γ-Butyrobetaine Is A Proatherogenic Intermediate in Gut Microbial Metabolism of L-Carnitine to TMAO
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.
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.; and Hazen, Stanley L., "γ-Butyrobetaine Is A Proatherogenic Intermediate in Gut Microbial Metabolism of L-Carnitine to TMAO" (2014). Mathematics Faculty Publications. 248.
This research was supported by National Institutes of Health and Office of Dietary Supplements grants R01 HL103866 (S.L.H.), P20 HL113452 (S.L.H.), PO1 HL30568 (A.J.L.), PO1 H28481 (A.J.L.), R01 HL-094322 (A.J.L.), R01 HL098193 (J.D.S.), and the Leducq Fondation (S.L.H. and A.J.L.). S.L.H. is also partially supported by a gift from the Leonard Krieger Fund. E.O. was supported in part by a MOBILITAS Postdoctoral Research Grant (MJD252) and FP7-People-IOF (330381). R.A.K. was supported in part by US NIH grant T32 GM007250.