Department of Neurobiology, the University of Chicago, Chicago, IL, USA; Department of Internal Medicine, Division of Digestive Diseases, Rush University Medical Center, Chicago, IL, USA.
Department of Internal Medicine, Division of Digestive Diseases, Rush University Medical Center, Chicago, IL, USA.
Neurobiol Dis. 2020 Feb;135:104352. doi: 10.1016/j.nbd.2018.12.012. Epub 2018 Dec 21.
Recent evidence provides support for involvement of the microbiota-gut-brain axis in Parkinson's disease (PD) pathogenesis. We propose that a pro-inflammatory intestinal milieu, due to intestinal hyper-permeability and/or microbial dysbiosis, initiates or exacerbates PD pathogenesis. One factor that can cause intestinal hyper-permeability and dysbiosis is chronic stress which has been shown to accelerate neuronal degeneration and motor deficits in Parkinsonism rodent models. We hypothesized that stress-induced intestinal barrier dysfunction and microbial dysbiosis lead to a pro-inflammatory milieu that exacerbates the PD phenotype in the low-dose oral rotenone PD mice model. To test this hypothesis, mice received unpredictable restraint stress (RS) for 12 weeks, and during the last six weeks mice also received a daily administration of low-dose rotenone (10 mg/kg/day) orally. The initial six weeks of RS caused significantly higher urinary cortisol, intestinal hyperpermeability, and decreased abundance of putative "anti-inflammatory" bacteria (Lactobacillus) compared to non-stressed mice. Rotenone alone (i.e., without RS) disrupted the colonic expression of the tight junction protein ZO-1, increased oxidative stress (N-tyrosine), increased myenteric plexus enteric glial cell GFAP expression and increased α-synuclein (α-syn) protein levels in the colon compared to controls. Restraint stress exacerbated these rotenone-induced changes. Specifically, RS potentiated rotenone-induced effects in the colon including: 1) intestinal hyper-permeability, 2) disruption of tight junction proteins (ZO-1, Occludin, Claudin1), 3) oxidative stress (N-tyrosine), 4) inflammation in glial cells (GFAP + enteric glia cells), 5) α-syn, 6) increased relative abundance of fecal Akkermansia (mucin-degrading Gram-negative bacteria), and 7) endotoxemia. In addition, RS promoted a number of rotenone-induced effects in the brain including: 1) reduced number of resting microglia and a higher number of dystrophic/phagocytic microglia as well as (FJ-C+) dying cells in the substantia nigra (SN), 2) increased lipopolysaccharide (LPS) reactivity in the SN, and 3) reduced dopamine (DA) and DA metabolites (DOPAC, HVA) in the striatum compared to control mice. Our findings support a model in which chronic stress-induced, gut-derived, pro-inflammatory milieu exacerbates the PD phenotype via a dysfunctional microbiota-gut-brain axis.
最近的证据支持微生物群-肠道-大脑轴在帕金森病（PD）发病机制中的作用。我们提出，由于肠道通透性增加和/或微生物失调，炎症性肠道环境会引发或加重 PD 发病机制。一个导致肠道通透性增加和失调的因素是慢性应激，它已被证明会加速帕金森病啮齿动物模型中的神经元变性和运动缺陷。我们假设，应激引起的肠道屏障功能障碍和微生物失调导致促炎环境，从而加剧低剂量口服鱼藤酮 PD 小鼠模型中的 PD 表型。为了验证这一假设，研究人员对小鼠进行了 12 周的不可预测束缚应激（RS），在最后六周，小鼠还每天接受低剂量鱼藤酮（10mg/kg/天）口服治疗。最初六周的 RS 导致尿皮质醇显著升高，肠道通透性增加，而假定的“抗炎”细菌（乳酸杆菌）的丰度降低，与非应激小鼠相比。单独的鱼藤酮（即没有 RS）破坏了结肠紧密连接蛋白 ZO-1 的表达，增加了氧化应激（N-酪氨酸），增加了肌间神经丛肠神经胶质细胞 GFAP 的表达，并增加了结肠中的α-突触核蛋白（α-syn）蛋白水平，与对照组相比。RS 加剧了这些鱼藤酮诱导的变化。具体来说，RS 增强了鱼藤酮在结肠中的作用，包括：1）肠道通透性增加，2）紧密连接蛋白（ZO-1、Occludin、Claudin1）破坏，3）氧化应激（N-酪氨酸），4）神经胶质细胞炎症（GFAP+肠神经胶质细胞），5）α-syn，6）粪便阿克曼氏菌（黏液降解革兰氏阴性菌）相对丰度增加，7）内毒素血症。此外，RS 促进了鱼藤酮在大脑中的许多作用，包括：1）黑质（SN）中静止小胶质细胞数量减少，吞噬性小胶质细胞和（FJ-C+）死亡细胞数量增加，2）SN 中脂多糖（LPS）反应性增加，3）纹状体中的多巴胺（DA）和 DA 代谢物（DOPAC、HVA）减少，与对照组相比。我们的研究结果支持一种模型，即慢性应激诱导的、肠道来源的、促炎环境通过功能失调的微生物群-肠道-大脑轴加重 PD 表型。
