2. Academic Validation
  3. γ-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO

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

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: hazens@ccf.org.
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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