Microbiota‐Derived Inosine Suppresses Systemic Autoimmunity via Restriction of B Cell Differentiation and Migration

Abstract The role of gut microbiota dysbiosis in systemic lupus erythematosus (SLE) pathogenesis remains elusive. Here, it is shown that fecal microbiota transplantation (FMT) from healthy mice to lupus mice ameliorates lupus‐like symptoms. Microbiota reconstitution effectively reduces systemic class switch recombination (CSR) and elevates immunoglobulin heavy chain (IGH) naïve isotype. Microbiota profiling reveals an enrichment of Lactobacillus johnsonii post‐FMT, with a significant correlation to purine metabolites. Importantly, the L. johnsonii ‐derived inosine, an intermediate metabolite in purine metabolism, effectively alleviates lupus pathogenesis in mice. Inosine inhibits B cell differentiation and reduces renal B cell infiltration to protect mice from lupus. At the molecular level, inosine reprograms B cells through the eDDxtracellular signal‐regulated kinase (ERK)‐hypoxia‐inducible factor‐1alpha (HIF‐1α) signaling pathway. Therefore, this study highlights the discovery of a novel microbial metabolite modulating autoimmunity and suggests its potential for innovative microbiome‐based therapeutic approaches.