Gut dysbiosis contributes to autoimmune pathogenesis in lupus-prone mice

Abstract

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease mediated by a combination of genetic and environmental factors. We have used a congenic model of the disease, the B6.Sle1.Sle2.Sle3 (TC) mice, which share 95% of their genome with B6 controls. TC and B6 mice have a different distribution of gut bacteria based on 16S rDNA sequencing. Fecal transfers into germ free (GF) B6 mice showed that microbiota from aged TC mice was sufficient to induce the production of anti-dsDNA IgG. TC microbiota expanded germinal center (GC)-like organization in Peyer’s patches and TFH cells in the mesenteric lymph node. Co-housing TC and B6 mice for 6 months starting at weaning revealed significant interactions between disease status and the microbiota compared with independently housed mice from both strains. Remarkably, the frequency of TFH cells was decreased in co-housed TC mice, corresponding to a drastic reduction of autoantibodies and amelioration of renal disease. Co-housed TC and B6 mice showed a similar fecal metabolome profile, which was significantly different from those of independently housed mice. Studies to characterize the role of specific metabolites related to disease pathogenesis are ongoing. Finally, treatment of TC mice with a combination of antibiotics significantly delayed anti-dsDNA IgG induction and expanded Treg and TFR cells. Overall, our results suggest that the dysregulated gut microbiota in lupus contributes to disease pathogenesis either directly or indirectly, through the production of critical metabolites.