Department of Cellular and Molecular Medicine, Lerner Research Institute.
Center for Microbiome and Human Health, and.
J Clin Invest. 2019 Jan 2;129(1):373-387. doi: 10.1172/JCI94601. Epub 2018 Dec 10.
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.
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.
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.
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.
ClinicalTrials.gov NCT01731236.
NIH and Office of Dietary Supplements grants HL103866, HL126827, and DK106000, and the Leducq Foundation.
左旋肉碱是红肉中丰富的营养物质，通过多步途径涉及致动脉粥样硬化的中间产物γ-丁酰甜菜碱（γBB），经由肠道微生物群依赖性形成三甲胺（TMA）和三甲基胺 N-氧化物（TMAO），在小鼠中加速动脉粥样硬化。γBB 在人类肠道微生物群依赖性左旋肉碱代谢中的作用尚不清楚。
杂食者和素食者/素食者摄入氘标记的左旋肉碱（d3-l-carnitine）或 γBB（d9-γBB），并在基线、口服抗生素后或长期（≥2 个月）左旋肉碱补充后检查血浆代谢产物和粪便多微生物转化。鉴定出能够完成左旋肉碱→γBB→TMA 转化的每个步骤的人类粪便共生菌。
在抗生素暴露前后口服 d3-l-carnitine 或 d9-γBB 的研究揭示了肠道微生物群对代谢物在元生物体中的前两个步骤的贡献。此外，杂食者口服 d3-l-carnitine 后，d3-TMAO 的生成量显著增加，与素食者/素食者相比（>20 倍；P = 0.001），而素食者/素食者（n = 32）与杂食者（n = 40）的空腹内源性血浆左旋肉碱和 γBB 水平相似。在慢性左旋肉碱补充前后的粪便代谢转化研究和口服同位素示踪研究表明，杂食者和素食者都能迅速将肉碱转化为 γBB，而第二个肠道微生物转化，γBB→TMA，是饮食诱导的（左旋肉碱，杂食）。人类粪便的广泛厌氧亚培养未鉴定出能够将左旋肉碱转化为 TMA 的单一共生菌，有多种微生物可以将左旋肉碱转化为 γBB，只有一种梭状芽胞杆菌，即埃默西亚·提蒙尼斯（Emergencia timonensis），可以将 γBB 转化为 TMA。在共培养中，埃默西亚·提蒙尼斯（Emergencia timonensis）促进了左旋肉碱→TMA 的完全转化。
在人类中，膳食左旋肉碱通过 2 个连续的肠道微生物群依赖性转化，转化为动脉粥样硬化和血栓形成促进的代谢物 TMAO：（a）最初快速生成致动脉粥样硬化的中间产物γBB，随后（b）通过杂食者中的低丰度微生物群转化为 TMA，而在素食者/素食者中，转化程度要低得多。肠道微生物群γBB→TMA/TMAO 转化是由杂食性饮食模式和慢性左旋肉碱暴露诱导的。
ClinicalTrials.gov NCT01731236。
NIH 和膳食补充剂办公室的 HL103866、HL126827 和 DK106000 以及 Leducq 基金会。
