Potential role of Akkermansia massiliensis in multiple sclerosis protection by the FcRL3 gene

The contribution of human genetics in shaping the abundance of gut microbiota is small, about 5%; however, it can inform about disease etiopathogenesis, including multiple sclerosis (MS). Searching for MS-gut microbiota cross-comparison of reported genome-wide association studies (GWAS), we identified a coincident association of the disease with a commensal - Akkermansia massiliensis-in the selective Fc receptor of secretory IgA gene (FcRL3). Those two signals colocalized, supporting that lower abundance of A.massiliensis may contribute to MS predisposition. In cis, the FcRL3-MS predisposing signal downregulates the FcRL3 protein production and modulates the dynamic intron usage between naïve and mature B-cells, which we believe to be the primary molecular mechanism associated with MS risk in this region. The signal also increases the expression of the FcRL5 gene. In trans, it reduces the expression of neuropeptide B/W receptor 1 (NPBWR1) and azurocidin (AZU1), whereas it increases the expression of the tumor necrosis factor receptor superfamily, member 13B (TACI). Our view of MS etiopathogenesis suggests that low levels of FcRL3 and A. massiliensis may predispose to MS by causing impaired self-tolerance to commensal microbiota, dysregulation of B-cell function, and immune system effects on the neuroendocrine signaling by AZU1 and NPBWR1 proteins, which may be further investigated as targets for MS.