γ-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO.
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| Abstract |
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.
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| Authors | Robert A Koeth, Bruce S Levison, Miranda K Culley, Jennifer A Buffa, Zeneng Wang, Jill C Gregory, Elin Org, Yuping Wu, Lin Li, Jonathan D Smith, W H Wilson Tang, Joseph A DiDonato, Aldons J Lusis, Stanley L Hazen |
| Journal | Cell metabolism (Cell Metab) Vol. 20 Issue 5 Pg. 799-812 (Nov 04 2014) ISSN: 1932-7420 [Electronic] United States |
| PMID | 25440057 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2014 Elsevier Inc. All rights reserved. |
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