Disclosures Nothing to disclose Microbiome and Cardiovascular Disease Ma Somsouk, MD, MAS Associate Professor of Medicine Dean M. Craig Endowed Chair in Gastrointestinal Medicine Division of Gastroenterology Zuckerberg San Francisco General Microbiome Microbiome • What is it? • What is it? • Impact on health • Impact on health • Shaping the microbiome • Shaping the microbiome 1
The Rise of the Microbiome Diversity of the Human Microbiome Nat. Rev. Micro. 2011;9:279-290 Microbiome: DNA Encoding 16S rRNA The Human Microbiome Samples The Gut Microbiota • Human gut is home to ~ 100 trillion bacterial cells Microbes Sequence • Density of 10 11 to 10 12 per gram in 16S rRNA marker gene the colon Counts • Genome size of microbiota at least 100-fold greater than human • Large numbers species present, most uncultured Classify sequence è microbe Nat. Rev. Micro. 2011;9:279-290 2
Microbiome & disease Microbiome • What is it? • Impact on health • Shaping the microbiome Tang et al., NEJM 2013; Van Nood et al., NEJM 2013; Alang & Kelly. OFID 2015; Ridaura et al. Science , 2013 Microbiome as space occupying community Impact of microbiome on health C. difficile infection (CDI) • Up to 5% colonized by this organism • As a community • Disease associated with exposure to antibiotics • As a metabolic entity • Antibiotic treatment is first-line • Recurrence is 30% after first episode – More than 50% after 2 nd episode 3
Microbiome interacts with diet to TMA-producing bacteria affects serum affect metabolism & CVD TMAO levels Koeth et al., Nat Med 2013; Tang et al., NEJM 2013 Kymberleigh A. Romano et al. mBio 2015 Inhibiting microbial TMA lyase to treat Microbiome and nutrition/metabolism atherosclerosis Foamy macrophage OFID , 2015 Atherosclerotic lesions Ridaura et al. Science , 2013 Wang Z et al. Cell , 2015 4
Impact of microbiome on health Metabolism of digoxin • As a community • Unsaturated lactone is ten times more active than the saturated ring (dihydrolactone) • As a metabolic agent • As a pharmacoactive agent – Patient to patient variation – PK/PD altered by: • Antibiotics / diet • IV vs. oral formulation • 20% have substantial amount of dihydrolactone • Antibiotics increase serum levels of active agent Eggerthella lenta + cardiac glycoside Microbiome reductase (cgr) alters digoxin levels • What is it? • Impact on health • Shaping the microbiome (Prodrug) Bacterial reductase How might the microbiome be modulated? (Active) Haiser & Turnbaugh et al. Science 2013 5
Microbial steady states Fecal transplantation • ‘yellow soup’ used to treat abdominal diseases – Ge Hong 4 th & Li Shizhen 16 th century Infection (e.g., C. diff) Antibiotics • Camel feces as remedy for bacterial dysentery by Bedouins Diet Probiotics Stool transplant • In modern medicine, successful fecal treatment of 4 critically ill patients with fulminant pseudomembranous colitis – Eiseman B, Surgery , 1958 Two individuals’ microbiome Fecal microbial transplant (FMT) cures recurrent Clostridium difficile tracked over time Subject A Subject B Engraftment of donor microbiome Pre-FMT PC2 • Microbiome relatively stable – Disruption occurred while traveling Principal Coordinate (PC) 1 – Disruption occurred due to Salmonella infection • Microbiome stably altered David et al. Genome Biology, 2014 Van Nood et al., NEJM 2013; Seekatz AM Mbio, 2014 6
Introduction of the donor microbiome by colonoscopy Ileum Cecum Summary: Microbiome • Microbiome can affect cardiovascular health – Nutrient and drug metabolism • TMAO, digoxin, lovastatin, insulin resistance – Immunologic effects not discussed • Microbiome can be modulated – Fecal transplant effective for recurrent C diff – Potentially transferable (e.g., obesity) – Novel pharmacotherapeutic targets 7
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