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.
- short chain fatty acids
- brain/gut interaction
- colonic microflora
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PP-P and HBD contributed equally.
ADK and AK contributed equally.
Contributors (1) Research project: A. Conception, B. Organisation, C. Execution; D. Supervision; (2) statistical analysis: A. Design, B. Execution, C. Review and Critique; (3) manuscript preparation: A. Writing of the first draft, B. Review and critique. PP-P: 1A, 1B, 1C, 2A, 2B, 3A, 3B. HBD: 1A, 1B, 1C, 2A, 2B, 3A, 3B. PAE: 1B, 1C, 2A, 2B, 2C, 3B. CBF: 1B, 1C, 1D, 2C, 3B. AMH: 1B, 1C, 2B, 3B. MS: 1B, 2C, 3B. RMV: 1B, 2C, 3B. JHK: 1B, 2C, 3B. KMS: 1B, 2C, 3B. JG: 1B, 2C, 3B. ADK: 1A, 1C, 1D, 2C, 3B. AK: 1A, 1C, 1D, 2C, 3B.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests Professor Dr JG is an employee of Nutricia Research, Utrecht, The Netherlands. All other authors report no potential conflicts of interest.
Ethics approval Animal procedures were approved by the Ethical Committee of Animal Research of Utrecht University, The Netherlands.
Provenance and peer review Not commissioned; externally peer reviewed.