Systemic lupus erythematosus (SLE) is an autoimmune disease affecting 0.2% of the population. Despite substantial disease heterogeneity, lupus nephritis is a universal and major concern in patients with SLE, often leading to impaired kidney function or end-stage renal disease even with aggressive treatment. Because of unknown drivers of disease, current treatments for lupus nephritis fail to target the underlying pathophysiology and new approaches are urgently needed. We hypothesize that microbiome diversity is an important driver of disease that could be modified. Literature reports microbial alterations to be associated with SLE, but is unknown whether this association is causal. Our own preliminary data show that the disease manifestations of A20DC-KO mice which spontaneously develop an autoimmune disease resembling SLE including lupus nephritis, depend on the microbiology status of the mouse colony. First, given the prognostic significance of nephritis in SLE, we will further characterize kidney complications and the specificity of the B cell immune repertoire in this model. Next, we will investigate whether A20DC-KO mice suffer from dysbiosis and whether eliminating the microbiome completely or recolonization with distinct microbiomes of varying diversity has an effect on kidney disease and various other disease manifestations. If the microbiome indeed has a disease-modifying effect on SLE, modulation of the microbial composition may offer a new therapeutic opportunity.