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.

研究背景与目的：研究表明，抗血小板药物替格瑞洛（ticagrelor, TCG）可能对细菌产生影响。为此，本研究探讨了替格瑞洛对肠道菌群的作用。
方法：本研究对小鼠进行粪便菌群移植（fecal microbiota transplantations, FMT）；采用宏基因组学分析肠道菌群组成，通过代谢组学检测宿主血浆中的关键代谢物；使用氯吡格雷处理及P2Y12基因敲除小鼠，验证替格瑞洛受体在宿主体内的作用；招募34名患者，检测替格瑞洛治疗后肠道菌群与代谢谱的变化。
结果：替格瑞洛处理可显著提升肠道内嗜黏蛋白阿克曼氏菌（Akkermansia muciniphila, A. muc）的丰度，同时降低循环中三甲胺N-氧化物（trimethylamine N-oxide, TMAO）的水平；移植嗜黏蛋白阿克曼氏菌同样可降低血浆TMAO水平与血小板活性，而氯吡格雷处理或P2Y12基因敲除未表现出类似作用。机制分析显示，谷氨酸与Amuc_1253参与抑制产TMAO细菌的增殖；此外，替格瑞洛治疗的患者体内TMAO水平降低，同时粪便中嗜黏蛋白阿克曼氏菌丰度升高。
结论：替格瑞洛可提升肠道内嗜黏蛋白阿克曼氏菌的丰度，并通过竞争谷氨酸抑制产TMAO细菌的增殖，进而增强其抗血小板活性，该作用不依赖于P2Y12受体。