title: γ-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO.
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.
authors.affiliation: Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Koeth
authors.affiliation: Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Levison
authors.affiliation: Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Miranda K
authors.initials: MK
authors.lastname: Culley
authors.affiliation: Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Buffa
authors.affiliation: Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Gregory
authors.affiliation: Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Elin
authors.initials: E
authors.lastname: Org
authors.affiliation: Department of Mathematics, Cleveland State University, Cleveland, OH 44115, USA.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Smith
authors.affiliation: 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.
authors.forename: W H Wilson
authors.initials: WHW
authors.lastname: Tang
authors.affiliation: Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: DiDonato
authors.affiliation: Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: 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.
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000382:microbiology*; D001622:Betaine / Q000031:analogs & derivatives* / Q000378:metabolism; D002331:Carnitine / Q000378:metabolism*; D005260:Female; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000382:microbiology*; D008744:Methylamines / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota
chemical_list: D008744:Methylamines; D001622:Betaine; C002889:gamma-butyrobetaine; C005855:trimethyloxamine; D002331:Carnitine