l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans.

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(3)-L-carnitine) or gamma BB (d(9)-gamma BB), 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 ->gamma BB -> TMA transformation were identified. RESULTS. Studies with oral d(3)-L-carnitine or d(9)-gamma BB before versus after antibiotic exposure revealed gut microbiota contribution to the initial 2 steps in a metaorganismal L-carnitine ->gamma BB -> TMA -> TMAO pathway in subjects. Moreover, a striking increase in d(3)-TMAO generation was observed in omnivores over vegans/vegetarians (>20-fold; P = 0.001) following oral d(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 -> 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 gamma BB, and only 1 Clostridiales bacterium, Emergencia timonensis, that converted gamma BB 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 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 -> TMA/TMAO transformation is induced by omnivorous dietary patterns and chronic L-carnitine exposure.