Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2β1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2β1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis.

中文翻译：

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肠道微生物共代谢物 2-甲基丁酰肉碱通过结合并激活整合素 α2β1 加剧血栓形成

血栓形成是主要不良心血管事件（MACE）导致死亡和残疾的主要原因。 COVID-19 和代谢紊乱等多种病理状况可能导致血栓形成风险增加；然而，其根本机制仍然知之甚少。我们的研究表明，2-甲基丁酰肉碱 (2MBC)（一种支链酰基肉碱）在 COVID-19 患者和 MACE 患者体内积累。 2MBC 增强小鼠血小板高反应性和血栓形成。从机制上讲，2MBC 与血小板中的整合素 α2β1 结合，增强胞质磷脂酶 A2 (cPLA2) 激活和血小板高反应性。整合素α2β1的基因缺失或药理抑制在很大程度上逆转了2MBC的促血栓形成作用。值得注意的是，2MBC 可以以肠道微生物依赖的方式产生，而血浆 2MBC 的积累及其血栓形成加重作用在抗生素诱导的微生物消耗后大大改善。我们的研究表明 2MBC 作为一种代谢物，将肠道微生物群失调与血栓形成风险升高联系起来，为血栓形成提供了机制见解和潜在的治疗策略。