肠道菌群代谢产物短链脂肪酸调节α-synuclein的机制研究

The neuropathological hallmark of Parkinson’s disease (PD) is abnormal α-synuclein (α-Syn) aggregation, but the mechanism of α-Syn regulation is unclear. We reported that microbiome dysbiosis prior to α-Syn aggregation using an oral rotenone model of PD. Nevertheless, it remains unclear how microbiome dysbiosis could be contributed to the rotenone-induced PD. We found that short chain fatty acids (SCFAs), the product of gut microbiota metabolism, were reduced in rotenone-induced PD mice. SCFAs could inhibit rotenone-induced α-Syn aggregation and phosphorylation, while increasing PGC-1α expression. Literatures and our previous studies show that PGC-1α plays an important role in the regulation of α-Syn and PD pathogenesis. We hypothesized that a shift in gut microbiota might be associated with a shift in SCFAs in rotenone-induced PD mice. SCFAs may regulate α-Syn by modulating the expression of PGC-1α via histone acetylation modification or through the GLP-1 pathway. Our results will bring a new insight in the role of gut microbiota in rotenone-induced neurotoxicity and clarify the effect and the underlying mechanism of SCFAs on regulation of α-Syn. We will also explore the protective effect of probiotics and SCFAs which might provide a new therapeutic approach for PD.

帕金森病（PD）的主要病理变化为α-Syn异常聚集，而α-Syn调节机制尚不明确。我们发现鱼藤酮诱导的PD小鼠发病过程中肠道菌群失调早于脑内α-Syn聚集，但肠道菌群失调在鱼藤酮诱导的PD发病过程中的作用及机制尚不清楚。我们发现鱼藤酮PD小鼠肠道菌群代谢产物短链脂肪酸（SCFAs）减少，SCFAs可以抑制鱼藤酮引起的α-Syn聚集和磷酸化，同时增加PGC-1α表达。研究表明PGC-1α在调节α-Syn及PD发病中发挥重要作用。基于此，我们推测在鱼藤酮诱导的PD发病过程中，肠道菌群失调引起SCFAs改变，SCFAs一方面可能通过组蛋白乙酰化修饰，另一方面可能通过GLP-1途径调节PGC-1α表达，进而影响α-Syn。本课题将从肠道菌群角度探讨鱼藤酮致PD新的发病机制，明确肠道菌群代谢产物SCFAs对α-Syn的作用及其调控机制，探讨益生菌及SCFAs在PD中的保护作用，为PD治疗提供新思路。

帕金森病（PD）的主要病理变化为α-Syn异常聚集，而α-Syn调节机制尚不明确。鱼藤酮诱导的PD小鼠发病过程中肠道菌群失.调早于脑内α-Syn聚集，但肠道菌群失调在鱼藤酮诱导的PD发病过程中的作用及机制尚不清楚。鱼藤酮PD小鼠肠道菌群代谢产物短链脂肪酸（SCFAs）减少，SCFAs可以抑制鱼藤酮引起的α-Syn聚集和磷酸化。本课题从肠道菌群角度探索了鱼藤酮致PD的发病机制，发现了肠道菌群代谢产物SCFAs对α-Syn的作用及可能的调控机制。在体外试验中通过鱼藤酮处理的PC12细胞发现：（1）在三种SCFAs中，NaB能够对抗鱼藤酮诱导的毒性作用；（2）NaB通过上调PGC-1α表达激活自噬以减少α-synuclein表达；（3）NaB通过抑制组蛋白去乙酰化酶（HDAC）促进PGC-1α的表达。在前期细胞实验基础上，我们进一步探索NaB在PD小鼠中的保护作用，发现：（1）NaB保护鱼藤酮诱导的PD小鼠胃肠道功能及运动损害，减少结肠及中脑黑质α-synuclein表达；（2）NaB保护鱼藤酮诱导的肠道菌群及SCFA代谢紊乱；（3）NaB对抗鱼藤酮诱导的PD小鼠肠道、血清及黑质GLP-1含量降低。综上，本研究发现了肠道菌群代谢产物NaB在PD发病中的保护作用及可能的机制，为PD治疗提供新思路。