Transcript Perinatal Microbial Colonization

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
• 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 100fold greater than human
Nat. Rev. Micro. 2011;9:279-290
• Large numbers species present, most
uncultured
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
Host Gene-Microbial Interactions in the Pathogenesis of ImmuneMediated Diseases in “Modern Society”
Parental genotype
Infant
Establish normal
microbiome
Normal immune system
Immune tolerance
Regulated inflammation
Infections
Autoantigens
“Sanitized” Environment
Antibiotics
Diet
Perinatal
Failure to establish
normal microbiome
Inflammation & autoimmunityprone immune system
Bacteria
Viruses
Adapted from Virgin et al. Cell 2011;147:44
Environmental
cofactors
Microbial products
Autoantigens
Crohn’s Disease
Health
Diet
Other
Asthma
Type 1 Diabetes
Other
Perinatal Effects of the Gut Microbiota on
Host Immunity
PNAS 2011;108:4578
Germ-free
Adult Microbial
Colonization
Perinatal Microbial
Colonization
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Conventionally
Housed
Colonic and Lung
iNKT Cells
Oxazolone Colitis
and Asthma
Olszak et al. Science 2012;336:489
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
Differential Effects of Bacteria and Their Products on
Epithelial vs. Innate Immune Cells
Maloy KJ and Powie F. Nature 2011;747:298
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
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
Normon et al.
Gastro 2014, in
press
Viruses
Predator-Prey Enhanced
Relationship Pathogenicity
Bacteria
Archaea
Fungi
The Intestinal Mycobiome
18S and ITS amplicons for eukaryote
detection
Dollive et al. Genome Biol. 2012;13:R60
Bacterial clusters
Fungal clusters
Other
Basidiomycota
Ascomycota
Hoffmann et al. PLoS One 2013;e66019
1.00
0.65
0.50
0.35
0.20
0.09
0.07
0.05
0.03
0.01
0.006
0.004
0.002
0
Proportion of
total reads
The Mycobiome in IBD
ASCA and Crohn’s Disease
Genetic Polymorphisms Associated with IBD Occur in Distinct Pathways
Khor et al. Nature
2011;474:307
The Gut Microbiota, Maturation of the
Mucosal Immune System, and IBD Genetics
X = Genetic Polymorphisms Associated with IBD
SCFAs
Clostridium sp.
B. Fragilis (PSA)
SFB
Gut Lumen
IgA
X XX
Epithelium
Plasma Cell
Lamina Propria
X
X
X
B Cell
Th17
Treg
X
X
X
Pro-Inflammatory
Anti-Inflammatory