Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.
Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.
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DOI：
10.1056/nejmoa1109400
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发表时间：
2013-04-25
期刊：
影响因子：
--
通讯作者：
Hazen SL
中科院分区：
文献类型：
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作者：
Tang WH;Wang Z;Levison BS;Koeth RA;Britt EB;Fu X;Wu Y;Hazen SL
最近在动物中的研究表明，通过产生促动脉粥样硬化代谢物，三甲胺-N-氧化物（TMAO），饮食磷脂酰胆碱（卵磷脂）中胆碱部分的肠道微生物代谢与冠状动脉疾病之间存在机械联系。我们研究了人类肠道微生物群依赖的膳食磷脂酰胆碱代谢、TMAO水平和不良心血管事件之间的关系。我们通过液相色谱法和在线串联质谱法定量了健康参与者在口服广谱抗生素抑制肠道微生物群之前和之后的血浆和尿液TMAO水平以及磷脂酰胆碱挑战（摄入两个煮熟的鸡蛋和氘[d9]标记的磷脂酰胆碱）后的血浆和尿液TMAO水平和血浆胆碱和甜菜碱水平。我们进一步研究了4007例择期冠状动脉造影患者3年随访期间空腹血浆TMAO水平与主要不良心血管事件（死亡、心肌梗死或卒中）的关系。磷脂酰胆碱激发后，TMAO及其d9同位素体以及其他胆碱代谢产物的水平均呈时间依赖性增加。TMAO的血浆水平显着抑制后，管理的抗生素，然后重新出现后，撤药。血浆TMAO水平升高与主要不良心血管事件风险增加相关（最高与最低TMAO四分位数的风险比为2.54; 95%置信区间为1.96至3.28; P<0.001）。在校正传统危险因素后，TMAO水平升高预测主要不良心血管事件的风险增加（P<0.001），在低风险亚组中也是如此。从膳食磷脂酰胆碱产生TMAO依赖于肠道微生物群的代谢。TMAO水平的增加与主要不良心血管事件的风险增加有关。（由美国国立卫生研究院和其他机构资助。
Recent studies in animals have shown a mechanistic link between intestinal microbial metabolism of the choline moiety in dietary phosphatidylcholine (lecithin) and coronary artery disease through the production of a proatherosclerotic metabolite, trimethylamine-N-oxide (TMAO). We investigated the relationship among intestinal microbiota-dependent metabolism of dietary phosphatidylcholine, TMAO levels, and adverse cardiovascular events in humans. We quantified plasma and urinary levels of TMAO and plasma choline and betaine levels by means of liquid chromatography and online tandem mass spectrometry after a phosphatidylcholine challenge (ingestion of two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine) in healthy participants before and after the suppression of intestinal microbiota with oral broad-spectrum antibiotics. We further examined the relationship between fasting plasma levels of TMAO and incident major adverse cardiovascular events (death, myocardial infarction, or stroke) during 3 years of follow-up in 4007 patients undergoing elective coronary angiography. Time-dependent increases in levels of both TMAO and its d9 isotopologue, as well as other choline metabolites, were detected after the phosphatidylcholine challenge. Plasma levels of TMAO were markedly suppressed after the administration of antibiotics and then reappeared after withdrawal of antibiotics. Increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event (hazard ratio for highest vs. lowest TMAO quartile, 2.54; 95% confidence interval, 1.96 to 3.28; P<0.001). An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors (P<0.001), as well as in lower-risk subgroups. The production of TMAO from dietary phosphatidylcholine is dependent on metabolism by the intestinal microbiota. Increased TMAO levels are associated with an increased risk of incident major adverse cardiovascular events. (Funded by the National Institutes of Health and others.)