IL-17A controls CNS autoimmunity by regulating gut microbiota and inducing regulatory T cells

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system. The pathogenesis of MS and other autoimmune diseases is defined by a disrupted equilibrium between IL-17A-producing CD4 T cells (Th17) and regulatory CD4 T cells (Treg). The development of Treg and Th17 cells can be regulated by the gut microbiota, however, it is unclear how the gut microbiota is impacted by IL-17A and how this, in turn, modulates Treg and disease. Here, we show that IL-17A deficiency promotes interferon-I-related gene expression and expands gut microbes that induce the Treg cells, resulting in milder disease in a mouse model of MS. Utilizing HLA-DR3.IL17A-/- transgenic mice, we showed significant enrichment of Treg-promoting gut microbes such as Prevotella sp. MGM1, Parabacteroides distasonis and Bacteroides sartorii species. Further, we observed enrichment of bacterial-specific short-chain fatty acid metabolic pathways that promote Treg function in HLA-DR3.IL17A-/- transgenic mice. Notably, disease severity was reversed in IL-17A sufficient mice that received fecal transplants from, and cohoused with, IL-17A-deficient mice, highlighting a critical role for the gut microbiota in inducing Treg and reducing disease severity. Collectively, we show that IL-17A is an important regulator of the gut microbiota-Treg axis, which mediates immune homeostasis, inflammation, and diseases such as MS. Tissue sections from the colon of both DR3.IL17A-/- and DR3 mice before EAE induction were collected and RNA was isolated.