1. L-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans
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Koeth, Robert A., Lam-Galvez, Betzabe Rachel, Kirsop, Jennifer, Wang, Zeneng, Levison, Bruce S., Gu, Xiaodong, Copeland, Matthew F., Bartlett, David, Cody, David B., Dai, Hong J., Culley, Miranda K., Li, Xinmin S., Fu, Xiaoming, Wu, Yuping, Li, Lin, DiDonato, Joseph A., Tang, W.H. Wilson, Garcia-Garcia, Jose Carlos, and Hazen, Stanley L.
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Carnitine -- Research ,Omnivores -- Research ,Microbiota (Symbiotic organisms) -- Research ,Health care industry - Abstract
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, [gamma]-butyrobetaine ([gamma]BB). The contribution of [gamma]BB in gut microbiota- dependent L-carnitine metabolism in humans is unknown.METHODS. Omnivores and vegans/vegetarians ingested deuterium-labeled L-carnitine ([d.sub.3]-L-carnitine) or [gamma]BB ([d.sub.9]-[gamma]BB), and both plasma metabolites and fecal polymicrobial transformations were examined at baseline, following oral antibiotics, or following chronic ([greater than or equal to] 2 months) L-carnitine supplementation. Human fecal commensals capable of performing each step of the L-carnitine [right arrow] [gamma]BB [right arrow] TMA transformation were identified.RESULTS. Studies with oral [d.sub.3]-L-carnitine or [d.sub.9]-[gamma]BB before versus after antibiotic exposure revealed gut microbiota contribution to the initial 2 steps in a metaorganismal L-carnitine [right arrow] [gamma]BB [right arrow] TMA [right arrow] TMAO pathway in subjects. Moreover, a striking increase in [d.sub.3]-TMAO generation was observed in omnivores over vegans/vegetarians (>20-fold; P = 0.001) following oral [d.sub.3]-L-carnitine ingestion, whereas fasting endogenous plasma L-carnitine and [gamma]BB 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 [gamma]BB, whereas the second gut microbial transformation, [gamma]BB [right arrow] TMA, was diet inducible (L-carnitine, omnivorous). Extensive anaerobic subculturing of human feces identified no single commensal capable of L-carnitine [right arrow] TMA transformation, multiple community members that converted L-carnitine to [gamma]BB, and only 1 Clostridiales bacterium, Emergencia timonensis, that converted [gamma]BB to TMA. In coculture, E. timonensis promoted the complete L-carnitine [right arrow] 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 [gamma]BB, followed by (b) transformation into TMA via low-abundance microbiota in omnivores, and to a markedly lower extent, in vegans/vegetarians. Gut microbiota [gamma]BB [right arrow] TMA/TMAO transformation is induced by omnivorous dietary patterns and chronic L-carnitine exposure.TRIAL REGISTRATION. ClinicalTrials.gov NCT01731236.FUNDING. NIH and Office of Dietary Supplements grants HL103866, HL126827, and DK106000, and the Leducq Foundation., IntroductionRecent studies identify a mechanistic link between a Western diet, gut microbiota-dependent metabolism, and development of both cardiovascular disease (CVD) and metabolic diseases (1-3). For example, the ingestion of trimethylamine-containing [...]
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- 2019
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