杂食者的肠道菌群可促进饮食中的L-肉毒碱转化为有害的TMAO
  • 素食和杂食者口服同位素标记的L-肉毒碱和γ-丁酰甜菜碱(γ-BB),随后进行短期口服抗生素或长期补充L-肉毒碱干预,检测血浆代谢产物和粪便菌群的代谢转化;
  • 肠道菌群介导了体内L-肉毒碱→γ-BB→三甲胺(TMA)→氧化三甲胺(TMAO)代谢途径的前两步;
  • 杂食者和素食者都能将肉碱迅速转化为γ-BB,但肠道菌群介导的γ-BB向TMA转化在杂食者中更高;
  • 体外培养发现,复合菌群介导了肉碱转化为γ-BB,而只有一种梭菌能够将γ-BB转化为TMA。
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来自Journal of Clinical Investigation发表的一项最新研究,发现相比于素食者,杂食者的肠道菌群可促进饮食(特别是肉类)中的L-肉毒碱转化为TMAO,后者在心血管疾病中发挥重要作用。
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l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans

杂食性饮食中的L-肉毒碱诱导人体中致粥样硬化的肠道菌群通路

10.1172/JCI94601

2018-12-10, Article

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BACKGROUND.: l-Carnitine, an abundant nutrient in red meat, accelerates atherosclerosis in mice via gut microbiota–dependent formation of trimethylamine (TMA) and trimethylamine N-oxide (TMAO) via a multistep pathway involving an atherogenic intermediate, γ-butyrobetaine (γBB). The contribution of γBB in gut microbiota–dependent l-carnitine metabolism in humans is unknown.
METHODS. : Omnivores and vegans/vegetarians ingested deuterium-labeled l-carnitine (d3-l-carnitine) or γBB (d9-γBB), and both plasma metabolites and fecal polymicrobial transformations were examined at baseline, following oral antibiotics, or following chronic (≥2 months) l-carnitine supplementation. Human fecal commensals capable of performing each step of the l-carnitine→γBB→TMA transformation were identified.
RESULTS. : Studies with oral d3-l-carnitine or d9-γBB before versus after antibiotic exposure revealed gut microbiota contribution to the initial 2 steps in a metaorganismal l-carnitine→γBB→TMA→TMAO pathway in subjects. Moreover, a striking increase in d3-TMAO generation was observed in omnivores over vegans/vegetarians (>20-fold; P = 0.001) following oral d3-l-carnitine ingestion, whereas fasting endogenous plasma l-carnitine and γBB levels were similar in vegans/vegetarians (n = 32) versus omnivores (n = 40). Fecal metabolic transformation studies, and oral isotope tracer studies before versus after chronic l-carnitine supplementation, revealed that omnivores and vegans/vegetarians alike rapidly converted carnitine to γBB, whereas the second gut microbial transformation, γBB→TMA, was diet inducible (l-carnitine, omnivorous). Extensive anaerobic subculturing of human feces identified no single commensal capable of l-carnitine→TMA transformation, multiple community members that converted l-carnitine to γBB, and only 1 Clostridiales bacterium, Emergencia timonensis, that converted γBB to TMA. In coculture, E. timonensis promoted the complete l-carnitine→TMA transformation.
CONCLUSION. : In humans, dietary l-carnitine is converted into the atherosclerosis- and thrombosis-promoting metabolite TMAO via 2 sequential gut microbiota–dependent transformations: (a) initial rapid generation of the atherogenic intermediate γBB, followed by (b) transformation into TMA via low-abundance microbiota in omnivores, and to a markedly lower extent, in vegans/vegetarians. Gut microbiota γBB→TMA/TMAO transformation is induced by omnivorous dietary patterns and chronic l-carnitine exposure.

First Authors:
Robert A Koeth

Correspondence Authors:
Stanley L Hazen

All Authors:
Robert A Koeth,Betzabe Rachel Lam-Galvez,Jennifer Kirsop,Zeneng Wang,Bruce S Levison,Xiaodong Gu,Matthew F Copeland,David Bartlett,David B Cody,Hong J Dai,Miranda K Culley,Xinmin S Li,Xiaoming Fu,Yuping Wu,Lin Li,Joseph A DiDonato,WH Wilson Tang,Jose Carlos Garcia-Garcia,Stanley L Hazen

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