DOP068 Vedolizumab counteracts Parkinson’s disease-related brain pathology driven by gut-primed IBD T cells

Abstract Background The gut-brain axis has been increasingly recognized as a critical pathway linking Inflammatory Bowel Diseases (IBD) with neurodegenerative diseases. Chronic inflammation resulting from IBD can extend beyond the gut, and epidemiological data have also linked to the increased prevalence of neurodegenerative conditions like Parkinson’s disease (PD). However, the exact mechanisms underlying this interconnection are largely unclear. We therefore investigated how gut-primed T cells from IBD patients may drive neurodegenerative processes seen in PD. Methods Peripheral blood T cells from IBD patients were analyzed for co-expression of gut-homing integrin α4β7 and brain-homing integrin β1. Using gut-specific photoconversion in a Kaede T cell Transfer Colitis mouse model, we assessed the infiltration of gut-primed T cells into the brain tissue. To model and elucidate the interplay of T cells with the brain tissue ex vivo, we developed an innovative three-dimensional co-culture system involving human stem cell-derived Brain Organoids (hBrO) and peripheral blood T cells from IBD patients and controls. Vedolizumab, an anti-α4β7 integrin antibody, was used to assess its potential in blocking T cell accumulation and subsequent neurotoxicity in hBrO cultures. Results Gut-primed T cells from IBD patients co-expressed brain-homing integrins, suggesting that they are able to enter brain tissue. Clear evidence of gut-to-brain T cell trafficking was obtained in the Kaede T cell Transfer Colitis mouse model, confirming the capacity of gut-primed T cells to migrate across the blood-brain barrier under conditions of chronic intestinal inflammation. In the hBrO co-culture model, neurons expressed MAdCAM-1, and MAdCAM-1 expression in neurons was also found in single cell RNA sequencing of postmortem brain tissue. Consistently, α4β7+ IBD T cells accumulated specifically in the vicinity of neurons, leading to neuronal cell death and aSyn aggregation (a hallmark of PD) in hBrO. In line, Vedolizumab treatment reduced IBD T cell accumulation in hBrO and preserved neural cell integrity. Conclusion Our data, for the first time, show a T cell trafficking-driven axis of gut-to-brain communication with pathogenic potential for the central nervous system in the context of IBD. Moreover, our findings suggest that neurotoxic T cell-neuron interaction is mediated by MADCAM1 and α4β7 integrin. Thus, our study reveals a novel pathway, by which IBD T cells may contribute to neurodegeneration, linking chronic gut inflammation to brain tissue pathology and synucleinopathy. Blocking α4β7-mediated T cell-induced neurotoxicity and aSyn pathology presents a potential therapeutic approach for IBD patients at risk of neurodegenerative diseases such as PD.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.