gary d. wu, m.d

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

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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. - PowerPoint PPT Presentation

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Gary D. Wu, M.D

Ferdinand G. Weisbrod Professor of MedicineDivision of GastroenterologyPerelman School of Medicine

University of Pennsylvania

The Microbiome: What’s the immune system got to do with it?

• 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 unculturedNat. Rev. Micro. 2011;9:279-290

The Human Microbiome

Association of the Gut Microbiota with Disease

• 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

Diabetes: Type 1 DM (MyD88-dependent in NOD Mice); Type 2 DM (TLR4 and TLR5 KOs)

Colon Cancer: Enterotoxigenic Bacteroides fragilis and Fusobacterium

Atherosclerosis: Oral, gut and plaque microbiota; Microbial metabolism of choline to TMA

Inflammatory Bowel Disease: Dysbiosis

Asthma: Sanitized environment

•Many associated with diet

Host Gene-Microbial Interactions in the Pathogenesis of Immune-Mediated Diseases in “Modern Society”

Parental genotype

Infant

Adapted from Virgin et al. Cell 2011;147:44

Establish normal microbiome

Normal immune systemImmune tolerance

Regulated inflammation

Infections Autoantigens

Health

“Sanitized” EnvironmentAntibioticsDiet

Failure to establish normal microbiome

Inflammation & autoimmunity-prone immune system

Environmental cofactors

Microbial productsAutoantigens

Crohn’s Disease

Asthma

Type 1 Diabetes

Other

BacteriaViruses

DietOther

Perinatal

Germ-free

Colonic and Lung iNKT Cells

Oxazolone Colitis and Asthma

++++

++++

Conventionally Housed

+

+

Olszak et al. Science 2012;336:489

Adult Microbial Colonization

++++

++++

Perinatal Microbial Colonization

+

+

Perinatal Effects of the Gut Microbiota on Host Immunity

PNAS 2011;108:4578

Medzhitov. Nat. Rev. Immunol. 2001;1:135

Kanneganti et al. Immunity 2007;27:549

Innate Immune Receptors Recognize Bacterial Products Known as “Pathogen Associate Molecular Patterns” (PAMPS)

Maloy KJ and Powie F. Nature 2011;747:298

Differential Effects of Bacteria and Their Products on Epithelial vs. Innate Immune Cells

Kostic A D et al. Cancer Immunol Res 2013;1:150-157

The Gut Microbiota, Inflammation and Colon Cancer

Sears, CL Cell Host & Microbe 2014

Jin et al. Cell Met. 2013;17:873

Vjay-Kumar Cell Met. 2012;15:419

Nature 2012;482:179

The Gut Microbiota, Inflammation and Metabolic Disease

Normon et al. Gastro 2014, in press

Bacteria

Viruses

FungiArchaea

CompetitionSyn

troph

y

Enhanced Pathogenicity

Predator-PreyRelationship

The Intestinal Mycobiome

00.0020.0040.0060.010.030.050.070.090.200.350.500.651.00

Ascomycota

Basidiomycota

Other

Fungal clusters

Bacterial clusters

Proportion of total reads

18S and ITS amplicons for eukaryote detection

Hoffmann et al. PLoS One 2013;e66019

Dollive et al. Genome Biol. 2012;13:R60

The Mycobiome in IBD

ASCA and Crohn’s Disease

Khor et al. Nature 2011;474:307

Genetic Polymorphisms Associated with IBD Occur in Distinct Pathways

Anti-Inflammatory

Treg

Pro-Inflammatory

Th17B CellPlasma Cell

Gut Lumen

Epithelium

Lamina Propria

The Gut Microbiota, Maturation of the Mucosal Immune System, and IBD Genetics

X XX

X = Genetic Polymorphisms Associated with IBD

X XXXXX

IgA

SFB B. Fragilis (PSA)Clostridium sp.

SCFAs