Role of TLR4 in the gut-brain axis in Parkinson's disease: a translational study from men to mice. Issue 5 (15th December 2018)

• Record Type: Journal Article
• Authors: Perez-Pardo, Paula; Dodiya, Hemraj B; Engen, Phillip A; Forsyth, Christopher B; Huschens, Andrea M; Shaikh, Maliha; Voigt, Robin M; Naqib, Ankur; Green, Stefan J; Kordower, Jeffrey H; Shannon, Kathleen M; Garssen, Johan; Kraneveld, Aletta D; Keshavarzian, Ali
• Is Part Of: Gut. Volume 68:Issue 5(2019)
• Page Start: 829
• Page End: 843
• Publication Date: 2018-12-15
• Subjects: inflammation -- short chain fatty acids -- brain/gut interaction -- colonic microflora; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2018-316844
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Objective: 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. Design: 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. Results: 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. Conclusion: 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.