Mucin degradation by Akkermansia muciniphila promotes Alistipes-dependent tryptophan metabolism and Th17-driven autoimmunity

Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system associated with alterations in gut commensals, including Akkermansia muciniphila (A. muciniphila). However, its role in MS remains unclear. Here, we report elevated serum lipopolysaccharide (LPS) and anti-LPS IgG levels in patients with relapsing-remitting MS (RRMS), indicating compromised gut barrier integrity. Notably, RRMS patients also exhibited increased serum anti-A. muciniphila IgA and enhanced A. muciniphila-induced Th17 responses in peripheral blood mononuclear cells (PBMCs). Using experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, we found that A. muciniphila colonization worsened EAE severity, with increased infiltration of GM-CSF⁺CD4⁺ and IL-17A⁺CD4⁺ T cells in spinal cord. Mechanistically, A. muciniphila colonization enhanced tryptophan metabolism and elevated levels of aryl hydrocarbon receptor (AhR) agonists, including indole derivatives, during EAE. Although A. muciniphila does not directly metabolize tryptophan, it promotes expansion of tryptophan-utilizing bacterium Alistipes onderdonkii (A. onderdonkii) through mucin degradation. We further demonstrate that A. onderdonkii utilizes mucin-derived metabolites, including galactose and N-acetylneuraminic acid (NANA). Importantly, dietary tryptophan restriction significantly attenuated EAE severity. Collectively, these findings reveal a cross-feeding mechanism in which A. muciniphila supports growth of A. onderdonkii, thereby enhancing microbial tryptophan metabolism and production of AhR agonists that drive Th17-mediated neuroinflammation.