Akkermansia muciniphila M21蛋白激活Toll样受体信号通路介导促炎反应在帕金森病中的机制研究

Gut microbiota plays an important role in the pathogenesis of Parkinson's disease (PD), but the specific mechanism is still unclear. Our previous study has found that patients with PD have gut microbiota dysbiosis. Moreover, the levels of Akkermansia muciniphila (A. muciniphila) of PD patients was much higher than that of the healthy spouses by detection the feces using metagenomics sequencing. Furthermore, a panel of 25 markers was established to diagnosis PD, of which Marker-21 increased significantly in PD patients. Additionally, Marker-21 was annotated to the functional protein related with A.muciniphila (Protein-M21). Particularly, recent studies have shown that A. muciniphila can mediate the production of pro-inflammatory factors by Toll-Like receptors (TLRs). We have found that the TLR2 signaling pathway and inflammatory factors could be activated in a PD mouse model. Consequently, we hypothesized that A. muciniphila could act on the TLR signaling pathway through the Protein-M21 to induce the inflammatory response to promote the pathogenesis of PD. The study, containing both in vivo and in vitro experiments, is designed to clarify the role and mechanism of A. muciniphila associated with TLR signaling pathway in the pathogenesis of PD, and to explore the therapeutic potential of A. muciniphila Protein-M21 in PD, providing new fields for treatment in PD.

肠道菌群在帕金森病（Parkinson’s disease, PD）发病中起重要作用，但具体机制尚不清楚。我们前期研究证实PD患者存在肠道菌群紊乱；菌群宏基因组学分析发现PD患者Akkermansia muciniphila（A.muciniphila）显著增多；建立了诊断PD的25个标志物，其中标志物-21在PD患者显著增高，并注释到与A.muciniphila相关的功能蛋白（M21蛋白）。研究表明A.muciniphila可介导Toll样受体（TLRs）产生促炎因子，我们已发现PD小鼠中肠道TLR2信号通路及炎症因子激活。故我们推测A.muciniphila通过M21蛋白作用TLR信号通路介导炎症反应促使PD发病。本课题拟通过体内外实验，阐明A.muciniphila如何通过TLR信号通路促进PD发病，探讨干预A.muciniphila M21蛋白在PD中的治疗潜能，为治疗提供新思路。

肠道菌群在帕金森病（Parkinson’s disease, PD）发病中起重要作用，但具体机制尚不清楚。我们前期研究证实PD患者存在肠道菌群紊乱；菌群宏基因组学分析发现PD患者Akkermansia muciniphila（A.muciniphila）显著增多；建立了诊断PD的25个标志物，其中标志物-21在PD患者显著增高，并注释到与A.muciniphila相关的功能蛋白（M21蛋白）。研究表明A.muciniphila可介导Toll样受体（TLRs）产生促炎因子。本课题首先通过生物信息学等方法研究证实M21蛋白存在，构建纯化M21蛋白；通过体内实验发现A.muciniphila加重对于鱼藤酮灌胃所致PD模型小鼠肠道症状、使得肠道通透性增加、肠道TLR炎症受体表达增加、炎症因子增加及其运动症状变重、脑内胶质细胞激活程度严重、a-syn聚集加重和多巴胺能神经元死亡加重的影响。通过体外实验，发现A.muciniphila促进鱼藤酮诱导肠上皮细胞的炎症反应。构建敲除M21基因的A.muciniphila，发现其可以延缓鱼藤酮诱导的PD小鼠发病，同时发现对鱼敲除A.muciniphila上M21蛋白延缓鱼藤酮诱导肠上皮细胞的炎症反应。说明A.muciniphila通过M21蛋白作用TLR信号通路介导炎症反应促使PD发病，A.muciniphila M21蛋白可以作为未来PD治疗新的潜在靶点，为治疗提供新思路。