γ-Butyrobetaine Is a Proatherogenic Intermediate in Gut Microbial Metabolism of L-Carnitine to TMAO

• Published in: Cell metabolism Vol. 20; no. 5; pp. 799 - 812
• Main Authors: Koeth, Robert A., Levison, Bruce S., Culley, Miranda K., Buffa, Jennifer A., Wang, Zeneng, Gregory, Jill C., Org, Elin, Wu, Yuping, Li, Lin, Smith, Jonathan D., Tang, W.H. Wilson, DiDonato, Joseph A., Lusis, Aldons J., Hazen, Stanley L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.11.2014
• Subjects: Animals; Atherosclerosis - metabolism; Atherosclerosis - microbiology; Betaine - analogs & derivatives; Betaine - metabolism; Carnitine - metabolism; Female; Gastrointestinal Tract - metabolism; Gastrointestinal Tract - microbiology; Methylamines - metabolism; Mice; Mice, Inbred C57BL; Microbiota
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2014.10.006

L-carnitine, a nutrient in red meat, was recently reported to accelerate atherosclerosis via a metaorganismal pathway involving gut microbial trimethylamine (TMA) formation and host hepatic conversion into trimethylamine-N-oxide (TMAO). Herein, we show that following L-carnitine ingestion, γ-butyrobetaine (γBB) is produced as an intermediary metabolite by gut microbes at a site anatomically proximal to and at a rate ∼1,000-fold higher than the formation of TMA. Moreover, we show that γBB is the major gut microbial metabolite formed from dietary L-carnitine in mice, is converted into TMA and TMAO in a gut microbiota-dependent manner (like dietary L-carnitine), and accelerates atherosclerosis. Gut microbial composition and functional metabolic studies reveal that distinct taxa are associated with the production of γBB or TMA/TMAO from dietary L-carnitine. Moreover, despite their close structural similarity, chronic dietary exposure to L-carnitine or γBB promotes development of functionally distinct microbial communities optimized for the metabolism of L-carnitine or γBB, respectively. [Display omitted] •γ-butyrobetaine (γBB) is a major gut microbial metabolite of L-carnitine in mice•γBB is an intermediate in gut microbe-dependent formation of TMAO from L-carnitine•Gut microbiota-generated γBB is atherogenic in the C57BL/6J Apoe−/− mouse model•Distinct microbes are associated with γBB or TMA/TMAO production from carnitine The ingestion of L-carnitine, a nutrient in red meat, accelerates atherosclerosis via gut microbe-dependent formation of trimethylamine-N-oxide (TMAO). Koeth et al. now identify γ-butyrobetaine as a major gut microbial intermediate in L-carnitine metabolism into TMAO, which is proatherogenic and produced by microbes distinct from those associated with TMAO formation.