PT  - JOURNAL ARTICLE
AU  - Perez-Pardo, Paula
AU  - Dodiya, Hemraj B
AU  - Engen, Phillip A
AU  - Forsyth, Christopher B
AU  - Huschens, Andrea M
AU  - Shaikh, Maliha
AU  - Voigt, Robin M
AU  - Naqib, Ankur
AU  - Green, Stefan J
AU  - Kordower, Jeffrey H
AU  - Shannon, Kathleen M
AU  - Garssen, Johan
AU  - Kraneveld, Aletta D
AU  - Keshavarzian, Ali
TI  - Role of TLR4 in the gut-brain axis in Parkinson’s disease: a translational study from men to mice
AID  - 10.1136/gutjnl-2018-316844
DP  - 2019 May 01
TA  - Gut
PG  - 829--843
VI  - 68
IP  - 5
4099  - http://gut.bmj.com/content/68/5/829.short
4100  - http://gut.bmj.com/content/68/5/829.full
SO  - Gut2019 May 01; 68
AB  - 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.