γ-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO

  • Cell Metab. 2014 Nov 4;20(5):799-812. doi: 10.1016/j.cmet.2014.10.006.
Robert A Koeth  1 ,  Bruce S Levison  1 ,  Miranda K Culley  1 ,  Jennifer A Buffa  1 ,  Zeneng Wang  1 ,  Jill C Gregory  1 ,  Elin Org  2 ,  Yuping Wu  3 ,  Lin Li  1 ,  Jonathan D Smith  4 ,  W H Wilson Tang  4 ,  Joseph A DiDonato  1 ,  Aldons J Lusis  2 ,  Stanley L Hazen  5
Affiliations
  • 1. Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 2. Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
  • 3. Department of Mathematics, Cleveland State University, Cleveland, OH 44115, USA.
  • 4. Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 5. Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: [email protected].
PMID: 25440057 DOI: 10.1016/j.cmet.2014.10.006
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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