1. Academic Validation
  2. Gut-derived metabolites drive Th17 cell pathogenicity in multiple sclerosis

Gut-derived metabolites drive Th17 cell pathogenicity in multiple sclerosis

  • Cell Rep. 2025 Sep 19;44(10):116326. doi: 10.1016/j.celrep.2025.116326.
J Rebeaud 1 S Vigne 1 V Bressoud 1 R Carre 1 F Ruiz 1 B Peter 1 N E Phillips 2 L Siewert 3 T Roloff 4 A Egli 4 J Kuhle 3 T-H Collet 5 A K Pröbstel 3 C Pot 6
Affiliations

Affiliations

  • 1 Laboratories of Neuroimmunology, Center for Research in Neuroscience and Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital, and University of Lausanne, Lausanne, Switzerland.
  • 2 Laboratories of Neuroimmunology, Center for Research in Neuroscience and Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital, and University of Lausanne, Lausanne, Switzerland; Service of Endocrinology and Diabetology, Geneva University Hospitals, Geneva, Switzerland.
  • 3 Departments of Neurology, Biomedicine, and Clinical Research & Research Center for Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital and University of Basel, Basel, Switzerland.
  • 4 Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland.
  • 5 Service of Endocrinology and Diabetology, Geneva University Hospitals, Geneva, Switzerland; Diabetes Centre, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
  • 6 Laboratories of Neuroimmunology, Center for Research in Neuroscience and Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital, and University of Lausanne, Lausanne, Switzerland. Electronic address: caroline.pot-kreis@chuv.ch.
Abstract

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.

Keywords

CP: Metabolism; CP: Neuroscience; Th17 lymphocytes; blood biomarker; experimental autoimmune encephalomyelitis; gut-brain axis; indole derivatives; microbiota-derived metabolites; multiple sclerosis; neuroinflammation.

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