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Our Gut Flora: the Internist's Guide

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Our Gut Flora: the Internist's Guide Our Gut Flora: The Internist’s Guide Walter J. Coyle, MD, FACP,FACG Scripps Clinic Grand Rounds 2012 Disclosures Speaker’s Bureau: Takeda Pharmaceuticals Consultant: CSA Medical Specifically, I have no financial relationships with any probiotic or prebiotic company Movement of the Talk Describe the Microbiome Microbiology 101 Review the diversity of human gut flora Understand how our bacteria influence our metabolism, obesity, and selected diseases Review the plethora of probiotics Describe prebiotics and synbiotics and their potential uses Conclusions and the Future The Human Microbiome Definitions: Microbiome: Aggregate of all gut species Microbiota: Individual bacterial species in the biome Over 100 trillion organisms (1014) Passengers in the mobile colonic petri dish Over 500 species identified so far (70 divisions) 90% of the cells in our body our microbial! 100 fold more genes in our gut then in us Our flora are an integral part of our genetic landscape and evolution Anatomic Regions of the Gut Upper GI tract: 102 –104 cells/ml Lactobacilli, streptococci, H pylori Ileum: 106-1012 cells /ml, upper bacteria plus Faculative anaerobes: Enterobacteriaceae Obligate anaerobes: Bacteroides, Veillonella, Fusobacterium and Clostridium species Colon: distal human colon is the most biodense natural ecosystem known (1010-1012 cells/ml) Complex and diverse Comprise most of our bacterial biomass Microbes and Humans Dethlefsen Nature 2007; 449:812-818 Micro 101 Pace in Science 1997 276:735-740 The Human Gut Flora DiBiase, et al. Mayo Clin Proc 2008;83:460-469 Mouse intestine, mucus gel layer Home to billions of organisms Sonnenburg J, et al. in Nature Immunology 2004:5 The Microbiome: Who’s there? Early gut colonization has four phases Phase 1: Sterile gut Phase 2: Initial acquisition: vagina, feces, hospital Phase 3: Breast feeding or bottle-feeding (different) Breast fed more bifidobacteria (up to 90% of flora) Bottle fed more diverse; more Bacteroides , and Clostridial species Phase 4: Start of solids; move to adult flora Bifidobacteria remain key flora into adulthood Ley, Peterson, Gordon. Cell 2006 ;124:837 Ley, et al. PNAS. 2005, 102: 11070 Edwards, et al. Br J Nutr. 2002 The Microbiome: Who’s there? Adult Microbiome: Increasing diversity of flora as we age In some newer PCR (16S rRNA) studies, up to 92% of the flora in adults were “novel” species Serial stool collections show remarkable stability by an individual Greatest concordance with twins Less concordance with households Host genetic influence unexplored. McCartney and Gibson in Gastrointestinal Microbiology, 51-73, 2006 16s ribosomal RNA Important tool for bacterial identification 1500 bp Unique to bacteria and conserved through time Over 8000 species can be identified by 16s rRNA The Microbiome: Who’s there? Multiple species: eukaryotic, bacterial, archael Firmicutes (Gram +/ motile) and Bacteroidetes (Gram -) : Majority These two groups comprise > 90% Anaerobes / aerobes: 1000:1 Far fewer species than the environment High levels of interpersonal diversity My stool is not your stool Ley, Peterson, Gordon. Cell 2006 ;124:837 Ley, et al. Science 2005; 307: 1915 Ley R, et al in Cell 2006:124:837-848 Gut Flora and Metabolism Metabolomics Study of the metabolites and small molecules that the body and gut bacteria produce. New area of science Broader than proteonomics Includes bacteria products with our own genetic products Pioneered by Jeremy Nicholson and Jeff Gordon Gut Flora and Metabolism Microbial genomes enhance our metabolic activity May indirectly or directly effect our metabolism The colon is very active metabolically 20-70 gms of carbos and 5-20 gms of protein/day Over 100 kcal per day! Mass of colonic microbiome = single kidney Metabolically as active as the liver Hooper, et al. Annu Rev Nutr, 2002 Gut Flora and Metabolism Energy salvage: esp via the short-chain fatty acids Acetate, butyrate, propionate (SCFAs) Absorbed into body and used by liver and others organs Acetate and propionate modulate glucose metabolism in the liver and adipocytes (glycemic index) 50-70% of colonic cell energy derived from butyrate Number and diversity of organisms key Do we acquire flora that program us for obesity or normal weight? Mackowiak, NEJM, 1982; 307:83-93 Hooper, et al. Annu Rev Nutr, 2002 Gut Flora Metabolic Reactions Metabolic reactions Goldin BR in Gastrointestinal Microbiology 138-154, 2006 Gut Flora in Health and Disease Koch’s postulates: old view of microbes New view: microecologic disease or “pathogenic microbial community” Disease not due to one organism but changes in mix Dysbiosis: Abnormal state of the microbial ecosystem in the host Harmful and protective species or families Gut Enterotypes: New Concept Recent evidence suggests 3 distinct gut types exist May be independent of geography May be programmed early Can we change the gut type No clear link in this study to BMI or metabolic syndrome Nature 2011; 473:174-180 The Human Microbiome Immunologically active environment Protection: 2 levels Colonization resistance: Competition, pH, gases, bacteriocins, etc… Stimulate immune function: Indigenous bacteria stimulate mucosal defense and immune development GALT: Gut-associated lymphoid tissue J Allergy Clin Immunol 2011;127:1087-94 J Allergy Clin Immunol 2011;128:646-52.) Gut Flora and Immunity Neonates by vaginal delivery have more diverse microbiota more bifidobacteria, lactobacilli, and Bacteroides vs C-section neonates Atopic children have less bifidobacteria, lactobacilli, and Bacteroides Loss of diversity in children associated with more atopy, eczema, and obesity Studies with probiotics have not been able to reliably influence atopy, eczema, or asthma J Allergy Clin Immunol 2011;127:1087-94 J Allergy Clin Immunol 2011;128:646-52 Gut Flora and Immunity Gut flora differ from industrialized society and 3rd world nations Possible connection Data supports vitamin D being important in the immune reaction to gut flora Possible role in allergy and obesity Convincing data that manipulation of the gut flora can help is limited. J Allergy Clin Immunol 2011;127:1087-94 Obesity and the Gut Flora Ley, et al. PNAS. 2005, 102: 11070-75 The Microbiome: Changes in flora Mice and humans have different gut flora but the two largest divisions are shared in common Bacteroidetes (Gram -) Firmicutes (Gram +) These flora change in response to diet and obesity of host Ley, et al. PNAS. 2005, 102: 11070-75 Ley, et al. PNAS. 2005, 102: 11070-75 The Microbiome: Changes in flora Obesity changes the relative proportions of divisions. Obese mice AND obese people have more Firmicutes than Bacteroidetes: dieting and weight gain shifts these proportions. What are the implications of the change in our colonic metabolic machine Chicken or the egg? Ley, et al. PNAS. 2005, 102: 11070-75 Gut Flora and Obesity Germ free mice studied by Gordon, et al Control mice (remaining germ free) were changed from low fat diet to “Western” diet Mice given normal gut flora (conventialized mice) also had same diet change. Low fat diet: 5% lipids “Western” diet: 41% lipids, 41% carbos (with simple sugars), 18% protein Gordon J, et al, PNAS 2007;104:983 Gut Flora and Obesity Mice then studied for change in weight and fat pad size Assessed response to fatty meal loading Assessed locomotion of mice via gastrocnemius muscle activity. Results: See Figures Gordon J, et al, PNAS 2007;104:983 Gut Flora and Obesity Gordon J, et al, PNAS 2007;104:983 Gut Flora and Obesity GF mice are “resistant” to the Western diet Gut flora are responsible for increasing energy production from food “Doctor, I don’t eat” May be partially true! Gut flora also influence lipid production, adipose cell storage, and appear to influence mouse locomotor activity “Couch potato” gut flora My gut flora made me do it! Gordon J, et al, PNAS 2007;104:983 “Let food be thy medicine and medicine be thy food.” Hippocrates The Microbiome: transplant experiments Wild type mouse Ob Ob mouse Turnbaugh, et al. Nature 2006; 444:1027 The Microbiome: transplant experiments Germ-free mice given ob/ob or wild-type flora Chow consumption and exercise the same for both groups Both sets had similar starting weight and % BF. The ob/ob microbiota promote host adiposity Turnbaugh, et al. Nature 2006; 444:1027 Human Flora and Obesity Mice data links gut flora with obesity and diet Studied 12 obese human subjects; low calorie diet for one year Fat-restricted (FAT-R) Carbohydrate restricted (CARB-R) Microbiota studied for one year (16s rRNA) Firmicutes and bacteroidetes dominated (92.6%) Ley R, et al in Nature 2006:444 Human Flora and Obesity Ley R, et al in Nature 2006:444 Human Flora and Obesity Firmicutes dominate in obese subjects All subjects (no diff with diet) had bloom of all Bacteroidetes with decline in Firmicutes CARB-R: Change began at 2% wgt loss FAT-R: Change began at 6% wgt loss Dynamic link between obesity and gut flora exists in humans (proven 1st in mice) Ley R, et al in Nature 2006:444 Murine model Given various antibiotics early in life Found changes in fat composition Metabolic changes also occurred The mix of flora changed Firmacutes >> Bacteroidetes Blaser, et al. Nature 2012 Antibiotic exposure in mice Blaser, et al. Nature 2012 Studied 11,532 children in Avon, UK (91-93) Mapped antibiotic use (<6m,6-14m,15-23m) Body mass documented at 6wks, 10m, 20m, 38m and 7 yrs Multivariate analysis: role of tob, mother’s
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