Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk

By Weifei Zhu, J. Gregory, E. Org, J. Buffa, N. Gupta, Zeneng, Wang, Lin Li, Xiaoming Fu, Yuping Wu and 9 more. Cell, 2016

1,732 citations recorded by the source corpus.

SUMMARY 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>4000) independently predicted incident (3 yr) thrombosis (heart attack, stroke) risk. Direct exposure of platelets to TMAO enhanced submaximal 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.

Subfields: Molecular Biology, Pathology and Forensic Medicine, Physiology

View Paper: https://www.semanticscholar.org/paper/c1d20656bf10824b826955eab76ba4782a313045

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Citations in the corpus

The gut microbiome: Relationships with disease and opportunities for therapy (2018, background): “Metabolism of these compounds produces trimethylamine (TMA), which is oxidized in the liver to trimethylamine-N-oxide, an amine oxide associated with development of atherosclerosis (Wang et al., 2011, 2015; Koeth et al., 2013; Zhu et al., 2016).”
Understanding the Holobiont: How microbial metabolites affect human health and shape the immune system (2017, background): “Beyond a direct effect on atherosclerosis, TMAO has also been reported to increase platelet responsiveness by enhancing intracellular Ca2+ release, thus increasing the likelihood of thrombotic events and thereby cardiovascular disease (Zhu et al., 2016).”
Ischemia/Reperfusion (2016, positive): “(921) suggested that plasma TMAO directly activated platelets to produce a prothrombogenic phenotype.”
Gut Microbiota in Cardiovascular Health and Disease (2017, background): “platelet calcium signaling and elicits a prothrombotic effect in vivo.(10) These observations suggest that TMAO could be a”
NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications (2020, neutral): “97 .”