Cell reportsSep 21, 2025

Gut metabolites linked to harmful Th17 immune cells in multiple sclerosis

Gut-Brain Axis Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

Gut-derived tryptophan metabolites, especially I3CA, may amplify pathogenic Th17 activity in MS-related neuroinflammation.

Evidence

Preclinical and translational experiments in EAE mice, in vitro Th17 assays, fecal metabolomics, and PwMS blood samples linked microbiome disruption, fecal filtrates, and I3CA to Th17 pathogenicity, EAE acceleration, and disease severity.

Caveat

Human I3CA data were associative, while causal effects were tested mainly in EAE and in vitro models.

Simplified

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.

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Gut metabolites linked to harmful Th17 immune cells in multiple sclerosis

Abstract

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