Gut-derived metabolites drive Th17 cell pathogenicity in multiple sclerosis
The gut-brain axis is an emerging factor in promoting multiple sclerosis (MS). However, the underlying mechanisms and strategies to target this axis are not established. Here, we investigated how the gut environment influences myelin-specific Th17 cell pathogenicity. We used the adoptive Th17 cell transfer experimental autoimmune encephalomyelitis (EAE) model and antibiotic treatment to disrupt the intestinal microbiome. We observed reduced pathogenic Th17 cell signature in the colon of antibiotic-treated mice. Treatment with fecal filtrates enhanced myelin-specific Th17 cell encephalitogenic properties both in vitro and in vivo. Fecal metabolomic profiling identified altered tryptophan-derived metabolites, including indole-3-carboxylate (I3CA). Oral I3CA supplementation accelerated EAE development. I3CA concentration in blood samples from persons with MS (PwMS) was associated with increased disease severity mirrored by increased serum neurofilament light chain levels. Altogether, our study shows that microbiota-derived metabolites play a key role in the intestine during neuroinflammation, offering potential therapeutic insights for PwMS.
Authors
- Valentine Bressoud
- Solenne Vigne (ORCID: https://orcid.org/0000-0002-8786-0198)
- Nancy E. Phillips
- Tim C. Roloff (ORCID: https://orcid.org/0000-0003-3435-4723)
- Jessica Rebeaud
- Jens Kühle (ORCID: https://orcid.org/0000-0002-6963-8892)
- Francisco Órtega Ruiz (ORCID: https://orcid.org/0000-0003-1902-0522)
- Lena K. Siewert (ORCID: https://orcid.org/0000-0003-3808-3377)
- Adrian Egli (ORCID: https://orcid.org/0000-0002-3564-8603)
- Tinh‐Hai Collet (ORCID: https://orcid.org/0000-0002-3243-1222)
- Bastian Peter
- Caroline Pot (ORCID: https://orcid.org/0000-0002-1146-3129)
- Anne‐Katrin Pröbstel (ORCID: https://orcid.org/0000-0002-7748-1872)
- Romeo Carre
Institutions
- University of Geneva (CH)
- University of Zurich (CH)
- Centre Hospitalier Universitaire Vaudois (CH)
- University Hospital of Basel (CH)
- University Hospital of Geneva (CH)
- Department of Biomedicine Basel (CH)
- Geneva College (US)
- University of Lausanne (CH)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-09-23
- DOI
- https://doi.org/10.1016/j.celrep.2025.116326
- Citations
- 1
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Science Foundation
- Novartis Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Novartis Stiftung für Medizinisch-Biologische Forschung
- Gottfried und Julia Bangerter-Rhyner-Stiftung
- Fondation Leenaards
- Université de Lausanne
- Vontobel-Stiftung
- Fondation Pierre Mercier
- Fondation Pierre Mercier pour la Science