A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice.
A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice.
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DOI：
10.7554/elife.81453
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发表时间：
2022-11-08
期刊：
影响因子：
7.7
通讯作者：
Mazmanian SK
中科院分区：
文献类型：
--
作者：
Abdel-Haq R;Schlachetzki JCM;Boktor JC;Cantu-Jungles TM;Thron T;Zhang M;Bostick JW;Khazaei T;Chilakala S;Morais LH;Humphrey G;Keshavarzian A;Katz JE;Thomson M;Knight R;Gradinaru V;Hamaker BR;Glass CK;Mazmanian SK
帕金森病 (PD) 是一种以神经炎症、α-突触核蛋白病理学和神经变性为特征的运动障碍。大多数帕金森病病例是非遗传性的，这表明环境因素起着很大的作用，并且推测疾病可能起源于胃肠道 (GI) 等外周组织，然后影响大脑。动物研究表明，帕金森病患者的肠道微生物群发生了改变，可能会影响运动和胃肠道症状，尽管肠道-大脑相互作用的机制尚未完全确定。肠道细菌将膳食纤维发酵成短链脂肪酸，这些分子的粪便水平在帕金森病、健康对照以及小鼠模型中存在差异。除其他作用外，膳食微生物代谢物可以调节小胶质细胞的激活，小胶质细胞是与帕金森病有关的大脑驻留免疫细胞。因此，我们研究了富含纤维的饮食是否影响 α-突触核蛋白过度表达 (ASO) 小鼠的小胶质细胞功能，这是一种具有 PD 样症状和病理学的临床前模型。饲喂益生元高纤维饮食可减轻小鼠黑质中的运动缺陷并减少 α-突触核蛋白聚集。与此同时，ASO 小鼠的肠道微生物组在益生元治疗后呈现出与健康相关的特征，这也减少了小胶质细胞的激活。对黑质和纹状体小胶质细胞的单细胞 RNA-seq 分析发现，与标准饮食的野生型小鼠相比，ASO 小鼠的促炎症信号传导增加，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，尽管使用益生元饮食喂养 ASO 小鼠，但使用 CSF1R 抑制剂消除小胶质细胞后，仍会恢复 ASO 小鼠的运动缺陷，从而消除了益生元的有益作用。这些研究揭示了小鼠饮食和运动症状之间一种新的依赖小胶质细胞的相互作用，这一发现可能对神经炎症和帕金森病有影响。
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.