Nonlethal Inhibition of Gut Microbial Trimethylamine N-oxide Production Improves Cardiac Function and Remodeling in a Murine Model of Heart Failure.
Nonlethal Inhibition of Gut Microbial Trimethylamine N-oxide Production Improves Cardiac Function and Remodeling in a Murine Model of Heart Failure.
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DOI：
10.1161/jaha.119.016223
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发表时间：
2020-05-18
影响因子：
5.4
通讯作者：
Lefer DJ
中科院分区：
文献类型：
--
作者：
Organ CL;Li Z;Sharp TE 3rd;Polhemus DJ;Gupta N;Goodchild TT;Tang WHW;Hazen SL;Lefer DJ
在心力衰竭期间，冠状动脉疾病和不良预后风险增加的患者表现出循环三甲胺N-氧化物（TMAO）水平升高，TMAO是膳食磷脂酰胆碱代谢中形成的代谢物。我们研究了饮食戒断TMAO以及使用TMAO生产的肠道微生物靶向抑制剂对心力衰竭期间心脏功能和结构的有效性。雄性C57 BLK/6 J小鼠在横主动脉缩窄前3周开始喂食对照饮食、含有TMAO（0.12%wt/wt）的饮食、含有胆碱（1%wt/wt）的饮食或含有胆碱（1%wt/wt）加微生物胆碱三甲胺裂解酶抑制剂碘甲基胆碱（0.06%wt/wt）的饮食。在横向主动脉缩窄后6周，TMAO组中的一部分动物在研究的剩余时间转换为对照饮食。每3周监测一次左心室结构和功能。与TMAO组相比，从饮食中撤出TMAO减轻了不利的心室重构并改善了心功能。类似地，与胆碱喂养组相比，用胆碱三甲胺裂解酶抑制剂碘甲基胆碱抑制肠道微生物将胆碱转化为TMAO，改善了重塑和心脏功能。这些实验结果具有临床相关性，并且它们表明，TMAO水平在长期暴露期后是可以改变的，无论是饮食中TMAO的戒断还是肠道微生物对TMAO生成的阻断。此外，这些降低循环TMAO水平的治疗策略减轻了饮食胆碱和TMAO在心力衰竭中的负面影响。
Patients at increased risk for coronary artery disease and adverse prognosis during heart failure exhibit increased levels of circulating trimethylamine N‐oxide (TMAO), a metabolite formed in the metabolism of dietary phosphatidylcholine. We investigated the efficacy of dietary withdrawal of TMAO as well as use of a gut microbe‐targeted inhibitor of TMAO production, on cardiac function and structure during heart failure. Male C57BLK/6J mice were fed either control diet, a diet containing TMAO (0.12% wt/wt), a diet containing choline (1% wt/wt), or a diet containing choline (1% wt/wt) plus a microbial choline trimethylamine lyase inhibitor, iodomethylcholine (0.06% wt/wt), starting 3 weeks before transverse aortic constriction. At 6 weeks after transverse aortic constriction, a subset of animals in the TMAO group were switched to a control diet for the remainder of the study. Left ventricular structure and function were monitored at 3‐week intervals. Withdrawal of TMAO from the diet attenuated adverse ventricular remodeling and improved cardiac function compared with the TMAO group. Similarly, inhibiting gut microbial conversion of choline to TMAO with a choline trimethylamine lyase inhibitor, iodomethylcholine, improved remodeling and cardiac function compared with the choline‐fed group. These experimental findings are clinically relevant, and they demonstrate that TMAO levels are modifiable following long‐term exposure periods with either dietary withdrawal of TMAO or gut microbial blockade of TMAO generation. Furthermore, these therapeutic strategies to reduce circulating TMAO levels mitigate the negative effects of dietary choline and TMAO in heart failure.