Paula Perez-Pardo 1 , Hemraj B Dodiya 2 , Aletta D Kraneveld 1,3 , Ali Keshavarzian 1,2 , Phillip A Engen 2 , Christopher B Forsyth 2 , Andrea M Huschens 1 , Maliha Shaikh 2 , Robin M Voigt 2 , Ankur Naqib 4 , Stefan J Green 4,5 , Jeffrey H Kordower 6 , Kathleen M Shannon 6 , Johan Garssen 1,7 Show Affiliations »
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. © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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 . © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Entities: Chemical
Disease
Gene
Species
Keywords:
brain/gut interaction; colonic microflora; inflammation; short chain fatty acids
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Year: 2018
PMID： 30554160 DOI： 10.1136/gutjnl-2018-316844
Source DB: PubMed Journal: Gut ISSN： 0017-5749 Impact factor: 23.059