肠道菌群紊乱通过SCFAs/GPR43-NLRP3炎性途径在帕金森病发病中的作用及机制研究

Parkinson's disease (PD) is a neurodegenerative disease with high incidence and disability. Its pathogenesis is still not fully understood. Recent studies suggest that gut microbiota dysbiosis may be involved in the pathogenesis of PD, and its metabolites short chain fatty acids (SCFAs) may trigger neuroinflammation. Our previous study found that fecal microbes in PD patients were different from healthy controls, and activation of NLRP3 inflammasomes was involved in the pathogenesis of PD. Given that the binding of SCFAs to its receptor GPR43 promotes reactive oxygen species (ROS) production and ROS is a key signal for the activation of the NLRP3 inflammasomes, we hypothesize that gut microbiota dysbiosis leads to a decrease in its metabolite SCFAs, after the binding of the latter to its GPR43 receptor, it promotes ROS production, thereby actives NLRP3 inflammasomes, and induces abnormal aggregation of gut aSyn, thereby triggers the onset of PD. This study uses microbiota transplants, knockout mice and corresponding signal inhibitors to clarify the important role of gut microbiota dysbiosis in the pathogenesis of PD by SCFAs/GPR43-NLRP3 inflammatory pathway in many aspects，in order to provide the basis for finding new intervention targets for PD.

帕金森病(Parkinson’s disease，PD)是一种发病率高、致残率高的神经退行性疾病，其发病机制尚不完全清楚。新近研究提示肠道菌群紊乱可能参与PD发病，其代谢产物短链脂肪酸(SCFAs)可能触发神经炎症。我们前期研究发现PD患者粪便微生物异于健康对照组，NLRP3炎症小体的激活参与PD发病。鉴于SCFAs与其受体GPR43结合后可促进活性氧(ROS)产生，而ROS是NLRP3炎症小体活化的关键信号，我们推测：肠道菌群紊乱导致其代谢产物SCFAs降低，后者与GPR43受体结合后促进ROS产生，进而激活NLRP3炎症小体，诱导肠道aSyn异常聚集，从而引发PD发病。本项目运用菌群移植、基因敲除鼠及相应信号抑制剂，多角度阐明肠道菌群紊乱通过SCFAs/GPR43-NLRP3炎性途径在PD发病过程中发挥重要作用，为寻找PD新的干预靶点提供依据。

帕金森病（Parkinson‘s disease,PD）是高发病率的致残性中枢神经系统变性疾病，其发病机制尚未阐明。本研究利用不同浓度的SCFA处理小鼠肠道内分泌细胞STC-1，测定对细胞活力的影响，并收集其上清，培养SH-SY5Y细胞，然后分别用NLRP3干扰RNA和GPR43干扰RNA处理SH-SY5Y细胞，检测对SH-SY5Y产生的影响（凋亡、炎症，α-synuclein、TH等）；同时用MPTP构建PD小鼠，对其喂养含SCFAs的水，然后分别用NLRP3抑制剂和GPR43抑制剂处理小鼠，对小鼠进行行为学测试（转棒试验）、排便频率、粪便含水量、α-synuclein、TH、炎症等检测。我们发现10mM SCFA能促进STC-1的α-synuclein mRNA表达，促进磷酸化α-synuclein的表达。NLRP3干扰RNA及GPR43干扰RNA能改善SCFA对SH-SY5Y产生的不良影响（减少凋亡、减少炎症，减少α-synuclein、提高TH等），且GPR43干扰RNA能减少NLRP3炎症小体的产生；SCFA能促进多巴胺神经元损害，促进炎症小体形成，加重PD小鼠的排便障碍、运动功能，NLRP3抑制剂及GPR43抑制剂能改善SCFA 诱导的PD小鼠的病理，炎症，运动障碍等，且GPR43抑制剂能减少NLRP3炎症小体的产生。细胞实验及动物实验双重验证说明SCFA可通过与其受体GPR43结合，引发NLRP3炎症小体风暴，进而引起PD发病，通过抑制GPR43，可以减少NLRP3炎症小体风暴，进而减少PD症状的出现，提示SCFAs/GPR43-NLRP3炎性途径是肠道菌群紊乱参与PD发病的重要机制，靶标SCFA或GPR43的食物或药物可减少PD发病或减轻PD症状。