Gender Bias in Autoimmunity Is Influenced by Microbiota

Abstract

Summary Gender bias and the role of sex hormones in autoimmune diseases are well established. In specific pathogen-free (SPF) non-obese diabetic (NOD) mice, females have 1.3–4.4 times higher incidence of Type 1 diabetes (T1D). Germ-free (GF) mice lost the gender bias (female/male ratio 1.1–1.2). Gut microbiota differed in males and females, a trend reversed by male castration confirming that androgens influence gut microbiota. Colonization of GF NOD mice with defined microbiota revealed that some, but not all, lineages overrepresented in male mice supported a gender bias in T1D. Although, protection of males did not correlate with blood androgen concentration, hormone-supported expansion of selected microbial lineages may work as a positive feedback mechanism contributing to the sexual dimorphism of autoimmune diseases. Gene expression analysis suggested pathways involved in protection of males from T1D by microbiota. Our results favor a two-signal model of gender bias, in which hormones and microbes together trigger protective pathways.

Sexual dimorphism in cancer

“…In Non Obese Diabetic (NOD) mice, susceptible to autoimmune diabetes, the rise of testosterone after puberty promotes a divergent bacterial commensal population from adult females and prepuberal animals 69 . Such effect, which is reversed upon castration, is associated with reduced susceptibility to autoimmune reaction linked with changes in cytokine expression in lymphoid and myeloid cells.…”

Reciprocity in Microbiome and Immune System Interactions and its Implications in Disease and Health

“…Differences in gut microbial composition between two sexes play a major role in this sex bias and contribute to the differential testosterone levels in male and female NOD mice [60,61]. Accordingly, germ free NOD mice lose the sex bias for diabetes incidence and both sexes show a similar rate of disease incidence [61].…”

“…Accordingly, germ free NOD mice lose the sex bias for diabetes incidence and both sexes show a similar rate of disease incidence [61]. Colonization of germ free NOD mice in early life with commensal bacteria increases testosterone levels accompanied by protection from diabetes development [61]. The difference in number and composition of microbiota between male and female mice occurs after puberty.…”

“…The difference in number and composition of microbiota between male and female mice occurs after puberty. Analysis of microbiota composition before and after adulthood demonstrates that male mice after puberty gradually show variation from initial bacterial flora whereas microbiota from female mice remain stable [61]. These alterations in microbial composition are associated with rise in male hormonal levels and conversely male NOD mice undergoing castration show a bacterial composition similar to female NOD mice [61].…”

“…The altered microbiota and hormonal differences change the pathogenic potential of T cells so that adoptive transfer of T cells from manipulated NOD to NOD/SCID mice is no longer pathogenic in recipient mice [60]. The contribution of microbiota to the sex bias in susceptibility to autoimmune diseases might be beyond mere modulation of hormonal levels [61]. Thus, a two signal model proposed that both microbes and hormones in parallel or in series have a role in the development of autoimmune disease [61].…”