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.

Maternal diet and gut microbiome composition modulate early‐life immune development

“…These results support an early‐life induction of the colonic Th17 population that is driven by the maternal dietary fiber intake and mediated locally by A. muciniphila in the pups colons. Th17 cells play a key role in progression of multiple sclerosis, an autoimmune disease that has also been correlatively linked to the presence of A. muciniphila in patients (Jangi et al , 2016 ) and mechanistically in mouse models of multiple sclerosis (Lin et al , 2021 ). Although the precise nature of the link between Akkermansia and exacerbation of autoimmune encephalomyelitis has not yet been shown (e.g.…”

Maternal diet and gut microbiome composition modulate early life immune development

“…3D ). Th17 cells play a key role in progression of multiple sclerosis, an autoimmune disease that has also been correlatively linked to presence of A. muciniphila in patients (Jangi et al , 2016) and mechanistically in mouse models of multiple sclerosis (Lin et al , 2021). Although the precise nature of the link between Akkermansia and exacerbation of autoimmune encephalomyelitis has not yet been shown (e.g.…”