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Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk

2016; Cell Press; Volume: 165; Issue: 1 Linguagem: Inglês

10.1016/j.cell.2016.02.011

1097-4172

Weifei Zhu, Jill C. Gregory, Elin Org, Jennifer A. Buffa, Nilaksh Gupta, Zeneng Wang, Lin Li, Xiaoming Fu, Yuping Wu, Margarete Mehrabian, R. Balfour Sartor, Thomas M. McIntyre, Roy L. Silverstein, W.H. Wilson Tang, Joseph A. DiDonato, J. Mark Brown, Aldons J. Lusis, Stanley L. Hazen,

Alcohol Consumption and Health Effects

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.