Auxiliary role of gut microbiota alterations in the pathogenesis of resiquimod-induced autoimmune disease.

Dysbiosis and leaky gut are common in systemic lupus erythematosus (SLE). However, currently, it is unclear whether they initiate the pathogenesis or simply worsen it. In this study, using a resiquimod (R848; Toll-like receptor 7/8 agonist)-induced murine model of SLE-like disease, we investigated the effects of immune activation and the gut environment to elucidate the precise role of the gut microbiota in SLE pathogenesis. To induce SLE-like disease, R848 was transdermally administered to BALB/c mice. To assess the role of the gut environment, 1) leaky gut was induced to test whether it initiates autoimmunity, 2) fecal microbiota transplantation (FMT) from R848-treated mice was performed to test disease transmissibility, and 3) dysbiosis was induced with an antibiotic cocktail to test its impact on autoimmune responses. We demonstrated that R848 treatment induced systemic autoimmunity with elevated autoantibodies and dysbiosis, characterized by increased Bacteroidetes and decreased Firmicutes. Induced leaky gut did not appear to trigger autoimmunity, and FMT from R848-treated mice failed to consistently or reproducibly transfer autoimmune disease phenotypes. Interestingly, mice with pre-existing antibiotic-induced dysbiosis showed significantly increased splenic effector T cells and serum autoantibody titers at an early stage of R848 stimulation. These results suggest that dysbiosis and leaky gut in this model may be secondary to R848-driven systemic inflammation rather than primary causes. However, dysbiosis appears to play a crucial role in amplifying early autoimmune responses, suggesting that the gut microbiota may serve as an important modulatory factor in SLE pathogenesis. Thus, these findings may support therapies that combine immune modulation with gut-targeted interventions.