Format

Send to

Choose Destination
Cell. 2016 Mar 24;165(1):111-124. doi: 10.1016/j.cell.2016.02.011. Epub 2016 Mar 10.

Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk.

Author information

1
Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
2
Departments of Human Genetics and Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
3
Department of Mathematics, Cleveland State University, Cleveland, OH 44115, USA.
4
Departments of Medicine and Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
5
Department of Medicine, Medical College of Wisconsin and Blood Research Institute, Milwaukee, WI 53226, USA.
6
Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
7
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.

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.

PMID:
26972052
PMCID:
PMC4862743
DOI:
10.1016/j.cell.2016.02.011
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center