Overexpression of human alpha-Synuclein leads to dysregulated microbiome/metabolites with ageing in a rat model of Parkinson disease

Braak’s hypothesis stating that sporadic Parkinson’s disease follows a specific progression of the pathology from the peripheral to the central nervous system and can be monitored by detecting accumulation of the alpha-Synuclein protein. There is growing interest in understanding how the gut (commensal) microbiome can regulate alpha-Synuclein accumulation which can lead to PD. We studied a transgenic rat model overexpressing the human alpha-Synuclein and found that the protein overexpression resulted in gut alpha-Synuclein expression and aggregation in the gut neurons with advancing age. A progressive gut microbial composition alteration characterized by the reduction of Firmicutes to Bacteroidetes ratio could be detected in the young transgenic rat model and interestingly this ratio was then increased with aging. This observation was accompanied in older animals by intestinal inflammation, increase gut permeability and a robust alteration in metabolites production characterized by the increase of succinate level in the feces and serum. Manipulation of the gut bacteria by short-term antibiotics treatment revealed a complete loss of short-chain fatty acids (SCFAs) and reduction in succinate levels. Although antibiotics treatment did not change alpha-synuclein expression in the enteric nervous system of the colon, it can reduce alpha-synuclein expression in the olfactory bulb of the transgenic rats. In summary, synchronous with ageing, our data emphasize that the gut microbiome dysbiosis leads to a specific alteration of gut metabolites which are reflected in the serum and can be modulated by the environment.Braak假说（Braak's hypothesis）指出，散发性帕金森病的病理进程遵循从外周神经系统向中枢神经系统发展的特定模式，可通过检测α-突触核蛋白（alpha-Synuclein protein）的聚集进行监测。当前学界对理解肠道共生微生物组如何调控可诱发帕金森病的α-突触核蛋白聚集的兴趣与日俱增。本研究采用过表达人源α-突触核蛋白的转基因大鼠模型，发现随着年龄增长，该蛋白的过表达会引发肠道神经元内的α-突触核蛋白表达与聚集。在年轻的转基因大鼠模型中即可检测到以厚壁菌门（Firmicutes）与拟杆菌门（Bacteroidetes）比值降低为特征的肠道菌群组成进行性改变；有趣的是，该比值会随衰老进程出现升高。该现象在老年动物中伴随出现肠道炎症、肠道通透性升高，以及以粪便与血清中琥珀酸水平升高为特征的代谢产物生成显著改变。通过短期抗生素处理干预肠道菌群后，可观察到短链脂肪酸（short-chain fatty acids, SCFAs）完全缺失，同时琥珀酸水平降低。尽管抗生素处理并未改变结肠肠神经系统内的α-突触核蛋白表达，但可降低转基因大鼠嗅球中的α-突触核蛋白表达水平。综上，本研究数据证实，与衰老同步发生的肠道菌群失调会引发肠道代谢产物的特异性改变，此类改变可在血清中体现，且可受环境因素调控。