粪菌移植通过TLR4-NFκB途径对小鼠帕金森病模型的神经保护机制

Recent studies showed that gut dysbacteriosis induced inflammation play important roles in intestinal and other diseases. Based on this mechanism, fecal microbiota transplantation (FMT) present significant therapy effect on some mental and neurological diseases. Like patients with Parkinson’s disease (PD), PD mice showed gut dysbacteriosis, however, the mechanism of gut dysbacteriosis in PD is little known. We found that after accepting fecal microbiota transplantation (FMT), behavior dysfunction of MPTP induced PD mice was improved and the expression of tyrosine hydroxylase in substantia nigra in PD mice’s was restored, meanwhile, the number of activated microglia in substantia nigra and expression of inflammatory factor such as TLR4 and NFκB was increased in PD mice but reduced after FMT. Thus, we hypothesized that gut dysbacteriosis pass gut-brain axis to activate TLR4-NFκB pathway which mediates neuroinflammation and promote the development of PD, and TLR4-NFκB may be important mediated pathway. To verify this hypothesis, we will measure the composition and content of gut microbiota and metabolites in PD mice before and after FMT treatment, and detect neuronal survival and neuroinflammation in substantia nigra and striatum. Besides, we will use TLR4-NFκB pathway inhibitor in cell experiment to figure out key bacterial metabolites induced inflammation, and use tlr4-/- mice to investigate the role of TLR4-NFκB pathway in FMT’s neuroprotection in PD. This project will reveal the possible mechanisms of gut dysbacteriosis in PD and FMT’s therapeutic effect on PD.

近年研究表明肠道菌群失调诱导的炎性机制在肠内外疾病发生发展中起重要作用，由此发展的粪菌移植（FMT）方法在多种精神神经疾病中疗效显著。帕金森病（PD）患者和PD小鼠同样出现肠道菌群失调，但其在PD中的作用及机制了解甚微。我们前期发现MPTP诱导的PD小鼠接受FMT后，运动障碍改善且黑质内TH表达恢复；另外，黑质中小胶质细胞激活减少，炎症分子TLR4和NFκB表达降低。我们假设：肠道菌群失调通过肠-脑轴激发神经炎症并促进PD发生发展，TLR4-NFκB或是重要介导通路。为验证该假设，将测定FMT前后PD小鼠的肠道菌群构成和细菌代谢物含量，检测黑质纹状体内神经元存活和神经炎症，还将采用TLR4-NFκB通路抑制剂的细胞实验寻找诱导炎症的细菌代谢物，并利用tlr4-/-小鼠验证FMT的保护作用是否由TLR4-NFκB通路介导。预期成果将揭示肠道菌群失调在PD中的作用机制和FMT的治疗效果。

帕金森病（PD）是最常见的神经退行性疾病之一，其发病机制不明且尚无有效治疗手段。近年研究表明肠道菌群参与多种疾病的发生发展，且粪菌移植（FMT）对多种神经系统疾病有治疗作用。在本基金的资助下，我们利用小鼠帕金森病模型明确了FMT通过TLR4/TBK1/NF-kB/TNF-a信号通路发挥对PD小鼠的神经保护作用，并深入探讨了肠道菌群代谢物SCFAs参与PD病理的机制。在此基础上，我们进一步开展了饮食干预（模拟空腹饮食和隔日禁食）、落新妇苷以及普芦卡必利对PD小鼠的神经保护作用及机制的研究。此外，脊髓损伤作为一种严重致残的神经系统疾病，会导致患者感觉和运动功能不可逆性损害。我们利用斑马鱼脊髓损伤模型，明确了ATF6、NPY和IGF-1促进斑马鱼脊髓损伤恢复的有益作用及机制。我们的研究为神经退行性疾病和神经损伤的临床治疗提供了坚实的实验数据和理论基础，有良好的应用前景。本项目共发表12篇SCI论文，其中高被引论文一篇。培养1名博士后和9名研究生。