Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, China.
College of Biological Science, University of California, Davis, CA 95616, USA.
Aging Dis. 2023 Dec 1;14(6):2193-2214. doi: 10.14336/AD.2023.0309.
Increasing evidence has shown that gut dysbacteriosis may play a crucial role in neuroinflammation in Parkinson's disease (PD). However, the specific mechanisms that link gut microbiota to PD remain unexplored. Given the critical roles of blood-brain barrier (BBB) dysfunction and mitochondrial dysfunction in the development of PD, we aimed to evaluate the interactions among the gut microbiota, BBB, and mitochondrial resistance to oxidation and inflammation in PD. We investigated the effects of fecal microbiota transplantation (FMT) on the physiopathology of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. The aim was to explore the role of fecal microbiota from PD patients and healthy human controls in neuroinflammation, BBB components, and mitochondrial antioxidative capacity via the AMPK/SOD2 pathway. Compared to control mice, MPTP-treated mice exhibited elevated levels of Desulfovibrio, whereas mice given FMT from PD patients exhibited enriched levels of Akkermansia and mice given FMT from healthy humans showed no significant alterations in gut microbiota. Strikingly, FMT from PD patients to MPTP-treated mice significantly aggravated motor impairments, dopaminergic neurodegeneration, nigrostriatal glial activation and colonic inflammation, and inhibited the AMPK/SOD2 signaling pathway. However, FMT from healthy human controls greatly improved the aforementioned MPTP-caused effects. Surprisingly, the MPTP-treated mice displayed a significant loss in nigrostriatal pericytes, which was restored by FMT from healthy human controls. Our findings demonstrate that FMT from healthy human controls can correct gut dysbacteriosis and ameliorate neurodegeneration in the MPTP-induced PD mouse model by suppressing microgliosis and astrogliosis, ameliorating mitochondrial impairments via the AMPK/SOD2 pathway, and restoring the loss of nigrostriatal pericytes and BBB integrity. These findings raise the possibility that the alteration in the human gut microbiota may be a risk factor for PD and provide evidence for potential application of FMT in PD preclinical treatment.
越来越多的证据表明，肠道菌群失调可能在帕金森病（PD）的神经炎症中起关键作用。然而，将肠道微生物群与 PD 联系起来的确切机制仍未被探索。鉴于血脑屏障（BBB）功能障碍和线粒体功能障碍在 PD 发展中的关键作用，我们旨在评估肠道微生物群、BBB 和线粒体氧化和炎症抵抗之间的相互作用在 PD 中的作用。我们研究了粪便微生物群移植（FMT）对 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理的小鼠生理病理学的影响。目的是通过 AMPK/SOD2 通路探索 PD 患者和健康人类对照的粪便微生物群在神经炎症、BBB 成分和线粒体抗氧化能力中的作用。与对照小鼠相比，MPTP 处理的小鼠中脱硫弧菌水平升高，而接受 PD 患者 FMT 的小鼠中阿克曼氏菌丰度增加，接受健康人类 FMT 的小鼠中肠道微生物群无明显变化。值得注意的是，PD 患者的 FMT 显著加重了运动障碍、多巴胺能神经退行性变、黑质纹状体胶质激活和结肠炎症，并抑制了 AMPK/SOD2 信号通路。然而，健康人类对照的 FMT 极大地改善了上述 MPTP 引起的作用。令人惊讶的是，MPTP 处理的小鼠显示出黑质纹状体周细胞的显著丧失，而健康人类对照的 FMT 可恢复其丧失。我们的研究结果表明，FMT 来自健康人类对照可以通过抑制小胶质细胞和星形胶质细胞的激活，通过 AMPK/SOD2 通路改善线粒体损伤，并恢复黑质纹状体周细胞和 BBB 完整性，纠正肠道菌群失调，改善 MPTP 诱导的 PD 小鼠模型中的神经退行性变。这些发现提示人类肠道微生物群的改变可能是 PD 的一个危险因素，并为 FMT 在 PD 临床前治疗中的潜在应用提供了证据。
