IL-17A-mediated alterations in gut microbiota composition, particularly changes in Prevotella abundance, impact Treg function in CNS Autoimmunity

A disrupted equilibrium among gut microbiota, IL-17A-producing CD4 T-cells (Th17), and regulatory CD4 T-cells (Treg) have been linked with the pathobiology of multiple sclerosis (MS). While gut microbiota can regulate both Treg and Th17 cells, the impact of IL-17A on this gut-immune connection remains unclear. Utilizing HLA-DR3 transgenic mouse model of MS, we show that IL-17A deficiency (HLA-DR3.IL17A-/-) resulted in milder disease characterized by increased Tregs and expansion of Treg-promoting gut microbes, including Prevotella . Cohousing HLA-DR3 mice with HLA-DR3.IL17A-/- transferred the milder disease phenotype and associated microbiota changes to DR3 mice, highlighting the dominant role of gut microbiota in Treg induction and disease amelioration. DR3.IL17A-/- mice also showed a higher abundance of functional pathways linked with short-chain fatty acid synthesis and elevated IL-10 in dendritic cells. Enrichment of the Treg-promoting PPAR signaling pathway expression in the colon of HLA-DR3.IL17A-/- mice and following Prevotella administration in HLA-DR3 mice underscores the importance of gut microbiota in IL-17A-mediated immune regulation. Thus, our study uncovers a previously unappreciated role for IL-17A in shaping gut microbiota and immune regulation, with far-reaching implications for MS treatment. One-Sentence Summary IL-17A modulates Treg and gut microbiota to control EAE ### Competing Interest Statement AKM is inventor of a technology claiming the use of Prevotella histicola for the treatment of autoimmune diseases. The patent for the technology is owned by Mayo Clinic, who has given exclusive license to Evelo Biosciences. AKM received royalties from Mayo Clinic (paid by Evelo Biosciences). However, no fund or product from the patent were used in the present study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.