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Gut-derived metabolites drive Th17 cell pathogenicity in multiple sclerosis
J Rebeaud1, S Vigne1, V Bressoud1
1Laboratories of Neuroimmunology, Center for Research in Neuroscience and Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital, and University of Lausanne, Lausanne, Switzerland.
Cell Reports
|September 21, 2025
Summary
Gut bacteria metabolites influence multiple sclerosis (MS) progression. Indole-3-carboxylate (I3CA), a gut microbe product, exacerbates EAE in mice and correlates with MS severity in humans, suggesting therapeutic targets.
Area of Science:
- Neuroimmunology
- Microbiome research
- Metabolomics
Background:
- The gut-brain axis is increasingly recognized for its role in multiple sclerosis (MS) pathogenesis.
- Mechanisms linking the gut environment to MS and therapeutic strategies remain unclear.
Purpose of the Study:
- To investigate how the gut environment, specifically microbiota-derived metabolites, influences the pathogenicity of myelin-specific Th17 cells in the context of MS.
Main Methods:
- Utilized the adoptive Th17 cell transfer experimental autoimmune encephalomyelitis (EAE) mouse model.
- Administered antibiotics to disrupt the intestinal microbiome and analyzed fecal filtrates.
- Performed fecal metabolomic profiling and oral supplementation with indole-3-carboxylate (I3CA).
- Assessed disease severity in mice and correlated I3CA levels with neurofilament light chain in persons with MS (PwMS).
Main Results:
- Antibiotic treatment reduced pathogenic Th17 cell signatures in the colon.
- Fecal filtrates enhanced myelin-specific Th17 cell encephalitogenic properties in vitro and in vivo.
- Identified altered tryptophan-derived metabolites, notably I3CA, in fecal samples.
- Oral I3CA supplementation accelerated EAE development in mice.
- Elevated blood I3CA levels in PwMS correlated with increased disease severity and serum neurofilament light chain.
Conclusions:
- Microbiota-derived metabolites play a critical role in gut-mediated neuroinflammation relevant to MS.
- Indole-3-carboxylate (I3CA) emerges as a key metabolite influencing disease pathogenicity.
- These findings offer potential therapeutic avenues targeting the gut-brain axis for MS management.
