symbiotic heirarchies of the intestinal tract: implications for health and disease woody emlen md

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  • Slide 1
  • Symbiotic Heirarchies of the Intestinal Tract: Implications for Health and Disease Woody Emlen MD
  • Slide 2
  • Our Gut Microbiome Woody Emlen MD S ymbiotic H eirarchies of the I ntestinal T ract
  • Slide 3
  • Slide 4
  • Why Now? Hot topic in medical and lay literature (NY Times/Economist/Science/Nature/TED/Mothe r Jones) Explosion of information over past 10 years Significant medical implications beginning to emerge (obesity, diabetes, allergy etc).
  • Slide 5
  • Whats the Big Deal: Whats 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!!
  • Slide 6
  • Bacterial Culture in Petri Dish
  • Slide 7
  • We are not Alone!!
  • Slide 8
  • Some Most of my closest Friends are germs! 100,000,000,000,000 bacteria on/in our body 10 pounds of bacteria!! Several biotain multiple sites: Skin Mucosa (oral, vaginal) GI tract (Large intestine>> small intestine) Each biota is a complex ecosystem in itself
  • Slide 9
  • Microbiota Sites
  • Slide 10
  • Are we really Human? 350,000,000People in US 7,000,000,000People on earth 10,000,000,000,000Cells in our body 100,000,000,000,000Bacteria in and on your body - RIGHT NOW! Are we merely a carrier for a huge bacterial colony?
  • Slide 11
  • Slide 12
  • 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 microbiota microbiome
  • Slide 13
  • The Gut Microbiota 500-1000 different species >5000 taxa (identifiably different on DNA analysis) Most bacteria anaerobic Densest bacterial colony on earth (> 10 12 /cm 3 ) Extremely complex ecosystem (rain forest)
  • Slide 14
  • YUCK!!
  • Slide 15
  • Questions Where do they come from? Why are they here? whats 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?
  • Slide 16
  • 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
  • Slide 17
  • Effect of Diet on MB Gnobiotic mice fed varying diets J J Faith et al. Science 2011;333:101-104 Published by AAAS
  • Slide 18
  • 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
  • Slide 19
  • Why are they here? If you cant 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
  • Slide 20
  • 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 cells to modulate metabolism Resistance to pathogenic bacteria Shape immune function & repertoire
  • Slide 21
  • Nutrition Enhance absorption of calories/nutrients Gnobiotic mice require 30% more calorie intake Break down non-digestible polysaccharides Generation of short-chain fatty acids (
  • Slide 22
  • 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
  • Slide 23
  • 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
  • Slide 24
  • 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)
  • Slide 25
  • 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)
  • Slide 26
  • Where does TMAO come from? 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 Normal After antibiotics Recovered from Abx
  • Slide 27
  • Dietary red meat / Eggs / cheese Conclusion: Foods thought to cause / contribute to heart disease exert their effects through the action of the gut Microbiota.
  • Slide 28
  • The Gut: Immune System Interactions Priority ONE protect me from the bugs!! 1 cell thick layer separating us from 10 14 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
  • Slide 29
  • 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
  • Slide 30
  • 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
  • Slide 31
  • Slide 32
  • Our Gut Ecosystem restores Restores gut ecosystem
  • Slide 33
  • 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)
  • Slide 34
  • Allergy/Asthma Hygiene Hypothesis Increasing incidence of allergy/asthma in western / 1 st 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
  • Slide 35
  • Types of Immune Response Type 1 Kill internal pathogens Internal inflammation Cell/bug death Type 2 Remove external irritants Sneezing Coughing Itching Excess Inflammation Autoimmunity Allergy Asthma Microbiota
  • Slide 36
  • Overview: MB Effects on Disease Host Genetics Gut Microbiome Type x Disease Early Environmental Effects maternal /other Genetic Predisposition Epi-genetic effects of MB products Generate / deplete Metabolites Environmental Exposures Diet
  • Slide 37
  • Gut Microbiota: Treatment Can we control or modify our microbiota to treat / prevent disease or alter our disease risk? Fecal transplants Probiotics Prebiotics
  • Slide 38
  • 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*
  • Slide 39
  • 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
  • Slide 40
  • 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
  • Slide 41
  • 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
  • Slide 42
  • Our Gut Ecosystem
  • Slide 43
  • 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.
  • Slide 44
  • The Future SHITTY treatment from our doctor may be just what we all want and need!!