TY - JOUR
T1 - Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk
AU - Zhu, Weifei
AU - Gregory, Jill C.
AU - Org, Elin
AU - Buffa, Jennifer A.
AU - Gupta, Nilaksh
AU - Wang, Zeneng
AU - Li, Lin
AU - Fu, Xiaoming
AU - Wu, Yuping
AU - Mehrabian, Margarete
AU - Sartor, R. Balfour
AU - McIntyre, Thomas M.
AU - Silverstein, Roy L.
AU - Tang, W.H. Wilson
AU - Didonato, Joseph A.
AU - Brown, J. Mark
AU - Lusis, Aldons J.
AU - Hazen, Stanley L.
PY - 2016/3/24
Y1 - 2016/3/24
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2016.02.011
DO - 10.1016/j.cell.2016.02.011
M3 - Article
C2 - 26972052
SN - 0092-8674
VL - 165
SP - 111
EP - 124
JO - Cell
JF - Cell
IS - 1
ER -