Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, United States.
Elife. 2022 Nov 8;11:e81453. doi: 10.7554/eLife.81453.
Parkinson's disease (PD) is a movement disorder characterized by neuroinflammation, α-synuclein pathology, and neurodegeneration. Most cases of PD are non-hereditary, suggesting a strong role for environmental factors, and it has been speculated that disease may originate in peripheral tissues such as the gastrointestinal (GI) tract before affecting the brain. The gut microbiome is altered in PD and may impact motor and GI symptoms as indicated by animal studies, although mechanisms of gut-brain interactions remain incompletely defined. Intestinal bacteria ferment dietary fibers into short-chain fatty acids, with fecal levels of these molecules differing between PD and healthy controls and in mouse models. Among other effects, dietary microbial metabolites can modulate activation of microglia, brain-resident immune cells implicated in PD. We therefore investigated whether a fiber-rich diet influences microglial function in α-synuclein overexpressing (ASO) mice, a preclinical model with PD-like symptoms and pathology. Feeding a prebiotic high-fiber diet attenuates motor deficits and reduces α-synuclein aggregation in the substantia nigra of mice. Concomitantly, the gut microbiome of ASO mice adopts a profile correlated with health upon prebiotic treatment, which also reduces microglial activation. Single-cell RNA-seq analysis of microglia from the substantia nigra and striatum uncovers increased pro-inflammatory signaling and reduced homeostatic responses in ASO mice compared to wild-type counterparts on standard diets. However, prebiotic feeding reverses pathogenic microglial states in ASO mice and promotes expansion of protective disease-associated macrophage (DAM) subsets of microglia. Notably, depletion of microglia using a CSF1R inhibitor eliminates the beneficial effects of prebiotics by restoring motor deficits to ASO mice despite feeding a prebiotic diet. These studies uncover a novel microglia-dependent interaction between diet and motor symptoms in mice, findings that may have implications for neuroinflammation and PD.
帕金森病（PD）是一种运动障碍疾病，其特征为神经炎症、α-突触核蛋白病理学和神经退行性变。大多数 PD 病例为非遗传性的，提示环境因素起重要作用，有人推测疾病可能起源于外周组织，如胃肠道（GI），然后再影响大脑。PD 患者的肠道微生物组发生改变，并可能通过动物研究表明影响运动和 GI 症状，尽管肠道-大脑相互作用的机制仍不完全明确。肠道细菌将膳食纤维发酵成短链脂肪酸，PD 患者和健康对照者以及在小鼠模型中的粪便中这些分子的水平存在差异。在其他作用中，饮食微生物代谢产物可以调节小胶质细胞的激活，小胶质细胞是 PD 中涉及的脑驻留免疫细胞。因此，我们研究了富含纤维的饮食是否会影响过表达α-突触核蛋白（ASO）的小鼠的小胶质细胞功能，ASO 小鼠是一种具有 PD 样症状和病理学的临床前模型。喂养益生元高纤维饮食可减轻运动缺陷并减少 ASO 小鼠黑质中的α-突触核蛋白聚集。同时，ASO 小鼠的肠道微生物组在接受益生元治疗后采用与健康相关的模式，这也减少了小胶质细胞的激活。来自黑质和纹状体的小胶质细胞的单细胞 RNA-seq 分析表明，与标准饮食的野生型对照相比，ASO 小鼠的促炎信号增加，稳态反应减少。然而，益生元喂养可逆转 ASO 小鼠的致病性小胶质细胞状态，并促进保护性疾病相关巨噬细胞（DAM）小胶质细胞亚群的扩张。值得注意的是，使用 CSF1R 抑制剂耗尽小胶质细胞会通过恢复 ASO 小鼠的运动缺陷来消除益生元的有益作用，尽管它们在喂食益生元饮食。这些研究揭示了饮食和运动症状之间在小鼠中存在新的小胶质细胞依赖性相互作用，这些发现可能对神经炎症和 PD 具有意义。
