Microbiota-derived Inosine Suppresses Systemic Autoimmunity via Restriction of B Cell Differentiation and Migration

The role of gut microbiota dysbiosis in systemic lupus erythematosus (SLE) pathogenesis remains elusive. Here, we show that fecal microbiota transplantation (FMT) from healthy mice to lupus mice ameliorated lupus-like symptoms. Microbiota reconstitution effectively reduced systemic class switch recombination and elevated IGH naïve isotype. Microbiota profiling revealed an enrichment of Lactobacillus johnsonii post-FMT, with a significant correlation to purine metabolites. Importantly, the Lactobacillus johnsonii-derived inosine, an intermediate metabolite in purine metabolism, effectively alleviated lupus-like symptoms by impeding B cell differentiation and reducing renal B cell infiltration. We further demonstrated that inosine reprograms B cells through the ERK-HIF-1a signaling pathway. Overall, our study highlights the discovery of a novel microbial metabolite modulating autoimmunity and suggests its potential for innovative microbiome-based therapeutic approaches. Overall design: kidney samples from pristane-induced C57BL/6j lupus mice treated with saline (n=2) and fecal microbiota transplanation (FMT) from MRL/MpJ mice (n=3).