The Microbiome in Health, Disease, and Therapeutics: Bugs, Guts and Drugs

The Microbiome in Health, Disease, and Therapeutics: Bugs, Guts and Drugs

Friday, October 4, 2013

The New York Academy of Sciences

Presented By

 

The host of microorganisms inhabiting the human body, or microbiome, plays essential roles in both health and the pathogenesis and resolution of disease. Symbioses between humans and the microbiome influence broad aspects of human biology including nutrition, immune function, and even brain development. Altered microbial community profiles are associated with a variety of chronic diseases such as inflammatory bowel disease, allergic conditions, obesity, and psychiatric and neurological disorders. The microbiome influences therapeutic interventions: metabolism of drugs by both intestinal bacteria and enterocytes, leading to systemic absorption may provide valuable insights into pre-systemic drug metabolism, delivery, and toxicity. A better understanding of the metabolic pathways may aid in drug development and toxicity evaluation processes. The microbiome itself may be a target of, or tool for new therapeutic strategies for diseases as diverse as irritable bowel syndrome, and Parkinson’s disease. This symposium reviews the basic biology of the human microbiome symbiosis and its systemic effects, the impact of the gut microbiome on drug metabolism, the opportunities offered by the microbiome for new drug development, and the essential role played by the microbiome in a variety of disease states.

*Reception to follow.

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Agenda

* Presentation titles and times are subject to change.


October 4, 2013

8:00 AM

Registration and Continental Breakfast

8:30 AM

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
Robert Martone, Covance Biomarker Center of Excellence

8:45 AM

The Human Microbiome Project
Lita M. Proctor, PhD, National Human Genome Research Institute, NIH

9:25 AM

Host-Microbiome Metabolic Interactions
Jeremy K. Nicholson, FMedSci, Imperial College London

10:05 AM

Coffee Break

10:40 AM

Interactions Between the Intestinal Microbiota and the Brain
Stephen M. Collins, MBBS, McMaster University, Ontario, Canada

11:20 AM

Host Microbial Interactions in Health and Disease
David Artis, PhD, University of Pennsylvania

12:00 PM

Building a Systems-Level Understanding of Microbiome Involvement in Disease
Dirk Gevers, PhD, The Broad Institute of MIT and Harvard

12:40 PM

Lunch break and poster session (Poster presenters to stand by posters 1:10–1:40 PM)

1:40 PM

A Gene-to-Molecule Approach to the Discovery and Characterization of Natural Products
Michael A. Fischbach, PhD, University of California, San Francisco

2:20 PM

Learning from Host–Microbiome Interactions for Development of the Next Generation of Therapeutics
Nilufer Seth, PhD, Pfizer Global Research and Development

3:00 PM

Coffee Break

3:30 PM

Development of a Therapeutic from Immunomodulatory Human Commensal Bacteria
Joseph A. Murray, MD, Mayo Clinic

4:10 PM

Moving from Microbiome Causality to Novel Drug Discovery in Metabolic Disease
Peter S. DiStefano, PhD, Second Genome, Inc.

4:50 PM

Short presentations: Selected presenters

5:00 PM

Networking Reception

6:00 PM

Close

Speakers

Organizers

Mercedes Beyna, MS

Pfizer Global Research and Development

Mercedes Beyna is a scientist in the Neuroscience Research Unit at Pfizer. Her research focuses on target identification and assay development in the areas of psychiatric as well as neurodegenerative disorders. Captivated by neuroscience, she has worked in the field for over 10 years, in both academic and industrial laboratory settings. Before joining pharmaceutical R&D, Mercedes held lab manager and senior lab technician positions at New York University (NYU). Mercedes attended Binghamton University, earning her undergraduate degree in Biology, and subsequently received her Master's Degree in Biology from NYU. As the Pfizer lead in the Biochemical Pharmacology Discussion Group at the New York Academy of Sciences, she enjoys developing interesting and educational symposia.

Robert Martone

Covance Biomarker Center of Excellence

Robert Martone is Neuroscience Therapeutic Area Lead for the Covance Biomarker Center of Excellence. He has extensive experience in the pharmaceutical industry leading neuroscience drug discovery and technology teams through all phases of discovery from target identification through clinical trials with expertise in both small molecule and protein therapeutics. He also has several years of academic research experience in molecular neurobiology, with a focus on the molecular genetics of familial neuropathies, and CNS tumor biomarker development.

Nilufer Seth, PhD

Pfizer Global Research and Development

Nilufer Seth is a scientist in the Host-Microbiome Interactions group in the Immuoscience Research Unit at Pfizer. She received her PhD from Medical College of Augusta, Augusta, Georgia in 1999 and joined the Dana-Farber Cancer Institute for post-doctoral training. Her research focused on ex vivo isolation and study of pathogenic CD4 T cells from individuals with infections or autoimmune disease. She studied human HIV and HCV antigen-specific T cells and antigen-specific CD4 T cells from NOD mice using a novel method she developed to generate MHC class II tetramers. In 2007 she joined the Department of Inflammation and Immunology in Wyeth where she worked on programs that were targeting inflammatory cytokines and other therapeutic mechanisms targeting B and T cells. Currently at Pfizer she is part of a group that is dedicated to discovering medicines that will reshape the treatment of inflammatory and autoimmune diseases by harnessing strategies and pathways used by the human gut microbiota to maintain immune homeostasis.

Richard Snyder, MS

Covance Biomarker Center of Excellence

Richard Snyder is the Assay Development Group Lead for the Covance Biomarker Center of Excellence. He has extensive experience in de novo immunoassay development on most commercial platforms. Additionally, he has several years of industry experience in therapeutic drug monitoring assay development for in vitro diagnostic use, as well as several years of academic research experience in high-throughput genetic analysis focused on metabolic bone disorders.

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

David Artis, PhD

University of Pennsylvania

Dr Artis completed his doctoral research training at the University of Manchester, UK focusing on regulation of immunity and inflammation in the intestine. Following receipt of a Wellcome Trust Prize Traveling Fellowship, he undertook his fellowship training at the University of Pennsylvania where he continued his research training in examining the regulation of immune responses at barrier surfaces. Dr Artis joined the faculty at Penn in 2005 and became an Associate Professor of Microbiology in 2010. Dr Artis has developed a research program focused on dissecting the pathways that regulate innate and adaptive immune cell function at barrier surfaces in the context of health and disease. His research program also encompasses a significant effort to translate research findings in pre-clinical models into patient-based studies of immune-mediated diseases. Dr Artis is funded by NIH, CCFA and BWF and has been the recipient of Young Investigator Awards from AAI, CCFA and ICIS, the Colyton Prize, the Stanley Cohen Prize and the AAI-BD Biosciences Investigator Award.

Stephen M. Collins, MBBS

McMaster University, Ontario, Canada

Dr Collins obtained his medical training at University College and Westminster Hospital London UK. He trained in gastroenterology at McMaster University in Canada before completing 3 years of research training in cell biology at the Digestive Diseases Branch, National Institutes of Health (NIH) in Bethesda, Maryland USA. He has been a staff gastroenterologist at McMaster University since 1981 and is currently the Associate Dean for Research. His research focuses on the roles of microbes in the initiation and maintenance of functional gastrointestinal disorders, and on interactions between the intestinal microbiome and the gut-brain axis.

Peter S. DiStefano, PhD

Second Genome, Inc.

Dr. DiStefano is Senior Vice President of Research and Development at Second Genome. He has over 25 years of experience in pharma and biotech, holding several positions in drug discovery and development. From 2001–2011 he was Chief Scientific Officer and Sr. VP of R&D at Elixir pharmaceuticals, transforming the science of aging platform into a metabolic disease clinical pipeline. Prior to that he was Sr. Director of Neurobiology at Millennium Pharmaceuticals (1997–2010). From 1991–1997 he was Sr. Staff Scientist at Regeneron Pharmaceuticals. Dr. DiStefano started his career at Abbott Laboratories (1986–1991) in Neuroscience Drug Discovery. In 2010 he founded Acylin Therapeutics, Inc., a biotech start-up company in Seattle, WA focused on cancer therapies. He currently serves on the Board of Directors at Acylin. Dr. DiStefano received his undergraduate degree in Biology from Kenyon College and his PhD in Pharmacology from Upstate Medical Center in Syracuse. He did his post-doctoral training in Pharmacology at Washington University in St. Louis. He has co-authored over 100 manuscripts, reviews and book chapters, is a co-inventor on 12 issued patents and has taken 8 drugs into clinical development.

Michael A. Fischbach, PhD

University of California, San Francisco

Michael Fischbach is an Assistant Professor in the Department of Bioengineering and Therapeutic Sciences at UCSF and a member of the California Institute for Quantitative Biosciences (QB3). Fischbach is a recipient of the NIH Director's New Innovator Award, a Fellowship for Science and Engineering from the David and Lucille Packard Foundation, a Medical Research Award from the W.M. Keck Foundation, and the Young Investigator Grant for Probiotics Research from the Global Probiotics Council. His laboratory uses a combination of genomics and chemistry to identify and characterize small molecules from microbes, with an emphasis on the human microbiome. Fischbach received his Ph.D. in chemistry from Harvard in 2007, where he studied the role of iron acquisition in bacterial pathogenesis and the biosynthesis of antibiotics. Before coming to UCSF, he spent two years as an independent fellow at Massachusetts General Hospital coordinating a collaborative effort based at the Broad Institute to develop genomics-based approaches to the discovery of small molecules from microbes. Fischbach is a member of the scientific advisory boards of Second Genome, Reckitt Bensicker, and Warp Drive Bio, and a consultant for Achaogen, Bayer CropScience, and Genentech.

Dirk Gevers, PhD

The Broad Institute of MIT and Harvard

Dirk Gevers joined the Broad Institute in early 2008 as a computational biologist shortly after the National Institutes of Health funded four major US Microbial Sequencing Centers to take on the Human Microbiome Project, an ambitious initiative to understand the microorganisms that live in and on humans. Within this large-scale metagenomics project, he has spearheaded the development of high-throughput capabilities for processing, organizing, and interpreting metagenomic datasets that enable a comprehensive examination of microbial communities.

In 2010, Gevers was appointed group leader of Microbial Systems and Communities in the Genome Sequencing and Analysis Program. Together with his colleagues and collaborators, he is taking on several projects that bring together advanced sequence-based technologies and novel bioinformatic tools to characterize the vast complexity of the human microbiome in both health and disease.

Gevers received his PhD in biochemistry from Ghent University, Belgium, in 2002 and has completed postdoctoral training at Ghent and at MIT in bioinformatics, comparative and evolutionary genome analysis, and microbial ecology.

Joseph A. Murray, MD

Mayo Clinic

Born in Ireland, Dr. Murray attended medical school at the National University of Ireland in Galway (1983–1984) followed by internal medicine training at Trinity College in Dublin (1984–1986) and internal medicine and gastroenterology training at Beaumont Hospital in Dublin (1986–1988). He further trained at the University of Iowa as a Fellow in Gastroenterology and Hepatology (1988–1990), and earned his Doctorate of Medicine by thesis from the National University of Ireland in Galway in 1992. Dr. Murray was on the faculty of the University of Iowa from 1990-1998, attaining the rank of Associate Professor of Medicine. In 1998, he joined Mayo Clinic in Rochester, MN and is a consultant in the Division of Gastroenterology and Hepatology and the Department of Immunology. He was appointed Professor of Medicine in 2004 and designated a research Clinician Investigator in January 2010. Dr. Murray has a strong background and experience in basic and clinical gastroenterology, focusing primarily on celiac disease and immune-related disorders of the small intestine. Dr. Murray is a member of many national/international professional scientific committees and review boards, including membership in the Gastrointestinal Mucosal Pathobiology Study Section of the National Institutes of Health. He has served on editorial boards of several journals and is a senior associate editor for the American Journal of Gastroenterology. He is the author/co-author of more than 235 scientific publications and 33 chapters. His work is funded by the NIH, private foundations and commercial entities. He is president of the North American Society for the Study of Celiac Disease, a fellow of the American Gastroenterologic Association and American College of Gastroenterology and a member of American Association of Immunology, American Motility Society, and serves on advisory boards for lay support groups and consults with several companies on the topic of celiac disease. His current work spans basic and translational research in the realm of celiac disease focusing on immunology, genetics of the disease and immune responses to food proteins.

Jeremy K. Nicholson, FMedSci

Imperial College London

Professor Nicholson obtained his PhD from London University (1980) and after numerous London University appointments (Full Professor, 1992), he became Head of Biological Chemistry at Imperial College London (1998) and then Head of the Department of Surgery and Cancer (2009). He is the Director of the MRC-NIHR National Phenome Centre and the Imperial-Institute of Cancer Research joint Centre for Systems Oncology. Professor Nicholson has authored over 500 peer-reviewed papers on molecular aspects of complex system failure and molecular spectroscopy. He leads the Imperial Biomedical Research Centre and AHSC research programmes in Stratified Medicine for optimising translational medicine for patient safety and healthcare delivery. His research has been recognised by awards such as: The Royal Society of Chemistry Silver (1992) and Gold (1997) Medals for Analytical Science and Chemistry respectively; The UK Chromatographic Society Jubilee Medal (1994); Pfizer Prize for Chemical and Medicinal Technology (2002); RSC medal for Chemical Biology (2003); The RSC Interdisciplinary Prize (2008); The RSC Theophilus Redwood Lectureship (2008); The Pfizer Global Research Prize for Chemistry (2006); The NIH Stars in Cancer and Nutrition Distinguished Lecturer (2010) and The Semelweiss-Budapest Prize for Biomedicine (2010). He is a Fellow of The Royal College of Pathologists, The Royal Society of Chemistry, The Society of Biology and The British Toxicological Society. In 2010 he was elected Fellow of The UK Academy of Medical Sciences. In 2012 he was elected as the first Honorary Fellow of the Metabolomics Society and in 2013 an Honorary Member of the US Society of Toxicology. He currently holds honorary professorships at 8 Universities including two Institutes of the Chinese Academy of Sciences and is a founder director of Metabometrix, an Imperial College spin-off company (founded 2001) specializing in molecular phenotyping, clinical diagnostics and toxicological screening.

Lita M. Proctor, PhD

National Human Genome Research Institute, NIH

Lita M. Proctor received her PhD in Oceanography from State University of New York - Stony Brook. She was a National Science Foundation Postdoctoral Fellow in the Department of Microbiology and Molecular Genetics at the University of California, Los Angeles. Her first appointment was in the Department of Oceanography, Florida State University and her second appointment, at the Institute of Marine Sciences, University of California, Santa Cruz.

Beginning in 2002, Dr. Proctor served as a program director at the National Science Foundation in both the Geosciences and the Biosciences Directorates, where she managed a wide range of microbiological, ecological, research resources and bioinformatics extramural research programs. Dr. Proctor joined the National Human Genome Research Institute at NIH, where she is responsible for oversight and coordination of the Human Microbiome Project (HMP), an 8-year, $194M trans-NIH Common Fund Initiative to create a community resource for this field.

Dr. Proctor is a member of the American Society for Microbiology, the International Human Microbiome Consortium and the Genome Standards Consortium. She also serves as a National Children's Study Scholar and chairs the trans-NIH Microbiome Working Group. She is an author or co-author of over 25 peer-reviewed scientific publications.

Nilufer Seth, PhD

Pfizer Global Research and Development

Nilufer Seth is a scientist in the Host-Microbiome Interactions group in the Immuoscience Research Unit at Pfizer. She received her PhD from Medical College of Augusta, Augusta, Georgia in 1999 and joined the Dana-Farber Cancer Institute for post-doctoral training. Her research focused on ex vivo isolation and study of pathogenic CD4 T cells from individuals with infections or autoimmune disease. She studied human HIV and HCV antigen-specific T cells and antigen-specific CD4 T cells from NOD mice using a novel method she developed to generate MHC class II tetramers. In 2007 she joined the Department of Inflammation and Immunology in Wyeth where she worked on programs that were targeting inflammatory cytokines and other therapeutic mechanisms targeting B and T cells. Currently at Pfizer she is part of a group that is dedicated to discovering medicines that will reshape the treatment of inflammatory and autoimmune diseases by harnessing strategies and pathways used by the human gut microbiota to maintain immune homeostasis.

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Nature

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The Biochemical Pharmacology Discussion Group is proudly supported by




Mission Partner support for the Frontiers of Science program provided by Pfizer

Abstracts

The Human Microbiome
Lita M. Proctor, PhD, National Human Genome Research Institute, NIH

We humans are host to a vast number and diversity of microbial life — bacteria, viruses and fungi — which along with their genes and genomes we now call the human microbiome. Though we have known for centuries that microbes are a part of the human body, the extent and complexity of these microbial communities, their natural history and the crucial roles they play in human health is only just being recognized. The NIH Human Microbiome Project (HMP) is an 8-year, $194M program to produce microbiome data, computational tools and scientific approaches as community resources to support this emerging field. An overview of the HMP and other NIH-supported human microbiome studies will provide the audience with a broad understanding of the human microbiome and its role in human health and disease.
 

Host-microbiome metabolic interactions
Jeremy K. Nicholson, Imperial College London

Symbiotic supra-organismal interactions greatly increase the degrees of freedom of the metabolic system that poses a significant challenges to fundamental notions on the nature of the human diseased state, the aetiopathogenesis of common diseases and current systems modelling requirements for personalized medicine. Metabolic phenotyping offers an important window on systemic activity and both advanced spectroscopic and mathematical modelling approaches can be used to characterize disease processes and responses to therapy (1). There is now wide recognition that the extensive metabolic cross-talk and signalling between the host and the symbiotic gut microbiome links to both to responses to therapy in individuals and disease risk factors in populations (2,3). Furthermore the recognition that transgenomic axes can be modulated via chemical and biological methods (4) may lead to a profound alteration to the concept of the druggable genome and with it greatly extend the range of interventional options for many common diseases.
 
1. Nicholson, J.K. et al (2012) Nature 491 384-392.
2. Swann, J.R. et al (2011) PNAS 108 4523-4530.
3. Nicholson, J.K. et al (2012) Science 336 1262- 1267.
4. Holmes et al (2012) Science Translational Medicine 4, 137rv6.
 

Interactions Between the Intestinal Microbiota and the Brain
Stephen M. Collins, McMaster University

Recent studies indicate that the intestinal microbiota influence brain development and behavior. Germ free mice display abnormal behavior and altered brain chemistry that reverse following bacterial colonization. Destabilization of the microbial composition of the gut by antibiotics or dietary change results in altered brain chemistry and behavior in mice. The behavioral phenotype can be adoptively transferred across mouse strains via the intestinal microbiota. Taken together these findings indicate that the intestinal microbiota influence brain function and are complemented by the recent demonstration that probiotic bacteria alter brain activity in healthy subjects. Interactions between the microbiota are bi-directional, as reflected by the observations that the induction of chronic stress, anxiety- or depression-like behavior shifts the microbial composition of the gut, likely via alterations in colonic physiology. The concept of a bi-directional microbiota-gut-brain axis is now established and may contribute to the psychiatric co-morbidity that often accompanies chronic intestinal disorders, as well as primary CNS disorders.
 

Regulation of Barrier Immunity
David Artis, PhD, University of Pennsylvania

Employing diverse models of microbial colonization, pathogen infection and chronic inflammation, research in the Artis lab is examining how mammalian host genetics and signals derived from commensal microbial communities influence innate and adaptive immune responses in the skin, lung and intestine. Epithelial cells (ECs) were recently shown to play a critical role in maintaining the balance of tolerance, immunity and inflammation at barrier surfaces including the gastrointestinal tract. We are employing inducible deletion or overexpression of genes in intestinal ECs to interrogate how they regulate the functions of intestinal myeloid and lymphocyte lineages. The long-term goals of these studies are to improve oral vaccination against enteric infections and prevent chronic inflammation associated with diseases including food allergy and inflammatory bowel disease. We are are employing gnotobiotic mice to examine the influence of commensal microbial communities on intestinal and peripheral immune cell development and function. Our findings indicate that commensal microbes have a major regulatory influence on CD4+ T cell and granulocyte function associated with susceptibility to multiple inflammatory diseases. In related studies, we are investigating how ECs regulate allergen- or helminth-induced type 2 inflammation at mucosal sites. Secretion of IEC-derived cytokines including IL-25, IL-33 and thymic stromal lymphopoietin (TSLP) appear to be important early events in influencing dendritic cell and CD4+ T cell responses required these responses. Our recent studies suggest that ECs also govern extramedullary hematopoiesis that can influence the development of TH2 cytokine responses. It is hoped that the results of these studies will advance understanding the pathophysiology of multiple mucosal inflammatory diseases, including asthma, allergy and inflammatory bowel disease and provide a framework to test the therapeutic potential of manipulating epithelial cell responses in these disease states.
 

Building a Systems-Level Understanding of Microbiome Involvement in Disease
Dirk Gevers, The Broad Institute of MIT and Harvard

We have evolved as a superorganism, covered with a complex community of microbial organisms, contributing immunologic and metabolic benefits. We typically receive the first microbiome constituents from our mother at birth, and continue to develop it during the first years of our life, after which it increases in stability and resilience.
 
Human microbiome studies have made tremendous progress in the past few years, showing that modern practices, including diet, antibiotic exposure, and hygiene practices, can disrupt the microbiome significantly. In addition, evidence now accumulates that an altered microbiome state is linked to inflammatory and other health disorders.
 
Key questions involve whether microbial species or their products play a causal role in certain diseases, and if so, how they can be monitored and modified to restore health.
 
In the past few years, I have served as a scientific liaison between the Broad's Genomics Platform, and both clinical and analytical collaborators. In that role, I helped develop high-throughput analytic capabilities for processing and interpreting large-scale metagenomics datasets, and initiated several large scale projects to characterize the vast complexity of the human microbiome across populations, age, and health conditions (including Inflammatory Bowel Disease, Type 1 Diabetes, and cancer). I will present highlights of several projects, and demonstrate the steps we are taking towards increasing our understanding of the host:microbiome interactions in a disease context.
 

A gene-to-molecule approach to the discovery and characterization of natural products
Michael A. Fischbach, PhD, University of California, San Francisco

The discovery of natural products — small molecules from microbes often used as drugs — has been an ad hoc pursuit for almost a century. The rapidly growing database of microbial genome sequences offers new opportunities to leverage genomics and bioinformatics toward discovering natural products and characterizing their roles in mediating interspecies interactions. This lecture will describe three convergent, ongoing lines of research: our use of genomics and bioinformatics to identify biosynthetic genes and predict the structures of their small molecule products, our characterization of a new class of biosynthetic gene clusters that produce a set of heavily modified peptide antibiotics, and our efforts to identify and characterize small molecules produced by human-associated microbes.
 

Learning from Host-Microbiome Interactions for Development of the Next Generation of Therapeutics
Nilufer Seth, Pfizer Global Research and Development

Interest in the role of human microbiota has been spurred by sequencing of the human microbiome and the METAHIT project. Associations of the microbiome with various human diseases including inflammatory bowel disease, psoriasis, colorectal carcinoma and cardiovascular diseases are well documented in the literature. However, whether dysbiosis is the cause or effect of the disease state remains unknown and there are studies ongoing to determine this. Very few molecular mechanisms and pathways involved in maintaining immune homeostasis between the host and its microbiota are known. Based on the current understanding in this area, at Pfizer we are targeting pathways involved in IL-10 generation, induction of regulatory immune cells (Tregs, alternatively activated macrophages and tolerogenic DCs), and restoration and maintenance of the gut epithelial barrier. We aim to develop therapeutics using 1. newly identified immunomodulatory bacterial strains with greater activity than probiotics 2. bacterial metabolites or their small molecule analogs 3. immunomodulatory bacterial products 4. synthetically engineered bacteria to deliver therapeutic molecules. This presentation outlines how we are applying the current knowledge in this nascent and rapidly growing area towards making next generation medicines that aim to restore immune and intestinal epithelial barrier homeostasis.
 

Development of a Therapeutic from Immunomodulatory Human Commensal Bacteria
Joseph A. Murray, MD, Mayo Clinic

We as humans have co-evolved with our Microbiome. In particular, the Microbiome has helped us adapt to the environment and most especially to changes in diet. Much of our gut function is devoted to its relationship to the resident ecology and the transitioning of foreign materials from which we derive our nutrition. A crucial part of this activity is the immune relationship with our resident ecology and the very diverse foods and other foreign materials that pass through our gut.
 
In contrast to the colon which functions with its resident large biomass of microbiota as a bioreactor, the small intestine has far less by way of microbiota and is largely responding to the transient food substances that make up our human nutrition. There are many human diseases both within and outside of the gut that are in some way triggered or modified by our gut interaction with bugs and/or foods. A prototypical example of this is celiac disease which is an immune based inflammation primarily but not limited to the small intestine to gluten. Our understanding of celiac disease includes knowledge of the primary external exogenous agent gluten, the host genetics (HLA), as well as much of the pathogenic processes that result in damage to the intestine. However, in an attempt to identify triggers for this disorder, we and others have explored the Microbiome of the GI tract. In a somewhat naïve effort, we cultured the proximal small intestine of patients undergoing evaluation for possible celiac disease. We discovered a frequent bacterial strain of anaerobic bacteria from the genus Prevotella that we hypothesized may be involved in driving or triggering celiac disease, given the other required ingredients of gluten sensitization and the host susceptibility genetics. However, we then transferred these bacteria to a mouse and found that rather than inducing inflammation, we rather discovered that it seemed to have immunosuppressive effects. We then applied this novel upper GI commensal to models of systemic autoimmunity that shared some of the HLA related risk to celiac disease. We found that this particular bacterium, when administered to murine models of MS and arthritis, suppressed or often completely prevented the manifestations of autoimmunity distant from the GI tract. We have explored the mechanisms by which this putative probiotic "drug" (bug-drug) can impact inflammatory responses and diseases well outside the GI tract. Thus we report a human commensal derived from the upper intestine which, when administered through the gut, has potent immunomodulatory effects that may be a therapy for systemic autoimmune disease.
 

Moving from Microbiome Causality to Novel Drug Discovery in Metabolic Disease
Peter S. DiStefano, PhD, Second Genome, Inc.

The trillions of microbes that reside within the mammalian gut can be viewed as an ecosystem, the balance of which is necessary to maintain health. Disruption of normal gut homeostasis (by diet, drugs, and genetic predisposition) is implicated in many disease states, including inflammation and metabolic disorders. Recent experimentation with fecal transplants in vivo suggests the microbiome plays a causal in disease, rather than merely correlative. Clues as to how the microbiome impacts disease lies in understanding the microbial community membership and function. Using next generation sequencing technologies, we have compare gut microbiome profiles in several modes of treatment in metabolic disease. Integration of multiple data sets allows the identification of bacterial species and associated functional changes common to restitution of metabolic homeostasis. Microbiome profiles from treated subjects provide a critical link between differentiated species, and their metabolites, leading to new strategies for amelioration of the disease phenotype. This provides a much-needed framework for understanding the molecular basis of microbial mechanisms in metabolic disease.
 

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