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?
Jan 02, 2016
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
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