Gut Microbiota and Cerebral Vascular Disease

项目总结： 脑血管疾病是世界范围内导致死亡和残疾的主要原因之一。缺血性中风， 占所有中风的大部分，发生在血液凝块阻塞局部脑血流时。这个 导致这一灾难性事件的病理生理过程通常是血小板的高反应性，升高 血栓形成的可能性。血小板反应性增强增加急性血栓闭塞的易感性 血管，如在缺血性中风和心脏病发作期间。在过去的几年里，我们发展了 西式饮食中营养素与肠道微生物群代谢产物三甲胺的形成之间的机制联系 一氧化氮(TMAO)、血小板高反应性和心血管疾病的发展。在……里面 令人兴奋的新的未发表的研究，我们已经获得了大量的证据表明，肠道微生物TMAO 通路可直接参与缺血性卒中的发展和严重程度及其下游不良反应 结果。我们的建议旨在证实和测试肠道微生物区系，通过元生物 (同时涉及微生物和宿主)TMAO途径，导致中风风险。我们将评估这一点的作用 通过影响血小板功能增加中风风险，促进更严重的功能损害 通过激活脑组织中的NLRP3炎症体来增强脑部炎症。我们还将研究 肠道微生物在调节卒中易感性和卒中后功能恢复中的作用 饮食增加缺血性中风风险的潜在机制，并探索新的治疗方法 针对肠道微生物贡献的脑血管疾病防治方法。 拟议研究的完成不仅将提供概念证明，还将提供临床前证据。 给微生物群下药可能会成为预防和治疗脑血管疾病的一种新策略。

Project Summary: Cerebral vascular disease is one of the leading causes of mortality and disability worldwide. Ischemic stroke, accounting for the majority of all strokes, occurs when a blood clot blocks regional cerebral blood flow. The precipitating pathophysiological process for this catastrophic event is often platelet hyperreactivity, heightening thrombosis potential. Enhanced platelet reactivity increases the susceptibility for acute thrombotic occlusion of vessels, such as during ischemic stroke and heart attack. Over the past few years, we have developed mechanistic links between nutrients in a Western diet, gut microbiota formation of the metabolite trimethylamine N oxide (TMAO), and development of both platelet hyper-responsiveness and cardiovascular diseases. In exciting new unpublished studies, we have obtained substantial evidence indicating that the gut microbial TMAO pathway can directly contribute to the development and severity of ischemic stroke and its downstream adverse outcomes. Our proposal aims to confirm and test the hypothesis that gut microbiota, through the metaorganismal (involving both microbes and host) TMAO pathway, contributes to stroke risks. We will evaluate the role of this pathway in enhancing stroke risks by impacting platelet function, fostering worse functional impairment by augmenting cerebral inflammation via NLRP3 inflammasome activation in brain tissue. We will also examine the role of gut microbes in modulating stroke susceptibility and functional recovery post stroke onset, identify potential mechanisms contributing diet enhanced ischemic stroke risks, and explore novel therapeutic approaches targeting gut microbial contributions for prevention and treatment in cerebrovascular disease. Completion of the proposed studies will not only provide proof of concept, but also provide preclinical evidence that drugging the microbiome may serve as a novel strategy to prevent and treat cerebrovascular diseases.