title: Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis.
abstract: Trimethylamine (TMA) N-oxide (TMAO), a gut-microbiota-dependent metabolite, both enhances atherosclerosis in animal models and is associated with cardiovascular risks in clinical studies. Here, we investigate the impact of targeted inhibition of the first step in TMAO generation, commensal microbial TMA production, on diet-induced atherosclerosis. A structural analog of choline, 3,3-dimethyl-1-butanol (DMB), is shown to non-lethally inhibit TMA formation from cultured microbes, to inhibit distinct microbial TMA lyases, and to both inhibit TMA production from physiologic polymicrobial cultures (e.g., intestinal contents, human feces) and reduce TMAO levels in mice fed a high-choline or L-carnitine diet. DMB inhibited choline diet-enhanced endogenous macrophage foam cell formation and atherosclerotic lesion development in apolipoprotein e(-/-) mice without alterations in circulating cholesterol levels. The present studies suggest that targeting gut microbial production of TMA specifically and non-lethal microbial inhibitors in general may serve as a potential therapeutic approach for the treatment of cardiometabolic diseases.
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: wangz2@ccf.org.
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Roberts
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Buffa
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Levison
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Weifei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Elin
authors.initials: E
authors.lastname: Org
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Zamanian-Daryoush
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Miranda K
authors.initials: MK
authors.lastname: Culley
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: DiDonato
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Fu
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Jennie E
authors.initials: JE
authors.lastname: Hazen
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Krajcik
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: DiDonato
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: Department of Cellular and Molecular Medicine, 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; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D002794:Choline / Q000031:analogs & derivatives* / Q000378:metabolism; D004032:Diet; D005243:Feces / Q000737:chemistry; D005487:Foam Cells / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000382:microbiology*; D000441:Hexanols / Q000008:administration & dosage*; D006801:Humans; D008190:Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008744:Methylamines / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota
chemical_list: D001057:Apolipoproteins E; D000441:Hexanols; D008744:Methylamines; C007469:3,3-dimethylbutan-1-ol; D002784:Cholesterol; D008190:Lyases; C023336:trimethylamine; D002794:Choline