肠道菌群失衡产生的氧化脂质对血脑屏障的破坏作用及机制研究

我们前期发现肠道菌群代谢产物TMAO不仅可以诱导大血管衰老和血管内皮功能下降，同时会导致脑认知功能障碍。对TMAO前期的研究主要集中在心血管领域，脑血管领域涉及很少。我们认为TMAO等肠道菌群代谢物（包括上游的分子例如胆碱与肉碱）可以促进脑血管内皮细胞中线粒体应激和ROS生成，从而一方面导致细胞自身功能损伤，血管内皮功能下降（这种情况我们只观察过大血管内皮细胞，还未对脑血管内皮细胞进行研究）；另一方面内皮细胞间的连接蛋白受到破坏，使细胞间连接减弱，导致脑微血管渗漏。两者共同作用导致脑血管衰老。我们将通过衰老模型鼠找到标志性差异代谢产物，并通过饮食干预验证，并将在细胞层面对肠道菌群代谢物导致线粒体氧化应激和细胞间连接损伤进行研究，证明我们的假设。

We have previously found that TMAO, one of the metabolic product of gut flora, could induce not only the aging of large vessels, but also brain cognitive dysfunction. The research of TMAO primarily focuses on cardiovascular areas, and cerebrovascular research of TMAO is seldom involved. We believe the TMAO and other metabolic products of gut flora will promote the mitochondrial stress and ROS production in cerebrovascular endothelial cells. This will lead to cell damage and vascular dysfunction. The junction proteins of endothelial cells break down and lead to cerebrovascular leakage. These two aspects work together and cause cerebrovascular aging. We are going to find remarkable metabolic products of gut flora through aging animal model. We will study on mitochondrial stress and intercellular connections damage to prove our hypothesis.