Shang Meiyu, Ning Jingwen, Zang Caixia, Ma Jingwei, Yang Yang, Jiang Yueqi, Chen Qiuzhu, Dong Yirong, Wang Jinrong, Li Fangfang, Bao Xiuqi, Zhang Dan
State Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Acta Pharm Sin B. 2025 Feb;15(2):973-990. doi: 10.1016/j.apsb.2024.10.011. Epub 2024 Oct 30.
Increasing evidence shows that the early lesions of Parkinson's disease (PD) originate from gut, and correction of microbiota dysbiosis is a promising therapy for PD. FLZ is a neuroprotective agent on PD, which has been validated capable of alleviating microbiota dysbiosis in PD mice. However, the detailed mechanisms still need elucidated. Through metabolomics and 16S rRNA analysis, we identified glycoursodeoxycholic acid (GUDCA) was the most affected differential microbial metabolite by FLZ treatment, which was specially and negatively regulated by , a differential microbiota with the strongest correlation to GUDCA production, through inhibiting bile salt hydrolase (BSH) enzyme. The protection of GUDCA on colon and brain were also clarified in PD models, showing that it could activate Nrf2 pathway, further validating that FLZ protected dopaminergic neurons through promoting GUDCA production. Our study uncovered that FLZ improved PD through microbiota-gut-brain axis, and also gave insights into modulation of microbial metabolites may serve as an important strategy for treating PD.
越来越多的证据表明，帕金森病（PD）的早期病变起源于肠道，纠正微生物群失调是一种很有前景的PD治疗方法。FLZ是一种对PD具有神经保护作用的药物，已被证实能够缓解PD小鼠的微生物群失调。然而，其详细机制仍有待阐明。通过代谢组学和16S rRNA分析，我们确定甘氨熊去氧胆酸（GUDCA）是FLZ处理后受影响最大的差异微生物代谢产物，一种与GUDCA产生相关性最强的差异微生物群通过抑制胆汁盐水解酶（BSH）对其进行特异性负调控。在PD模型中也阐明了GUDCA对结肠和大脑的保护作用，表明它可以激活Nrf2通路，进一步证实FLZ通过促进GUDCA的产生来保护多巴胺能神经元。我们的研究发现，FLZ通过微生物-肠道-脑轴改善PD，同时也揭示了调节微生物代谢产物可能是治疗PD的重要策略。
