Role of TLR4 in the gut-brain axis in Parkinson’s disease: a translational study from men to mice

• Published in: Gut Vol. 68; no. 5; pp. 829 - 843
• Main 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
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and British Society of Gastroenterology 01.05.2019; BMJ Publishing Group LTD
• Subjects: Animal models; Animals; Biopsy; Brain research; brain/gut interaction; Case-Control Studies; CD3 antigen; CD3 Complex - metabolism; Colon - metabolism; Colon - microbiology; Colon - pathology; colonic microflora; Constipation; Cytokines; Digestive system; Disease Models, Animal; Dysbacteriosis; Dysbiosis - etiology; Dysbiosis - metabolism; Dysbiosis - pathology; Fatty acids; Gastrointestinal tract; Gut microbiota; Gut-brain axis; Humans; Inflammation; Intestine; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiota; Movement disorders; Nervous system; Neurodegeneration; Neurodegenerative diseases; Oxidative stress; Parkinson Disease - etiology; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Pathogenesis; Pathology; Permeability; Rotenone; short chain fatty acids; TLR4 protein; Toll-Like Receptor 4 - physiology; Toll-like receptors; brain/gut interaction; inflammation; colonic microflora; short chain fatty acids
• ISSN: 0017-5749; 1468-3288; 1468-3288
• DOI: 10.1136/gutjnl-2018-316844

ObjectiveRecent 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.DesignTo 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.ResultsPatients 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.ConclusionTaken 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.