12/8/19 Influence of the Gut Microbiome on Atherosclerotic Disease Dylan Dodd Assistant Professor Stanford University 1 Disclosures I have nothing to disclose 2 1
12/8/19 The GI tract is home to trillions of microbes Oral Cavity 1,000,000-100,000,000 Microbes per teaspoon Stomach 10-1,000 Who is there? What are they doing? Colon 100,000,000,000 - 1,000,000,000,000 Small intestines 10,000-10,000,000 Mucus Colon Cells Image courtesy of Kristen Earle (Sonnenburg lab) and Gabriel Billings (KC Huang lab) 3 Tools to study the human gut microbiome Who is there? Culturing 16S rRNA sequencing Metagenomics (functional potential) Marissa Fessenden . Smithsonian.com (2015) 4 2
12/8/19 Tools to study the human gut microbiome Who is there? Culturing 16S rRNA sequencing Metagenomics (functional potential) Andrew Y. Koh . Clin Chem (2017) 5 Tools to study the human gut microbiome Who is there? Culturing 16S rRNA sequencing Metagenomics (functional potential) Envgen (2019) 6 3
12/8/19 Tools to study the human gut microbiome What are they doing? Metatranscriptomics Metaproteomics Metabolomics National Academies of Sciences (2018) 7 The human gut microbiome Key facts about the human gut microbiome. • Most data from human feces • Colonization occurs after birth and microbial community changes with age • ~20 trillion cells, mainly bacteria, but also archaea, fungi, viruses • Mainly from five phyla, but >90% from the Firmicutes and Bacteroidetes • Roughly 600-1000 different taxa within individuals • High inter-individual diversity in microbiome (only ~20% of genes shared across individuals) • Influenced by diet and environmental exposures (pets, drugs, travel, etc.) 8 4
12/8/19 The human gut microbiome Role of the “healthy” gut microbiome in human physiology • Education of the immune system • Contribution to human metabolism • Provision of vitamins (B12 and K) • Fortification of the gut barrier • Protection against pathogens • Production of 100s of drug-like metabolites (endocrine function) • Important issue of causation vs. association 9 The human gut microbiome Health impacts of the microbiome Obesity Metabolic syndrome Diabetes Inflammatory bowel disease Intestinal permeability/motility Inflammatory arthritis GI infectious disease Molecular mechanism? Atherosclerotic heart disease Therapeutic target? Renal disease Treatment modality? Cancer immunotherapy response Vaccine immunity Parkinson’s disease Autism Microbiome therapeutics Functions can be programmed Excellent safety profile Mucus Epithelium Pathway to IND straightforward Image courtesy of Kristen Earle (Sonnenburg lab) and Gabriel Billings (KC Huang lab) 10 5
12/8/19 Establishing causality in the microbiome The microbiome and Koch’s Postulates; a special case Causal microbes are often masked by microbial community Can we consider a ‘dysbiotic’ microbial community as causative? Disease in animal models is often very different from humans Robert Koch, Nobel Prize (1905) 11 Identifying microbes and establishing causality Human Studies Gnotobiotic mice Charis Tsevis ( Science News ) Karlsson, et al . Diabetes (2013) 12 6
12/8/19 How might the gut microbiome influence atherosclerosis 1) Infection or translocation of bacteria 2) Modulation of lipid and cholesterol metabolism 3) Production of drug-like small molecules 13 How might the gut microbiome influence atherosclerosis 1) Infection or translocation of bacteria 2) Modulation of lipid and cholesterol metabolism 3) Production of drug-like small molecules 14 7
12/8/19 Impact of infection/bacterial translocation on atherosclerosis Proposed mechanisms • Chronic inflammation at distal site increases inflammatory mediators • Deposition of oral microbes in atherosclerotic plaques Oral microbes Significant association between periodontitis and atherosclerotic heart disease in humans • Dietrich, et al . J Clin Periodontol (2013) Bacteria isolated from plaques ( Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans ) increased atherosclerotic lesions in genetically predisposed animal models Lower GI tract Convincing human studies are lacking Mouse models suggest leaky gut barrier increases translocation of bacterial TLR ligands that promote inflammation and plaque formation Jonsson and Backhed . Nat Rev Cardiol (2017) 15 How might the gut microbiome influence atherosclerosis 1) Infection or translocation of bacteria 2) Modulation of lipid and cholesterol metabolism 3) Production of drug-like small molecules 16 8
12/8/19 Role of the microbiome in lipid/cholesterol metabolism Lipids and cholesterol Compared to germ-free mice, conventionally raised mice have decreased plasma cholesterol and triglycerides but these are increased in liver and adipose tissue • Velagapudi, et al . J Lipid Res (2010) Human studies showed fecal microbiome richness is inversely correlated with BMI and plasma triglycerides (LifeLines cohort) • Fu, et al . Circ Res (2015) Relationship between microbiome composition and plasma lipids and cholesterol exists, but significance for atherosclerosis remains unknown 17 Role of the microbiome in lipid/cholesterol metabolism Bile acids Primary bile acids are synthesized in the liver, conjugated to taurine or glycine, and excreted in the bile. Bacteria deconjugate primary bile acids and convert them to secondary bile acids. Germ free mice have increased bile acid pools and undetectable levels of secondary bile acids • Sayin, et al . Cell Metabolism (2013) FXR signalling by bile acids modulates glucose and lipid metabolism Conflicting data on role of FXR on atherosclerosis development in mouse models Very little human data available Frederick Suchy. Medical Physiology (2017) 18 9
12/8/19 How might the gut microbiome influence atherosclerosis 1) Infection or translocation of bacteria 2) Modulation of lipid and cholesterol metabolism 3) Production of drug-like small molecules 19 Small molecules as effectors of microbiome function The microbiome produces 100s of chemicals Van Treuren and Dodd . Ann Rev Pathol (2019) 20 10
12/8/19 Small molecules as effectors of microbiome function Microbial metabolites vary across individuals Van Treuren and Dodd . Ann Rev Pathol (2019) 21 TMAO and atherosclerotic heart disease Rak and Rader . Nature (2011) 22 11
12/8/19 TMAO and atherosclerotic heart disease 23 TMAO and atherosclerotic heart disease Summary of findings Human Studies Data supporting TMAO in atherosclerosis TMAO was identified from non-targeted metabolomics study of CVD patients who developed adverse events (MI, stroke, or death). Choline and betaine also associated with increased atherosclerotic plaque burden. In 4,007 patients undergoing elective coronary angiography, comparison of upper vs. lower quartile of TMAO levels revealed a hazard ratio of 2.54 for major adverse cardiovascular events. Data that suggest more studies are needed Most, but not all studies have identified an association between increased TMAO and cardiovascular disease. TMAO levels rise as the kidneys fail. Patient’s who develop MACE also have reduced kidney function. Therefore impaired kidney function is a potential confounder. Fish is high in TMA which bacteria (or the host) convert to TMAO. Yet a Charis Tsevis ( Science News ) large body of evidence link fish consumption as cardioprotective. 24 12
12/8/19 TMAO and atherosclerotic heart disease Summary of findings Mouse Models Data supporting TMAO in atherosclerosis Apoe -/- mice fed carnitine + choline, or TMAO develop increased atherosclerotic burden. These findings have been partly recapitulated by other groups. Data that suggest more studies are needed Mouse diets supplemented with carnitine and choline used non- physiologic levels (~12 times higher than normal chow). A separate study in Apoe -/- mice (under different conditions), showed a protective effect of TMAO on atherosclerotic lesions 25 Potential to manipulate the microbiome to treat atherosclerotic heart disease Wang, et al. Cell (2015); Jonsson and Backhed . Cell (2015) 26 13
12/8/19 TMAO and atherosclerotic heart disease Overall Summary The TMAO finding is the first mechanistic study linking microbiome function to human disease. The evidence that high levels of TMAO are associated with major adverse cardiovascular events is strong. Future studies should address whether TMAO predicts adverse events independent of poor kidney function. More detailed animal studies are warranted to address inconsistencies (details matter). 27 Conclusions Jonsson and Backhed . Nat Rev Cardiol (2017) 28 14
12/8/19 Further reading Jonsson and Backhed. Role of gut microbiota in atherosclerosis. Nat Rev Cardiol. 2017. 14(2): 79-87. Zeisel and Warrier. Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease. Annu Rev Nutr. 2017. 37: 157-181. Tang, et al. Intestinal Microbiota in Cardiovascular Health and Disease: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019. 73(16): 2089-2105. 29 15
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