Article Text

Download PDFPDF

Original article
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}uu.nl

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 (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

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

View Full Text

Statistics from Altmetric.com

Footnotes

  • 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.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.