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

Paula Perez-Pardo, Hemraj B. Dodiya, Phillip A. Engen, Christopher B. Forsyth, Andrea M. Huschens, Maliha Shaikh, Robin M. Voigt, Ankur Naqib, Stefan J. Green, Jeffrey H. Kordower, Kathleen M. Shannon, Johan Garssen, Aletta D. Kraneveld, Ali Keshavarzian

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

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 (TLR 4)-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 TLR 4 signalling in PD-induced neuroinflammation, we used TLR 4-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 TLR 4, 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 TLR 4-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 TLR 4-KO mice. Conclusion: Taken together, these studies suggest that TLR 4-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.

Original languageEnglish (US)
Pages (from-to)829-843
Number of pages15
JournalGut
Volume68
Issue number5
DOIs
StatePublished - 2019
Externally publishedYes

ASJC Scopus subject areas

  • Gastroenterology

Fingerprint

Dive into the research topics of 'Role of TLR4 in the gut-brain axis in Parkinson's disease: A translational study from men to mice'. Together they form a unique fingerprint.

Cite this