Disclosures Nothing to disclose Microbiome and Cardiovascular - - PDF document

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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

Disclosures

Nothing to disclose

Microbiome

• What is it?
• Impact on health
• Shaping the microbiome

Microbiome

• What is it?
• Impact on health
• Shaping the microbiome

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The Rise of the Microbiome

• Nat. Rev. Micro. 2011;9:279-290

Diversity of the Human Microbiome

The Gut Microbiota

• Human gut is home to ~ 100 trillion

bacterial cells

• Density of 1011 to 1012 per gram in

the colon

• Genome size of microbiota at least

100-fold greater than human

• Large numbers species present,

most uncultured

• Nat. Rev. Micro. 2011;9:279-290

The Human Microbiome

Microbiome: DNA Encoding 16S rRNA

Sequence 16S rRNA marker gene Classify sequence è microbe

Samples Microbes

Counts

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Microbiome

• What is it?
• Impact on health
• Shaping the microbiome

Microbiome & disease

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

• C. difficile infection (CDI)
• Up to 5% colonized by this organism
• Disease associated with exposure to antibiotics
• Antibiotic treatment is first-line
• Recurrence is 30% after first episode

– More than 50% after 2nd episode

Impact of microbiome on health

• As a community
• As a metabolic entity

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Microbiome interacts with diet to affect metabolism & CVD

Koeth et al., Nat Med 2013; Tang et al., NEJM 2013

TMA-producing bacteria affects serum TMAO levels

Kymberleigh A. Romano et al. mBio 2015

Inhibiting microbial TMA lyase to treat atherosclerosis

Wang Z et al. Cell, 2015

Foamy macrophage Atherosclerotic lesions

Microbiome and nutrition/metabolism

Ridaura et al. Science, 2013

OFID, 2015

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Impact of microbiome on health

• As a community
• As a metabolic agent
• As a pharmacoactive agent

– Patient to patient variation – PK/PD altered by:

• Antibiotics / diet
• IV vs. oral formulation

Metabolism of digoxin

• Unsaturated lactone is ten times more active

than the saturated ring (dihydrolactone)

• 20% have substantial amount of dihydrolactone
• Antibiotics increase serum levels of active agent

Eggerthella lenta + cardiac glycoside reductase (cgr) alters digoxin levels

Haiser & Turnbaugh et al. Science 2013

Bacterial reductase (Prodrug) (Active)

Microbiome

• What is it?
• Impact on health
• Shaping the microbiome

How might the microbiome be modulated?

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Microbial steady states

Infection (e.g., C. diff) Antibiotics Diet Probiotics Stool transplant

Fecal transplantation

• ‘yellow soup’ used to treat abdominal

diseases

– Ge Hong 4th & Li Shizhen 16th century

• Camel feces as remedy for bacterial

dysentery by Bedouins

• In modern medicine, successful fecal

treatment of 4 critically ill patients with fulminant pseudomembranous colitis

– Eiseman B, Surgery, 1958

Fecal microbial transplant (FMT) cures recurrent Clostridium difficile

Engraftment of donor microbiome

Van Nood et al., NEJM 2013; Seekatz AM Mbio, 2014

Pre-FMT Principal Coordinate (PC) 1 PC2

Two individuals’ microbiome tracked over time

• Microbiome relatively stable

– Disruption occurred while traveling – Disruption occurred due to Salmonella infection

• Microbiome stably altered

David et al. Genome Biology, 2014

Subject A Subject B

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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