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Symbiotic Heirarchies of the Intestinal Tract: Implications for Health and Disease

Symbiotic Heirarchies of the Intestinal Tract: Implications for Health and Disease. Woody Emlen MD. S ymbiotic H eirarchies of the I ntestinal T ract. Our Gut Microbiome. Woody Emlen MD. Why Now?.

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Symbiotic Heirarchies of the Intestinal Tract: Implications for Health and Disease

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  1. Symbiotic Heirarchies of the Intestinal Tract:Implications for Health and Disease Woody Emlen MD

  2. S ymbioticH eirarchiesof the I ntestinal T ract Our Gut Microbiome Woody Emlen MD

  3. Why Now? • Hot topic in medical and lay literature (NY Times/Economist/Science/Nature/TED/Mother Jones) • Explosion of information over past 10 years • Significant medical implications beginning to emerge (obesity, diabetes, allergy etc).

  4. What’s the Big Deal: What’s New? • Culture – Identify organisms by morphology/chemical tests • BUT - Only 20-30% of observable stool organisms grow in culture • Past 10-15 years – Identify by DNA analysis (metagenomics) • 16s rRNA sequencing • Full DNA sequencing • Revealed almost unbelievable diversity and numbers!!

  5. Bacterial Culture in Petri Dish

  6. We are not Alone!!

  7. Some Most of my closest Friends are germs! • 100,000,000,000,000 bacteria on/in our body • 10 pounds of bacteria!! • Several “biota”in multiple sites: • Skin • Mucosa (oral, vaginal) • GI tract (Large intestine>> small intestine) • Each biota is a complex ecosystem in itself

  8. Microbiota Sites

  9. Are we really Human? • 350,000,000 People in US • 7,000,000,000 People on earth • 10,000,000,000,000 Cells in our body • 100,000,000,000,000 Bacteria in and on your body - RIGHT NOW! Are we merely a carrier for a huge bacterial colony?

  10. Terminology • Microbiota – the organisms (bacteria, fungi, viruses, etc) living in/on us. • Microbiome: - the DNA contained in our microbiota • 23,000genes in the Human genome • >1,000,00genes in the microbiotamicrobiome

  11. The Gut Microbiota • 500-1000 different species • >5000 taxa (identifiably different on DNA analysis) • Most bacteria anaerobic • Densest bacterial colony on earth (> 1012/cm3) • Extremely complex ecosystem (rain forest)

  12. YUCK!!

  13. Questions • Where do they come from? • Why are they here? – what’s in it for us / for them? • How do we protect ourselves from them? • Do they have any effects on our lives – for better or worse? • Can we control / manipulate them?

  14. Where do they come from? • Sterile gut at birth • Initial colonization from mother during childbirth • Significant differences in MB from babies delivered by C-section • Differences based on breast vs formula feeding • Differences based on diet • MB grows in complexity over first 3 years – gradually stabilizes to “adult” MB • Development can be significantly altered / limited by early antibiotic use

  15. Effect of Diet on MB Gnobiotic mice fed varying diets J J Faith et al. Science 2011;333:101-104 Published by AAAS

  16. Microbiota Stability • “Adult” MB relatively stable over time • Stable by function rather than by specific organisms (stability is with microbiome) • Shaped by diet, host genetics, family members, family pets, family behaviors • May be disrupted by antibiotics / stress / disease / drug / infection / etc • Return to baseline MB over 2-4 weeks in most individuals but may develop new stable MB • Decreased complexity of MB with age

  17. Why are they here?If you can’t fight ‘em, join ‘em!! • Advantages to both: co-evolution has led to true symbiosis • Microbiota: • Nice warm, anaerobic home • Constant food supply (50 tons!) • Surrounded by friends – the good life! • Host: • Supplement nutrition • Remove toxins • Protect from pathogenic bugs • Enhance / augment immune system

  18. The Gut Microbiota: Function • Express 50-100 times more genes than the host (us)!! • Digestive enzymes • Products of fermentation • signaling molecules • vitamins • Metabolism/Nutrition • Extract nutrients and energy from our diet • Breakdown of xenobiotics (including drugs) • Signals to liver/fat cellsto modulate metabolism • Resistance to pathogenic bacteria • Shape immune function & repertoire

  19. Nutrition • Enhance absorption of calories/nutrients • Gnobiotic mice require 30% more calorie intake • Break down non-digestible polysaccharides • Generation of short-chain fatty acids (<6 C; promote colon health, anti-inflammatory in colon) • Convert / generate some essential nutrients to usable/absorbable forms • Vitamin K and B, folic acid derivatives • Generate small molecule “messengers” (36% of small molecules in circulation are MB origin) • Alter Drug Metabolism • Drug breakdown

  20. Gut Microbiota: “Enterotypes” • Several general “types” of ecosystems • Characterization very complex and still inexact controversial • Best defined by functional activity rather than species types or heterogeneity • More species diversity is usually a more stable and “healthy” microbiota. • Useful in seeking correlations with health status/disease

  21. MB, Obesity and Diabetes • MB of lean and obese mice differ • “Obese” MB is more efficient at extracting energy from diet • Obesity and diabetes are transmissible to gnobiotic mice with appropriate MB colonization non-obese MB Obese MB • Differences in MB of obese and non-obese humans • similar to differences in mice

  22. MB, Obesity and Diabetes in Humans • Compared MB of lean and obese twins (monozygotic and dizygotic) and their mothers. • MB similarity between pairs of monozygotic and pairs of dizygotic twin equal; both very similar to their mothers. • MB from lean twins similar to each other but different from MB of obese twins. CONCLUSIONS • Environment is major determinant of MB rather than genetics • May be able to define/describe “obese” MB • Experiments in humans underway in Netherlands (at 6 weeks – improved insulin sensitivity but no weight loss)

  23. Can MB Generate Harmful Molecules? • Red meat/high fat diet accepted as a risk factor for CVD • Rich in lipids / also rich in choline & lecithin • Metabolite of choline (TMAO) induces heart disease in mice • Is TMAO a risk factor for CVD in humans? – YES • Epidemiology study of 4000 subjects – high TMAO gave 5 fold increased risk of heart disease (after correction for other risk factors)

  24. Where does TMAO come from? Normal After antibiotics Recovered from Abx • Choline challenge given and TMAO levels measured (visit 1) • Treated with 1 week of antibiotics to remove MB –challenge repeated (visit 2) • Third challenge given 2 weeks after antibiotics stopped after MB recovery

  25. Dietary red meat / Eggs / cheese Conclusion: Foods thought to cause / contribute to heart disease exert their effects through the action of the gut Microbiota.

  26. The Gut: Immune System Interactions • Priority ONE – protect me from the bugs!! • 1 cell thick layer separating us from 1014 bugs • Need to protect surface area as large as a tennis court • Leakage of bacteria into blood – sepsis & death • When Pathogens invade: • Produce toxins that kill competition • Induce body to produce endogenous toxins to which they are resistant (decrease competition) • Induce inflammation • Similarity to antibiotic effects – markedly damage the normal MB

  27. Pathogen Resistance by MB • Competition for nutrients (stable ecosystem is a complex ecosystem) • Production of anti-microbial peptides (direct and induced) • Mucous layer to keep bacteria away from gut wall • Drive Immune System to produce antibodies (IgA) and immune cells • Disrupted by antibiotics

  28. Clostridium Difficile • Antibiotic treatment leads to overgrowth of C. Difficile – chronic diarrhea • Treatment with antibiotics to try to kill the C Difficile – requires repeated treatment • Fecal Transplants to restore normal MB in patients unresponsive to antibiotics • Given by enema / colonoscopy / NG tube • 91% success rate at 6 weeks

  29. Our Gut Ecosystem restores Restores gut ecosystem

  30. Effect of Gut MB on host Immune System • Drive development of gut immune system • Gnobiotic mice • Shape repertoire of immune responses • What organisms do we recognize / respond to? • Maintains “balance” between different types of immune response (TH1 vs. TH2)

  31. Allergy/AsthmaHygiene Hypothesis • Increasing incidence of allergy/asthma in western / “1st world” countries • “Civilization” of East Germany • Excessive “hygiene” pre-disposes our children to develop allergies/asthma • Microbiota: • Childhood antibiotic use associated with increased allergy/asthma • Mouse models – early antibiotics: more severe asthma

  32. Types of Immune Response Microbiota Type 2 Remove external irritants Sneezing Coughing Itching Type 1 Kill internal pathogens Internal inflammation Cell/bug death Allergy Asthma Excess Inflammation Autoimmunity

  33. Overview: MB Effects on Disease Environmental Exposures Host Genetics Epi-genetic effects of MB products Disease Generate / deplete Metabolites Gut Microbiome “Type x” Diet Genetic Predisposition Early Environmental Effects – maternal /other

  34. Gut Microbiota: Treatment • Can we control or modify our microbiota to treat / prevent disease or alter our disease risk? • Fecal transplants • Probiotics • Prebiotics

  35. Probiotics • Strains of microorganisms which confer health benefits on the host • A “probiotic” MB is one that supports health • A “dysbiotic” MB is associated with disease • Probiotics as supplements must: • Survive and metabolize in the gut • Confer beneficial effects • Non-pathogenic and non-toxic*

  36. Probiotics – Current Status • Clinical Studies – few controlled • Decreases antibiotic induced-diarrhea 50-60% • No benefit in travellers diarrhea • ? Effect in Inflammatory Bowel Disease • No effect in diabetes/obesity (to date) • Generally safe (few cases of sepsis) • Shotgun approach: • What is the appropriate probiotic or prebiotic for any given disease not yet defined • MB of individuals not defined – unclear what is needed

  37. Probiotics – Current Status • $16B industry • Strain / number of organisms per dose varies from 5-100B • Storage conditions / QC vary • Survival of organisms in gut and change in MB as yet undocumented • Tremendous therapeutic potential in future • Buyer beware at present

  38. Prebiotics • Foods that promote growth and activity of beneficial bacteria • Resistant to digestion (acid/enzymes/absorption) • Able to be fermented/metabolized by intestinal organisms • Promote growth/activity of beneficial intestinal organisms • Egs: Fiber/complex polysaccharides • Still very little research on what foods/prebiotics promote what bacteria, and in turn what bacteria we want to promote • Combined with probiotics - synbiotic

  39. Our Gut Ecosystem

  40. The Future • Human Microbiome Project (HMP) underway • Probiotic bandwagon is well underway • Right now a better financial investment than a health investment • Not yet a clear-cut good health investment – but it likely will be • In 20 years: • We will all know our “fecotype” just like we know our blood type • Personalized medicine will include and utilize knowledge of both our genome and our microbiome.

  41. The Future • SHITTY treatment from our doctor may be just what we all want and need!!

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