The study investigates the role of gut microbiota in promoting experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). It shows that germ-free (GF) mice, which lack microbial colonization, develop significantly less severe EAE compared to conventionally colonized mice. GF animals produce lower levels of proinflammatory cytokines IFN-γ and IL-17A, and have increased CD4+CD25+Foxp3+ regulatory T cells (Tregs). Mechanistically, gut dendritic cells from GF animals are less effective at stimulating proinflammatory T cell responses. Colonization with segmented filamentous bacteria (SFB) promotes IL-17A-producing CD4+ T cells (Th17) in the CNS, and SFB-colonized GF mice develop EAE, indicating that gut bacteria can influence neurologic inflammation. These findings suggest that the intestinal microbiota profoundly impacts the balance between pro- and anti-inflammatory immune responses during EAE, and that modulation of gut bacteria may provide therapeutic targets for extraintestinal inflammatory diseases like MS. The study highlights the role of the microbiota in shaping immune responses, particularly in the gut and CNS, and underscores the importance of gut bacteria in immune regulation. The results indicate that microbial signals can modulate the Th1/Th17 vs. Treg axis, influencing autoimmune diseases such as MS. The study also shows that the microbiota can influence immune responses outside the gut, and that microbial colonization is critical for immune system development and function. The findings have implications for understanding the role of the microbiota in autoimmune diseases and for developing therapeutic strategies targeting the gut microbiota.The study investigates the role of gut microbiota in promoting experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). It shows that germ-free (GF) mice, which lack microbial colonization, develop significantly less severe EAE compared to conventionally colonized mice. GF animals produce lower levels of proinflammatory cytokines IFN-γ and IL-17A, and have increased CD4+CD25+Foxp3+ regulatory T cells (Tregs). Mechanistically, gut dendritic cells from GF animals are less effective at stimulating proinflammatory T cell responses. Colonization with segmented filamentous bacteria (SFB) promotes IL-17A-producing CD4+ T cells (Th17) in the CNS, and SFB-colonized GF mice develop EAE, indicating that gut bacteria can influence neurologic inflammation. These findings suggest that the intestinal microbiota profoundly impacts the balance between pro- and anti-inflammatory immune responses during EAE, and that modulation of gut bacteria may provide therapeutic targets for extraintestinal inflammatory diseases like MS. The study highlights the role of the microbiota in shaping immune responses, particularly in the gut and CNS, and underscores the importance of gut bacteria in immune regulation. The results indicate that microbial signals can modulate the Th1/Th17 vs. Treg axis, influencing autoimmune diseases such as MS. The study also shows that the microbiota can influence immune responses outside the gut, and that microbial colonization is critical for immune system development and function. The findings have implications for understanding the role of the microbiota in autoimmune diseases and for developing therapeutic strategies targeting the gut microbiota.