Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis

被引：1059

作者：

Wang, Zeneng ^{[1
]}

Roberts, Adam B. ^{[1
]}

Buffa, Jennifer A. ^{[1
]}

Levison, Bruce S. ^{[1
]}

Zhu, Weifei ^{[1
]}

Org, Elin ^{[2
]}

Gu, Xiaodong ^{[1
]}

Huang, Ying ^{[1
]}

Zamanian-Daryoush, Maryam ^{[1
]}

Culley, Miranda K. ^{[1
]}

DiDonato, Anthony J. ^{[1
]}

Fu, Xiaoming ^{[1
]}

Hazen, Jennie E. ^{[1
]}

Krajcik, Daniel ^{[1
]}

DiDonato, Joseph A. ^{[1
]}

Lusis, Aldons J. ^{[2
]}

Hazen, Stanley L. ^{[1
,3
]}

机构：

[1] Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH 44195 USA

[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Cardiol, Los Angeles, CA 90095 USA

[3] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44195 USA

来源：

CELL | 2015年 / 163卷 / 07期

关键词：

CONTAINING MONOOXYGENASE 3; N-OXIDE; INTESTINAL MICROBIOTA; PROGNOSTIC VALUE; CHOLINE; METABOLISM; PHOSPHATIDYLCHOLINE; DEGRADATION; DISEASE; BETAINE;

D O I：

10.1016/j.cell.2015.11.055

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1585 / 1595

页数：11

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