Gut microbiota differently contributes to intestinal immune phenotype and systemic autoimmune progression in female and male lupus-prone mice

Abstract

1.AbstractThe risk of developing systemic lupus erythematosus (SLE) is about 9 times higher among women compared to men. Our recent report, which used (SWRxNZB) F1 (SNF1) mouse model of spontaneous lupus, showed a potential link between immune response initiated in the gut mucosa at juvenile age (sex hormone independent) and SLE susceptibility. Here, this mouse model, we show that gut microbiota contributes to a pro-inflammatory immune response in the intestine and autoimmune progression, primarily in females, leading to an associated gender bias. We found that gut microbiota composition in male and female littermates are significantly different only at adult age and depletion of gut microbes causes suppression of autoimmune progression only in females. In agreement, microbiota depletion suppressed the pro-inflammatory cytokine response of gut mucosa in both juvenile and adult females. In male SNF1 mice, on the other hand, orchidectomy (castration) caused changes in the composition of gut microbiota and a modest acceleration of autoimmune progression. However, cecum microbiota transplantation studies failed to show superior protection of females from autoimmunity by androgen-influenced gut microbiota. Overall, our work shows that microbiota-dependent pro-inflammatory immune response in the gut mucosa of females initiated at juvenile ages and androgen-dependent protection of males contributes to gender differences in the intestinal immune phenotype and systemic autoimmune progression.