Journal
CELL
Volume 163, Issue 7, Pages 1585-1595Publisher
CELL PRESS
DOI: 10.1016/j.cell.2015.11.055
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Funding
- NIH
- Office of Dietary Supplements [R01 HL103866, P20 HL113452, R01106000, P01H28481]
- American Heart Association Scientist Development grants
- Esperion
- Procter Gamble
- Astra Zeneca
- Pfizer
- Roche
- Takeda
- Cleveland Heart Laboratory
- Siemens
- Frantz Biomarkers, LLC
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Trimethylamine (TMA) N-oxide (TMAO), a gut-microbiota-dependent metabolite, both enhances atherosclerosis in animal models and is associated with cardiovascular risks in clinical studies. Here, we investigate the impact of targeted inhibition of the first step in TMAO generation, commensal microbial TMA production, on diet-induced atherosclerosis. A structural analog of choline, 3,3-dimethyl-1-butanol (DMB), is shown to non-lethally inhibit TMA formation from cultured microbes, to inhibit distinct microbial TMA lyases, and to both inhibit TMA production from physiologic polymicrobial cultures (e.g., intestinal contents, human feces) and reduce TMAO levels in mice fed a high-choline or L-carnitine diet. DMB inhibited choline diet-enhanced endogenous macrophage foam cell formation and atherosclerotic lesion development in apolipoprotein e(-/-) mice without alterations in circulating cholesterol levels. The present studies suggest that targeting gut microbial production of TMA specifically and non-lethal microbial inhibitors in general may serve as a potential therapeutic approach for the treatment of cardiometabolic diseases.
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