Androgens may influence lupus development via an effect on the composition and metabolic activities of intestinal microbiota in BWF1 mice

Abstract

Abstract Like many autoimmune diseases, systemic lupus erythematosus (SLE) occurs much more often in females than males in humans and spontaneous mouse models of lupus, such as NZBxNZWF1 (BWF1) mice. Castration increases disease incidence, severity, and mortality in BWF1 males, and BWF1 females are protected from disease by androgen treatment, suggesting that male sex steroids, androgens, play a protective role in lupus. Accumulating evidence suggests that microbiota dysbiosis is associated with development of autoimmune diseases, and the microbiota influences and is influenced by androgens. Our previous research has linked sex differences in microbiota to the sex-bias of SLE and differences in immunoregulation in BWF1 mice. To investigate the role of androgen in this sex-bias, we have studied the effects of androgen depletion via castration on male BWF1 mice. Fecal samples were collected from castrated and control male and female BWF1 mice, and analyzed for microbiota composition, function, and metabolites. We found that androgen-depletion induced a significant shift in the overall microbiota profile away from that found in control male mice, and toward one that was more similar to BWF1 female mice. Androgen-depletion also altered the fecal metabolite profile; 72 metabolites were altered in castrated compared to control male mice, and of these, 34 were also differentially produced in control female vs male mice. These changes in microbiota and metabolite profiles correlated with increased disease/mortality and altered immunoregulation in castrated male mice. Taken together, these data indicate that androgens have a dramatic effect on the microbiota, and it may be through the microbiota that androgens affect SLE development.