Akkermansia muciniphila induces Th17 cells by mediating tryptophan metabolism and exacerbates experimental autoimmune encephalomyelitis (EAE)

Abstract Multiple sclerosis patients have been shown to have increased Akkermansia muciniphila (Akk) colonization. However, the role of Akk to regulate MS remains poorly understood. Here, we utilized fecal microbiota transplantation (FMT) model and generated Akk+ and Akk− SPF C57BL/6 mice. When subjected to EAE, Akk+ mice displayed worse clinical scores. An increase of spinal cord infiltrating IL-17A-producing and GM-CSF-producing CD4+ T cells was observed in Akk+ mice at 15 days post EAE induction. Moreover, ileum explant culture showed an elevated IL-17A production in Akk+ mice. Furthermore, we found dysregulated tryptophan in the cecal contents of naïve Akk+ mice. Additionally, using Kovac’s reagent, Akk was confirmed to utilize tryptophan and produce indole, an aryl hydrocarbon receptor (AhR) ligand. AhR activation has previously been shown to promote Th17 differentiation. Therefore, we performed Th17 differentiation in vitro. The treatment of Akk-derived tryptophan metabolites significantly induced IL-17A response. CH-223191, an AhR antagonist, abrogated the induction of Akk-mediated Th17 differentiation, suggesting that Akk-mediated Th17 differentiation was dependent on AhR. In addition, increased AhR agonists were observed in the feces of MOG immunized Akk+ mice as compared to Akk− mice. In conclusion, our data showed that Akk exacerbated EAE possibly by tryptophan-dependent induction of IL-17A-producing CD4+ T cells.