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