cultural traditions, 38 WO-18 Factors modifying mother-to-child microbial transmission, 39 WO-19 Influence of birth cohort on risk of breast cancer among BRCA-1 and BRCA-2 mutation carriers, 41 WO-20 Phylogenetic surveys of the vaginal microbiome of healthy women identified five distinct clusters, 43 WO-21 Epithelial cell sensitivity—organism threshold hypothesis, 46

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TABLES, FIGURES, AND BOXES xxi WO-22 Potential consequences of commensal-specific memory T cells, 49 WO-23 Chronic viral infections in humans, 50 WO-24 The Bacteriophage Adherence to Mucus Immunity model, 54 WO-25 Worldwide Crohn’s disease incidence rates and/or prevalence for countries reporting data before 1960, from 1960 to 1979, and after 1980, 57 WO-26 Bacterial phyla identified in the human gut microbiota, 58 WO-27 IBD as a multifactorial disorder, 60 WO-28 Potential mechanisms of NKT cell control in mucosal tissues by commensal microbiota during early life, 61 WO-29 Proposed metabolic roles of the gut microbiome in IBD, 63 WO-30 Therapeutic modulation of the gut microbiota: from the cradle to the grave, 66 WO-31 Natural products with medicinal relevance, 67 WO-32 Genomics can reveal cryptic natural products, 69 WO-33 The secreted anti-infective protein/peptide arsenal of innate immunity, 70 WO-34 Wound healing in a severely wounded bottlenose dolphin, 72 WO-35 Atopic dermatitis (AD) progression hypothesis, 74 WO-36 Fecal microbiota transplantation for patients with recalcitrant Clostridium difficile infection, 75 WO-37 Rates of cure without relapse during 10 weeks of follow-up for recurrent Clostridium difficile infection, 76 A1-1 Commensal-specific T cells at homeostasis and during infection, 97 A1-2 Potential consequences of commensal-specific memory T cells, 102 A2-1 The effect of maternal status on the resident microbiota of the next generation, 117 A2-2 Helicobacter pylori prevalence in the United States by age and year of birth, 119 A2-3 Interactions between host and microbiota, 120 A3-1 Pathways in microbe-induced obesity, 132 A3-2 Pathways involving microbiome and immunity that contribute to obesity, 133 A3-3 Response of r- and K-selected species to environmental stress, 134 A3-4 Microbial equilibrium and host effects in relation to energy substrates, 135 A4-1 Intestinal bacteria-dependent accumulation of colonic iNKT cells in GF mice leads to high mortality in oxazolone-induced colitis, 155 A4-2 Microbial colonization during early life prevents the CD1d/iNKT cell- dependent high mortality in oxazolone colitis in GF mice, 157

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xxii TABLES, FIGURES, AND BOXES A4-3 The increased CD1d/iNKT cell-mediated allergic response sensitivity of GF mice is dependent on age of colonization, 159 A4-4 Microbiota affects tissue specific iNKT cell accumulation by genetic modifications of Cxcl16, 160 A5-1 Alternative community assembly scenarios could give rise to the compositional variations observed in the human microbiota, 168 A5-2 Disturbance can be illustrated using a stability landscape schematic, 173 A6-1 Principal coordinate analysis plots of unweighted UniFrac metrics for squirrel microbiotas, 187 A6-2 Alpha diversity rarefaction plots of squirrel cecal microbiotas, 192 A6-3 Phylogenetic trees of squirrel cecal microbiotas colored by seasonal taxa, 193 A6-4 Relative abundance of major taxa in squirrel cecal microbiotas, 194 A6-5 Schematic illustrating major changes in the ground squirrel gut microbiota over the annual hibernation, 198 A7-1 The insect IMD pathway and persistence of resident microorganisms, 211 A7-2 Coevolution of amino acid biosynthesis in plant sap–feeding insects and their bacterial symbionts, 219 A8-1 The superorganism, 230 A8-2 The dualistic and the continuum models of the microbial and immunological worlds, 234 A8-3 The continuum of microbial states and immune responses: a dynamic equilibrium, 237 A9-1 OPC: Protection, susceptibility, and results of treatment with ART/PI or IFN-g, 256 A9-2 Schematic diagrams representing the mechanism for the effects of vaginal S100 alarmins on PMN migration during VVC, 262 A9-3 Proposed model of immunopathogenesis of Candida-associated denture stomatitis, 266 A10-1 Microbial communities as networks, 278 A10-2 New opportunities in treatment and diagnostics, 280 A10-3 Microbiota-targeted therapy can shift a community to a healthier stable state, 281 A11-1 Heat map of log10 transformed proportions of microbial taxa found in the vaginal bacterial communities of 394 women of reproductive age, 298

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TABLES, FIGURES, AND BOXES xxiii A11-2 Representation of vaginal bacterial community groups within each ethnic group of women, 300 A11-3 Contribution of ethnicity to each of the five vaginal community groups expressed as percentage, 300 A11-4 Relationships among vaginal bacterial communities visualized by principal component analysis in which the relative abundances are expressed as proportions of the total community and displayed in three-dimensional (3-D) space, 304 A11-5 Assignment of vaginal community state types, 306 A11-6 Dynamics of vaginal community state types in 32 women over 16 weeks, 307 A11-7 Graphical representation of community state type transitions observed between all consecutive pairs of time points (905 transitions) and their frequencies among all women, 309 A11-8 Heat maps and interpolated bar plots of phylotype relative abundance observed in four selected subjects over 16 weeks, 310 A11-9 Temporal dynamics of vaginal bacterial communities in two women over 16 weeks, 311 A11-10 Modeling the dependence of the log of Jensen-Shannon divergence rate of change over the menstrual cycle, 313 A12-1 A zebrafish larva at 7 dpf (days post-fertilization), 327 A12-2 Schematic illustrations of fluorescence imaging techniques, 328 A12-3 Schematic illustration of our light sheet microscope setup, 330 A12-4 Colonization of a larval zebrafish gut by GFP-expressing and dTomato-expressing Aeromonas veronii bacteria, 334 A12-5 Fluorescently labeled enteroendocrine cells in a larval zebrafish gut, 337 A12-6 Population distributions as a function of time for the two coinoculated bacterial populations illustrated in Figure A12-4, 339 A12-7 Image auto- and cross-correlations, 340 A14-1 Structural diversity of glycans in human milk and corresponding glycosyl hydrolases in infant-gut associated bifidobacteria, 359 A14-2 Clusters of genes in B. infantis ATCC 15697 with assigned or putative functions in the utilization of milk glycans, 364 A15-1 Phage adhere to cell-associated mucus layers and mucin glycoprotein, 386 A15-2 Effect of phage adsorption on subsequent bacterial infection of epithelial cells, 389 A15-3 Effect of Hoc protein on phage–mucin interactions, 391 A15-4 Hoc-mediated glycan binding and Hoc-related phylogeny, 392 A15-5 The BAM model, 394

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xxiv TABLES, FIGURES, AND BOXES A16-1 Relative abundance of fungal genera and Malassezia species at different human skin sites, 404 A16-2 Median richness of fungal and bacterial genera, 406 A16-3 Forces that shape fungal and bacterial communities, 407 A16-4 Clinical involvement alters shared fungal community structure, 408 A17-1 Rarefaction curves for bacterial OTUs, clustering at 97% rRNA sequence similarity, 421 A17-2 Rarefaction curves for fungal OTUs, clustering at 95% rRNA sequence similarity, 422 A17-3 Bacterial classifications using the RDP classifier at 80% identity as implemented in mothur, shown at the phylum level except for Proteobacteria, which are classified by class, 423 A17-4 Fungal sequence classifications as identified from a consensus among the top BLAST scores against the SILVA LSU database, 424 A17-5 Principle coordinate analysis of bacterial and fungal communities, based on Fast UniFrac analysis, 425 A17-6 Heat map and hierarchical cluster analysis based on the relative abundances of the top OTUs identified in >5 samples in the bacterial and fungal data sets, 426 A18-1 Commensal fungi are present in the intestine and are recognized by Dectin-1, 437 A18-2 Dectin-1 regulates the severity of colitis, 439 A18-3 Defining the fungal microbiome and characterizing the specific role of Dectin-1–mediated host defense during colitis, 440 A18-4 Anti-fungal therapy ameliorates colitis in Clec7a−/− mice and CLEC7A associates with ulcerative colitis severity in humans, 442 A19-1 Perfect storms for developing Crohn’s disease and type 1 diabetes, 448 A19-2 Refining the relationship between genotype and phenotype in complex inflammatory diseases, 451 A19-3 The iterative redefinition of mechanism-based disease subtypes, 454 A19-4 Microbe plus gene interactions determine inflammatory bowel disease phenotypes, 457 A19-5 A metagenetic view of developing normal and pathological immune responses, 458 A20-1 From genetics to disease mechanisms, 473 A20-2 Inflammatory bowel disease (IBD) pathways and key cell types, 478 A20-3 Molecular pathogenesis of inflammatory bowel disease (IBD): assembling the evidence, 482

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TABLES, FIGURES, AND BOXES xxv Boxes WO-1 Human Microbiome Research Projects, 27 A2-1 The Human Microbiome Project, 112 A2-2 What Is a Pathogen?, 113 A2-3 The Gastric Microbiome, 118 A8-1 Definitions, 228 A8-2 Predictions, 231 A19-1 Definition of Terms, 447 A20-1 Key Genes Implicated in IBD, 479

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