Ai Penghui, Xu Shaoqing, Yuan Yuan, Xu Ziqi, He Xiaoqin, Mo Chengjun, Zhang Yi, Yang Xiaodong, Xiao Qin
Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Department of Geriatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Int J Mol Sci. 2025 May 30;26(11):5282. doi: 10.3390/ijms26115282.
Emerging evidence highlights the gut microbiota as a pivotal determinant of pharmacological efficacy. While ()-derived tyrosine decarboxylases () are known to decarboxylate levodopa (L-dopa), compromising systemic bioavailability, the causal mechanisms underlying microbiota-mediated pharmacodynamic variability remain unresolved. In our study, we employed antibiotic-induced microbiota depletion and fecal microbiota transplantation (FMT) to interrogate microbiota-L-dopa interactions in MPTP-induced Parkinson's disease (PD) mice. The study demonstrated that antibiotic-mediated microbiota depletion enhances L-dopa bioavailability and striatal dopamine (DA) level, correlating with improved motor function. To dissect clinical heterogeneity in the L-dopa response, PD patients were stratified into moderate responders and good responders following standardized L-dopa challenges. In vitro bioconversion assays revealed greater L-dopa-to-DA conversion in fecal samples from moderate responders versus good responders. FMT experiments confirmed mice receiving good-responder microbiota exhibited enhanced L-dopa bioavailability, higher striatal DA concentrations, and a heightened therapeutic effect of L-dopa relative to moderate-responder recipients. Collectively, our study provided evidence that the gut microbiota directly modulates L-dopa metabolism and microbial composition determines interindividual therapeutic heterogeneity. Targeted microbial modulation-through precision antibiotics or donor-matched FMT-is a viable strategy to optimize PD pharmacotherapy, supporting the potential for microbiota-targeted adjuvant therapies in PD management.
新出现的证据凸显了肠道微生物群作为药物疗效关键决定因素的作用。虽然已知（）衍生的酪氨酸脱羧酶（）可使左旋多巴（L-多巴）脱羧，从而降低全身生物利用度，但微生物群介导的药效学变异性背后的因果机制仍未得到解决。在我们的研究中，我们采用抗生素诱导的微生物群耗竭和粪便微生物群移植（FMT）来探究MPTP诱导的帕金森病（PD）小鼠中微生物群与L-多巴的相互作用。该研究表明，抗生素介导的微生物群耗竭可提高L-多巴的生物利用度和纹状体多巴胺（DA）水平，这与运动功能改善相关。为了剖析L-多巴反应中的临床异质性，在标准化的L-多巴激发试验后，将PD患者分为中度反应者和良好反应者。体外生物转化试验显示，中度反应者粪便样本中L-多巴向DA的转化率高于良好反应者。FMT实验证实，接受良好反应者微生物群的小鼠表现出更高的L-多巴生物利用度、更高的纹状体DA浓度，以及相对于中度反应者受体而言更强的L-多巴治疗效果。总体而言，我们的研究提供了证据，表明肠道微生物群直接调节L-多巴代谢，且微生物组成决定个体间的治疗异质性。通过精准抗生素或供体匹配的FMT进行靶向微生物调节是优化PD药物治疗的可行策略，支持了在PD管理中采用微生物群靶向辅助治疗的潜力。
