Ticagrelor inhibits platelet activity through gut microbiota remodeling and trimethylamine N-oxide reduction

Background and Aims: Studies suggest that ticagrelor (TCG), an antiplatelet drug, may affect bacteria. Thus, the effects of TCG on gut microbiota were explored.Methods: Fecal microbiota transplantations (FMT) were performed in mice. Gut microbiota composition was analyzed using metagenomics and key metabolites in the host plasma were detected using metabolomics. Clopidogrel and P2Y12 knockout mice were used to validate the role of the TCG receptor on host. 34 patients were recruited to detect changes in gut flora and metabolic profiles after TCG treatment.Results: TCG treatment induced a notable increase in the abundance of <i>Akkermansia muciniphila</i> (<i>A. muc</i>) in the gut with a concomitant reduction in circulating trimethylamine N-oxide (TMAO) levels. Transplantation of <i>A. muc</i><i> </i>also reduced plasma TMAO levels and platelet activity. Clopidogrel treatment or P2Y12 knockout did not show a similar function. Mechanistically, the results indicated that glutamate and Amuc_1253 contribute to the inhibition of TMAO-producing bacteria. Additionally, a reduction in TMAO levels in patients treated with TCG was observed, which accompanied by an elevated <i>A. muc</i> abundance in feces.Conclusions: TCG increases the abundance of <i>A. muc</i> in the gut and inhibits the growth of TMAO-producing bacteria through competition for glutamate, thereby enhancing its antiplatelet activity, which is independent of P2Y12.