Systemic lupus erythematosus (SLE) is much more prevalent in females than males in humans, and in the (NZBxNZW)F1 (BWF1) mouse model of lupus. Although estrogens can exacerbate disease in females, considerable evidence suggests that androgens play a critical role in protecting males from lupus in both humans and mice. The gut microbiota plays a major role in host health and microbiota dysbiosis is associated with development of autoimmune diseases. Androgens have been shown to affect the microbiota and vice versa. Recent studies suggest that the microbiota and androgens may collaborate to protect male mice from autoimmune disease (type 1 diabetes). In preliminary studies, we have found that both the microbiota composition and metabolomic profile differ significantly between mature female and male BWF1 mice, and transfer of male microbiota to female BWF1 mice protects female recipients from disease and increases survival. These data suggest that the male environment confers protective properties on the microbiota by altering microbiota composition and/or function (e.g., production of metabolites). Metabolites from commensal bacteria have been found to induce Treg differentiation both directly and through dendritic cells (DC), and we propose that male-specific microbiota metabolites protect males from disease through a similar mechanism, and may be used effectively in therapies for the treatment of lupus in females. We will test the hypothesis that the androgen-modified male microbiota produce metabolites that protect against lupus by acting through the gut CD103DC in three specific aims: Aim 1. To identify metabolites produced by gut microbiota that are “regulated” by androgens in lupus-prone mice; Aim 2. Determine the role of metabolites from male-imprinted gut microbiota in preventing lupus; and Aim 3. Determine the role of CD103DC in protection mediated by metabolites from male-imprinted microbiota. Metabolomic analysis of the mouse microbiota will be performed using state-of-the-art technology. The proposed project could lead to the development of novel therapeutic strategies using microbiota metabolites for the treatment of lupus and other autoimmune diseases.