title: Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk.
abstract: Normal platelet function is critical to blood hemostasis and maintenance of a closed circulatory system. Heightened platelet reactivity, however, is associated with cardiometabolic diseases and enhanced potential for thrombotic events. We now show gut microbes, through generation of trimethylamine N-oxide (TMAO), directly contribute to platelet hyperreactivity and enhanced thrombosis potential. Plasma TMAO levels in subjects (n > 4,000) independently predicted incident (3 years) thrombosis (heart attack, stroke) risk. Direct exposure of platelets to TMAO enhanced sub-maximal stimulus-dependent platelet activation from multiple agonists through augmented Ca(2+) release from intracellular stores. Animal model studies employing dietary choline or TMAO, germ-free mice, and microbial transplantation collectively confirm a role for gut microbiota and TMAO in modulating platelet hyperresponsiveness and thrombosis potential and identify microbial taxa associated with plasma TMAO and thrombosis potential. Collectively, the present results reveal a previously unrecognized mechanistic link between specific dietary nutrients, gut microbes, platelet function, and thrombosis risk.
authors.affiliation: Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Weifei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Gregory
authors.affiliation: Departments of Human Genetics and 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 & Molecular Medicine, 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.
authors.forename: Nilaksh
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Department of Cellular & Molecular Medicine, 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.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Fu
authors.affiliation: Department of Mathematics, Cleveland State University, Cleveland, OH 44115, USA.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Departments of Human Genetics and Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Margarete
authors.initials: M
authors.lastname: Mehrabian
authors.affiliation: Departments of Medicine and Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: R Balfour
authors.initials: RB
authors.lastname: Sartor
authors.affiliation: Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: McIntyre
authors.affiliation: Department of Medicine, Medical College of Wisconsin and Blood Research Institute, Milwaukee, WI 53226, USA.
authors.forename: Roy L
authors.initials: RL
authors.lastname: Silverstein
authors.affiliation: Department of Cellular & Molecular Medicine, 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.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: DiDonato
authors.affiliation: Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Brown
authors.affiliation: Departments of Human Genetics and 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 & 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; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020212:Carotid Artery Injuries / Q000473:pathology; D002432:Cecum / Q000382:microbiology; D002712:Chlorides; D002794:Choline / Q000378:metabolism; D004032:Diet; D005260:Female; D005290:Ferric Compounds; D000069196:Gastrointestinal Microbiome; D005856:Germ-Free Life; D006801:Humans; D008744:Methylamines / Q000097:blood / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D013927:Thrombosis / Q000378:metabolism* / Q000473:pathology
chemical_list: D002712:Chlorides; D005290:Ferric Compounds; D008744:Methylamines; C005855:trimethyloxamine; D002794:Choline; D002118:Calcium; C024555:ferric chloride