Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
Department of Internal Medicine, Division of Digestive Disease and Nutrition, Rush University Medical Center, Chicago, Illinois, USA.
Gut. 2019 May;68(5):829-843. doi: 10.1136/gutjnl-2018-316844. Epub 2018 Dec 15.
Recent evidence suggesting an important role of gut-derived inflammation in brain disorders has opened up new directions to explore the possible role of the gut-brain axis in neurodegenerative diseases. Given the prominence of dysbiosis and colonic dysfunction in patients with Parkinson's disease (PD), we propose that toll-like receptor 4 (TLR4)-mediated intestinal dysfunction could contribute to intestinal and central inflammation in PD-related neurodegeneration.
To test this hypothesis we performed studies in both human tissue and a murine model of PD. Inflammation, immune activation and microbiota composition were measured in colonic samples from subjects with PD and healthy controls subjects and rotenone or vehicle-treated mice. To further assess the role of the TLR4 signalling in PD-induced neuroinflammation, we used TLR4-knockout (KO) mice in conjunction with oral rotenone administration to model PD.
Patients with PD have intestinal barrier disruption, enhanced markers of microbial translocation and higher pro-inflammatory gene profiles in the colonic biopsy samples compared with controls. In this regard, we found increased expression of the bacterial endotoxin-specific ligand TLR4, CD3+ T cells, cytokine expression in colonic biopsies, dysbiosis characterised by a decrease abundance of SCFA-producing colonic bacteria in subjects with PD. Rotenone treatment in TLR4-KO mice revealed less intestinal inflammation, intestinal and motor dysfunction, neuroinflammation and neurodegeneration, relative to rotenone-treated wild-type animals despite the presence of dysbiotic microbiota in TLR4-KO mice.
Taken together, these studies suggest that TLR4-mediated inflammation plays an important role in intestinal and/or brain inflammation, which may be one of the key factors leading to neurodegeneration in PD.
最近有证据表明，肠道来源的炎症在脑部疾病中起着重要作用，这为探索肠道-大脑轴在神经退行性疾病中的可能作用开辟了新的方向。鉴于肠道菌群失调和结肠功能障碍在帕金森病（PD）患者中较为突出，我们提出，Toll 样受体 4（TLR4）介导的肠道功能障碍可能导致 PD 相关神经退行性变中的肠道和中枢炎症。
为了验证这一假设，我们在人体组织和 PD 小鼠模型中进行了研究。测量了 PD 患者和健康对照组的结肠样本中的炎症、免疫激活和微生物群落组成，并对旋毛虫或载体处理的小鼠进行了研究。为了进一步评估 TLR4 信号在 PD 诱导的神经炎症中的作用，我们使用 TLR4 敲除（KO）小鼠结合口服旋毛虫给药来模拟 PD。
与对照组相比，PD 患者的肠道屏障破坏，微生物易位的标志物增强，结肠活检样本中的促炎基因谱更高。在这方面，我们发现 TLR4 的表达增加，TLR4 是细菌内毒素特异性配体，CD3+T 细胞，以及 PD 患者结肠活检中的细胞因子表达增加。与野生型动物相比，旋毛虫处理的 TLR4-KO 小鼠的肠道炎症、肠道和运动功能障碍、神经炎症和神经退行性变减少，尽管 TLR4-KO 小鼠存在肠道菌群失调。
总之，这些研究表明，TLR4 介导的炎症在肠道和/或大脑炎症中起着重要作用，这可能是导致 PD 中神经退行性变的关键因素之一。
