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The Human Microbiome: The Undiscovered Country. Walter J. Coyle, MD, FACP,FACG. 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

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movement of the talk
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

the human microbiome
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
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
microbes and humans
Microbes and Humans

Dethlefsen Nature 2007; 449:812-818

micro 101
Micro 101

Pace in Science 1997 276:735-740

the human gut flora
The Human Gut Flora

DiBiase, et al. Mayo Clin Proc 2008;83:460-469

slide8

Mouse intestine, mucus gel layer

Home to billions of organisms

Sonnenburg J, et al. in Nature

Immunology 2004:5

the microbiome who s there
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 there11
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

the microbiome who s there12
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

metabolomics
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 metabolism16
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 metabolism17
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
Gut Flora Metabolic Reactions

Metabolic reactions

Goldin BR in Gastrointestinal Microbiology 138-154, 2006

gut flora and the brain
Gut Flora and the Brain

Collins and Bercik in GASTRO 2009;136:2003–2014

the microbiome changes in flora
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

the microbiome changes in flora24
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
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 obesity26
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 obesity27
Gut Flora and Obesity

Gordon J, et al, PNAS 2007;104:983

gut flora and obesity28
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

the microbiome transplant experiments
The Microbiome: transplant experiments

Ob Ob mouse

Wild type mouse

Turnbaugh, et al. Nature 2006; 444:1027

the microbiome transplant experiments31
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
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 obesity33
Human Flora and Obesity

Ley R, et al in Nature 2006:444

human flora and obesity34
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

proposed mechanisms in obesity
Proposed Mechanisms in Obesity

DiBiase, et al. Mayo Clin Proc 2008;83:460-469

microbiome regulators
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”
the gut and obesity options
The Gut and Obesity: Options
  • Diet may manipulate flora
    • Low carbs, high fat
    • High carbs, low fat
  • Probiotics
  • Prebiotics
  • Stool transplants
    • “Guarantee weight loss with thin people’s feces!”
    • Could this be the future?
slide38

Coyle’s Corollary

It is better to be a stool donor than a recipient.

probiotics40
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

common probiotics
Common Probiotics

Khedkar and Ouwehand in GastrointestMicrobiology 315-334, 2006

probiotics42
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

probiotics43
Probiotics
  • Digestive Advantage
    • Ganeden BC30
    • Bacillus coagulans
    • Erythritol
    • Cellulose
    • Other minor ingredients
probiotics44
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

probiotics45
Probiotics
  • Saccharomyces boulardii
  • Other minor ingredients
  • Shown in Rand / PC trials to help prevent recurrent C. difficile infection
probiotics in food actimel
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.”

prebiotics48
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.

prebiotics49
Prebiotics
  • Inulin: plant polymers mainly comprising fructose units, use have a terminal glucose
  • Indigestable fiber
  • Gut flora produce H2, CO2, methane gas from inulin
prebiotics50
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
designing probiotics the future
Designing Probiotics: The Future?

GASTROENTEROLOGY 2009;136:2015–2031

conclusions
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.
conclusions53
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!
the future
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.