Fecal Microbiota Transplantation from Aged Mice Render Recipient Mice Resistant to MPTP-Induced Nigrostriatal Degeneration Via a Neurogenesis-Dependent but Inflammation-Independent Manner

MPTP公司 神经发生 肠道菌群 阿克曼西亚 双皮质醇 酪氨酸羟化酶 移植 神经炎症 多巴胺能 生物 炎症 内分泌学 内科学 帕金森病 多巴胺 免疫学 神经科学 医学 海马体 生物化学 疾病 齿状回 发酵 乳酸菌
作者
Chen-Meng Qiao,Yu Zhou,Wei Quan,Xiaoyu Ma,Liping Zhao,Yun Shi,Hui Hong,Jian Wu,Gu-Yu Niu,Yu-Nuo Chen,Shan Zhu,Chun Cui,Weijiang Zhao,Yan‐Qin Shen
出处
期刊:Neurotherapeutics [Springer Science+Business Media]
卷期号:20 (5): 1405-1426 被引量:16
标识
DOI:10.1007/s13311-023-01420-1
摘要

Accumulating data support a crucial role of gut microbiota in Parkinson’s disease (PD). However, gut microbiota vary with age and, thus, will affect PD in an age-dependent, but unknown manner. We examined the effects of fecal microbiota transplantation (FMT) pretreatment, using fecal microbiota from young (7 weeks) or aged mice (23 months), on MPTP-induced PD model. Motor function, pathological changes, striatal neurotransmitters, neuroinflammation, gut inflammation and gut permeability were examined. Gut microbiota composition and metabolites, namely short-chain fatty acids (SCFAs), were analyzed. Neurogenesis was also evaluated by measuring the number of doublecortin-positive (DCX+) neurons and Ki67-positive (Ki67+) cells in the hippocampus. Expression of Cd133 mRNA, a cellular stemness marker, in the hippocampus was also examined. Mice who received FMT from young mice showed MPTP-induced motor dysfunction, and reduction of striatal dopamine (DA), dopaminergic neurons and striatal tyrosine hydroxylase (TH) levels. Interestingly and unexpectedly, mice that received FMT from aged mice showed recovery of motor function and rescue of dopaminergic neurons and striatal 5-hydroxytryptamine (5-HT), as well as decreased DA metabolism after MPTP challenge. Further, they showed improved metabolic profiling and a decreased amount of fecal SCFAs. High-throughput sequencing revealed that FMT remarkably reshaped the gut microbiota of recipient mice. For instance, levels of genus Akkermansia and Candidatus Saccharimonas were elevated in fecal samples of recipient mice receiving aged microbiota (AM + MPTP mice) than YM + MPTP mice. Intriguingly, both young microbiota and aged microbiota had no effect on neuroinflammation, gut inflammation or gut permeability. Notably, AM + MPTP mice showed a marked increase in DCX+ neurons, as well as Ki67+ cells and Cd133 expression in the hippocampal dentate gyrus (DG) compared to YM + MPTP mice. These results suggest that FMT from aged mice augments neurogenesis, improves motor function and restores dopaminergic neurons and neurotransmitters in PD model mice, possibly through increasing neurogenesis.
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