Akkermansia genetic variation in vitamin K production as a potential modulator of MS disease progression 2300114

Abstract Introduction Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) with heterogenous clinical presentation and disease course. MS is driven by genetic and environmental risk factors, including altered gut microbiome composition and associated bacterial metabolites. A key feature of the MS gut microbiome is increased abundance of Akkermansia, a genus recently reclassified into several distinct species. How Akkermansia species- or strain-level variation influences MS initiation, severity, or progression is unclear. Methods In a longitudinal study of people with MS, we profiled the baseline gut microbiome, correlating microbial features to disease progression; with key findings replicated in additional patient cohorts. Inferred metagenomic analysis, in silico pathway reconstruction, and bacterial comparative genomics identified metabolic drivers of disease worsening, which were validated using in vitro bacterial culture and in vivo metabolite treatment in a mouse model of MS. Results 41 bacterial species were associated with disease worsening, including depletion in Akkermansia muciniphila, while A. timonensis and A. massiliensis showed minimal or opposite associations. These findings were replicated in the International MS Microbiome Study, where A. muciniphila abundance correlated with MS severity. Metagenomics revealed reduced microbial vitamin K2 (VitK) biosynthesis linked to Akkermansia. Genomic analysis of Akkermansia isolates identified species and strains with deletions or variants in enzymes central to VitK biosynthesis, mirrored by differential in vitro VitK production. In mouse models of MS, VitK supplementation reduced CNS autoimmunity in females, while VitK-deficient diets increased coagulopathy in males. Conclusion Akkermansia species-level genetic variation, particularly within the VitK pathway, may modify MS disease progression in a sex-dependent manner. Akkermansia and VitK may be indicated as a tailored therapeutic approach to modulate MS disease progression. Funding Source National MS Society Postdoctoral Fellowship Topic Categories Mucosal and Regional Immunology (MUC)