Mercury Dental Amalgams: The Controversy Continues by Gary Null, Ph.D., and Martin Feldman, M.D.
Gary D. Wu, M.D
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Transcript of Gary D. Wu, M.D
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