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Gary D. Wu, M.D

The Microbiome : What’s the immune system got to do with it?. Gary D. Wu, M.D. Ferdinand G. Weisbrod Professor of Medicine Division of Gastroenterology Perelman School of Medicine University of Pennsylvania. The Human Microbiome.

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Gary D. Wu, M.D

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  1. The Microbiome: What’s the immune system got to do with it? Gary D. Wu, M.D Ferdinand G. Weisbrod Professor of Medicine Division of Gastroenterology Perelman School of Medicine University of Pennsylvania

  2. The Human Microbiome • Comprised of Bacteria, Viruses, others (Archaea, Eukaryotes) • Distinctive microbiomes at each body site (gut, lung, skin, mucosa etc.) • The Gut Microbiota • Human gut is home to ~ 100 trillion bacterial cells • Density of 1011 to 1012 per gram in the colon • Genome size of microbiota at least 100-fold greater than human • Large numbers species present, most uncultured Nat. Rev. Micro. 2011;9:279-290

  3. Association of the Gut Microbiota with Disease Diabetes: Type 1 DM (MyD88-dependent in NOD Mice); Type 2 DM (TLR4 and TLR5 KOs) Atherosclerosis: Oral, gut and plaque microbiota; Microbial metabolism of choline to TMA Asthma: Sanitized environment Colon Cancer: Enterotoxigenic Bacteroides fragilis and Fusobacterium Inflammatory Bowel Disease:Dysbiosis • Pathogenesis involves both genetic and environmental factors • All associated with inflammation • Many show rapidly increasing incidence over the past few decades • Many associated geographically with more industrialized nations • Many associated with diet

  4. Host Gene-Microbial Interactions in the Pathogenesis of Immune-Mediated Diseases in “Modern Society” Parental genotype Infant “Sanitized” Environment Perinatal Establish normal microbiome Failure to establish normal microbiome Antibiotics Diet Inflammation & autoimmunity-prone immune system Normal immune system Immune tolerance Regulated inflammation Diet Bacteria Environmental cofactors Viruses Other Infections Autoantigens Microbial products Autoantigens Crohn’s Disease Type 1 Diabetes Health Other Asthma Adapted from Virgin et al. Cell 2011;147:44

  5. Perinatal Effects of the Gut Microbiota on Host Immunity Adult Microbial Colonization Perinatal Microbial Colonization ++++ + ++++ + PNAS 2011;108:4578 Conventionally Housed Germ-free Colonic and Lung iNKT Cells + ++++ Oxazolone Colitis and Asthma + ++++ Olszak et al. Science 2012;336:489

  6. Innate Immune Receptors Recognize Bacterial Products Known as “Pathogen Associate Molecular Patterns” (PAMPS) Medzhitov. Nat. Rev. Immunol. 2001;1:135 Kanneganti et al. Immunity 2007;27:549

  7. Differential Effects of Bacteria and Their Products on Epithelial vs. Innate Immune Cells Maloy KJ and Powie F. Nature 2011;747:298

  8. The Gut Microbiota, Inflammation and Colon Cancer Sears, CL Cell Host & Microbe 2014 Kostic A D et al. Cancer Immunol Res 2013;1:150-157

  9. The Gut Microbiota, Inflammation and Metabolic Disease Nature 2012;482:179 Vjay-Kumar Cell Met. 2012;15:419 Jin et al. Cell Met. 2013;17:873

  10. Normon et al. Gastro 2014, in press Viruses Enhanced Pathogenicity Predator-Prey Relationship Bacteria Competition Syntrophy Archaea Fungi

  11. The Intestinal Mycobiome 18S and ITS amplicons for eukaryote detection Dollive et al. Genome Biol. 2012;13:R60 Proportion of total reads Hoffmann et al. PLoS One 2013;e66019

  12. The Mycobiome in IBD ASCA and Crohn’s Disease

  13. Genetic Polymorphisms Associated with IBD Occur in Distinct Pathways Khor et al. Nature 2011;474:307

  14. The Gut Microbiota, Maturation of the Mucosal Immune System, and IBD Genetics X = Genetic Polymorphisms Associated with IBD SCFAs Clostridium sp. SFB B. Fragilis (PSA) Gut Lumen IgA X X X X X X Epithelium Treg Th17 B Cell Plasma Cell X X X Lamina Propria Anti-Inflammatory Pro-Inflammatory

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