帕金森病(PD)是第二常见的神经退行性疾病,但是由于对PD发病机制的了解有限,目前的PD治疗方法都不能阻止疾病的进展。在PD发展中,受肠道微生物群影响的大脑和胃肠道系统之间的交流被称为微生物群-肠-脑轴。然而,微生物群失调在PD发育中的明确机制尚未得到很好的阐明。FLZ,一个新的squamosamide衍生物,已被证明在许多PD模型中有效,并且正在中国进行治疗PD的I期临床试验。此外,我们先前的药代动力学研究表明,肠道菌群可以调节体内FLZ的吸收。我们研究的目的是评估FLZ治疗对PD的保护作用,并通过使用FLZ作为工具进一步探索PD的潜在微生物群相关机制。在目前的研究中,长期口服鱼藤酮用于诱导小鼠模型以模拟PD的病理过程。在这里,我们发现FLZ治疗缓解了胃肠功能障碍,运动症状,鱼藤酮攻击小鼠的多巴胺能神经元死亡。16SrRNA测序发现,鱼藤酮诱导的PD相关微生物群改变可通过FLZ处理逆转。值得注意的是,FLZ给药减轻肠道炎症和肠屏障破坏,随后抑制全身性炎症。最终,FLZ治疗通过抑制黑质(SN)中星形胶质细胞和小胶质细胞的激活来恢复血脑屏障结构并抑制神经炎症。进一步的机制研究表明,FLZ处理抑制了SN和结肠中的TLR4/MyD88/NF-κB途径。总的来说,FLZ治疗通过抑制TLR4途径改善微生物群菌群失调保护PD模型,这有助于其神经保护作用下的潜在机制之一。我们的研究还支持微生物群-肠-脑轴在PD发病机理中的重要性,提示其作为PD治疗新的治疗靶点的潜在作用。
Parkinson\'s disease (PD) is the second most common neurodegenerative disease, but none of the current treatments for PD can halt the progress of the disease due to the limited understanding of the pathogenesis. In PD development, the communication between the brain and the gastrointestinal system influenced by gut microbiota is known as microbiota-gut-brain axis. However, the explicit mechanisms of microbiota dysbiosis in PD development have not been well elucidated yet. FLZ, a novel squamosamide derivative, has been proved to be effective in many PD models and is undergoing the phase I clinical trial to treat PD in China. Moreover, our previous pharmacokinetic study revealed that gut microbiota could regulate the absorption of FLZ in vivo. The aims of our study were to assess the protective effects of FLZ treatment on PD and to further explore the underlying microbiota-related mechanisms of PD by using FLZ as a tool. In the current study, chronic oral administration of rotenone was utilized to induce a mouse model to mimic the pathological process of PD. Here we revealed that FLZ treatment alleviated gastrointestinal dysfunctions, motor symptoms, and dopaminergic neuron death in rotenone-challenged mice. 16S rRNA sequencing found that PD-related microbiota alterations induced by rotenone were reversed by FLZ treatment. Remarkably, FLZ administration attenuated intestinal inflammation and gut barrier destruction, which subsequently inhibited systemic inflammation. Eventually, FLZ treatment restored blood-brain barrier structure and suppressed neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra (SN). Further mechanistic research demonstrated that FLZ treatment suppressed the TLR4/MyD88/NF-κB pathway both in the SN and colon. Collectively, FLZ treatment ameliorates microbiota dysbiosis to protect the PD model via inhibiting TLR4 pathway, which contributes to one of the underlying mechanisms beneath its neuroprotective effects. Our research also supports the importance of microbiota-gut-brain axis in PD pathogenesis, suggesting its potential role as a novel therapeutic target for PD treatment.