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Role of TLR4 in the gut-brain axis in Parkinson’s disease: a translational study from men to mice
  1. Paula Perez-Pardo1,
  2. Hemraj B Dodiya2,
  3. Phillip A Engen2,
  4. Christopher B Forsyth2,
  5. Andrea M Huschens1,
  6. Maliha Shaikh2,
  7. Robin M Voigt2,
  8. Ankur Naqib3,
  9. Stefan J Green3,4,
  10. Jeffrey H Kordower5,
  11. Kathleen M Shannon5,
  12. Johan Garssen1,6,
  13. Aletta D Kraneveld1,7,
  14. Ali Keshavarzian1,2
  1. 1 Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
  2. 2 Department of Internal Medicine, Division of Digestive Disease and Nutrition, Rush University Medical Center, Chicago, Illinois, USA
  3. 3 Sequencing Core Research Resources Center, University of Illinois at Chicago, Chicago, Illinois, USA
  4. 4 Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois, USA
  5. 5 Department of of Neurology, Rush University Graduate College, Chicago, Illinois, USA
  6. 6 Nutricia Research, Utrecht, The Netherlands
  7. 7 Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
  1. Correspondence to Dr Paula Perez-Pardo, Universiteit Utrecht, Utrecht 3584CG, The Netherlands; p.perezpardo{at}


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.

  • inflammation
  • 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.