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 Ca2+ 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.
Zhu, Weifei; Gregory, Jill C.; Org, Elin; Buffa, Jennifer A.; Gupta, Nilaksh; Wang, Zeneng; Li, Lin; Fu, Xiaoming; Wu, Yuping; Mehrabian, Margarete; Sartor, R. Balfour; McIntyre, Thomas M.; Silverstein, Roy L.; Tang, W.H. Wilson; DiDonato, Joseph A.; Brown, J. Mark; Lusis, Aldons J.; and Hazen, Stanley L., "Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk" (2016). Mathematics Faculty Publications. 197.
This research was supported by grants from the NIH and the Office of Dietary Supplements (R01HL103866, P20HL113452, HL28481, HL30568, R01DK106000, R01 HL122283, P40 OD010995, and P30 DK034987). GeneBank was supported by NIH grants (P01HL076491, P01HL098055, R01HL103931 and UL1TR 000439). W.Z. and Z.W. were supported in part by AHA Scientist Development Grants. E.O. was supported by an FP7 grant (no. 330381).