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The Human Microbiome: The Undiscovered Country


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  • 1. The Human Microbiome: The Undiscovered Country
    Walter J. Coyle, MD, FACP,FACG
  • 2. Movement of the Talk
    Describe the Microbiome
    Microbiology 101
    Review the diversity of human gut flora
    Understand how our bacteria influence our metabolism and obesity
    Review the plethora of probiotics
    Describe prebiotics and their potential uses
    Conclusions and the Future
  • 3. The Human Microbiome
    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
  • 4. 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, FusobacteriumandClostridium 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
  • 5. Microbes and Humans
    Dethlefsen Nature 2007; 449:812-818
  • 6. Micro 101
    Pace in Science 1997 276:735-740
  • 7. The Human Gut Flora
    DiBiase, et al. Mayo Clin Proc 2008;83:460-469
  • 8. Mouse intestine, mucus gel layer
    Home to billions of organisms
    Sonnenburg J, et al. in Nature
    Immunology 2004:5
  • 9.
  • 10. 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
  • 11. 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
  • 12. 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
  • 13. Ley R, et al in Cell 2006:124:837-848
  • 14. Gut Flora and Metabolism
  • 15. 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
  • 16. 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
  • 17. 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
  • 18. Gut Flora Metabolic Reactions
    Metabolic reactions
    Goldin BR in Gastrointestinal Microbiology 138-154, 2006
  • 19. Gut Flora and the Brain
    Collins and Bercik in GASTRO 2009;136:2003–2014
  • 20. Obesity and the Gut Flora
  • 21. Ley, et al. PNAS. 2005, 102: 11070-75
  • 22. 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
  • 23. Ley, et al. PNAS. 2005, 102: 11070-75
  • 24. 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
  • 25. 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
  • 26. 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
  • 27. Gut Flora and Obesity
    Gordon J, et al, PNAS 2007;104:983
  • 28. 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
  • 29. “Let food be thy medicine and medicine be thy food.”
  • 30. The Microbiome: transplant experiments
    Ob Ob mouse
    Wild type mouse
    Turnbaugh, et al. Nature 2006; 444:1027
  • 31. 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
  • 32. Ley R, et al in Nature 2006:444
    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%)
  • 33. Human Flora and Obesity
    Ley R, et al in Nature 2006:444
  • 34. 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)
  • 35. Proposed Mechanisms in Obesity
    DiBiase, et al. Mayo Clin Proc 2008;83:460-469
  • 36. Microbiome: regulators
    Archae: 1-2 % of mouse and human flora
    Represent a major microbial group in gut flora
    Increased in obese mice
    Many are methanogenic : Methanobactersmithii
    Converts CO2 and H2 gas to methane
    By decreasing the partial pressure of H2 gas these bacteria can drive bacterial metabolism
    The flora of obese mice are more efficient at extracting energy: “The Energy Harvest”
  • 37. The Gut and Obesity: Options
    Diet may manipulate flora
    Low carbs, high fat
    High carbs, low fat
    Stool transplants
    “Guarantee weight loss with thin people’s feces!”
    Could this be the future?
  • 38. Coyle’s Corollary
    It is better to be a stool donor than a recipient.
  • 39. Probiotics
  • 40. Probiotics
    Definition: Live microorganisms which when ingested in adequate amounts confer a health benefit on the host.
    Majority of probiotics are Gram +, lactic acid producers
    Bifidobacterial species and Lactobacillus species
    Survive transit through stomach and duodenum
    Others include: non-pathogenic streptococci, enterococci, E coli Nissle 1917, Saccharomyces boulardii (yeast)
    Fooks, et al. Int Dairy J, 1999
    Sheil, et al. In Gastrointestinal Microbiology, 2006
  • 41. Common Probiotics
    Khedkar and Ouwehand in GastrointestMicrobiology 315-334, 2006
  • 42. Probiotics
    VSL #3
    4 lactobacilli
    L. plantarum, casei, acidopholus, delbrueckiispp
    3 bidifobacteria
    B. infantis, breve, longum
    1 streptococcus
    Streptococcus salivarius ssp. thermophilus
    Rand, PC studies have shown efficacy
    in pouchitis and IBS
  • 43. Probiotics
    Digestive Advantage
    Ganeden BC30
    Bacillus coagulans
    Other minor ingredients
  • 44. Probiotics
    Bifidobacteriuminfantis 35624 aka Bifantis
    “Patented” strain of probiotic in Align
    Decreased symptoms in two large trials in subjects with IBS*
    *Whorwell P, et al. Am J Gastro 2006; 101
    O’Mahoney L, et al. Gastro 2005;128
  • 45. Probiotics
    Saccharomyces boulardii
    Other minor ingredients
    Shown in Rand / PC trials to help prevent recurrent C. difficile infection
  • 46. Probiotics in Food (Actimel)
    L. caseiImmunitas™
    Claim it is scientifically proven to be effective
    “Each bottle contains 10 billion live” bacteria “that survive and remain active in the
    digestive tract.”
  • 47. Prebiotics
  • 48. Prebiotics
    Ingested substances that selectively stimulate the proliferation and/or activity of desirable bacterial populations present in the host intestinal tract.
    Usually target bifidobacteria and lactobacilli
    Bifidogenic or bifidus factors explored in the 50s
    Usually are non-digestible oligosaccharides (NDOs)
    Lactulose, galacto-oligosaccharides, lactosucrose…
    Crittenden and Playne. In Gastrointestinal Microbiology, 2006, pg 285-314.
  • 49. Prebiotics
    Inulin: plant polymers mainly comprising fructose units, use have a terminal glucose
    Indigestable fiber
    Gut flora produce H2, CO2, methane gas from inulin
  • 50. Prebiotics
    Is is possible to design a food, sugar, protein, or fat that would alter your gut flora to promote weight loss?
    More likely possibility is to give a prebiotic that decreases your “Energy Harvest” of colonic bacteria
    ie. lose weight by making your gut flora less efficient at digesting your left over food
  • 51. Designing Probiotics: The Future?
    GASTROENTEROLOGY 2009;136:2015–2031
  • 52. Conclusions
    The human microbiome and the Microbiome Project: research just beginning…
    Gut flora by their genes, by-products, and metabolic activity influence our metabolism, weight, activity, immunity, health and disease.
    Manipulation of gut flora may be an integral part of weight loss programs and different disease treatments in the future.
  • 53. Conclusions
    Future studies must focus on the mechanisms of influence of our gut flora.
    Studies must be placebo controlled and high quality.
    Truly need translational science to work at the levels of the petri dish, genomics, and clinical outcomes.
    Much more to come!
  • 54. The Future
    Define who is there: in healthy subjects and those with disease
    Study at Scripps in subjects with diet change, NASH, and IBD
    Elucidate the gut flora host interaction
    Design trials that truly assess the potential for probiotics and prebiotics to make a difference in health and disease.
  • 55. Questions