The gut microbiome is different between the sexes.Depleting androgen via castration changed the gut microbiome of male mice to be more similar to that of females and improved glucose metabolism, while reintroducing dihydrotestosterone (DHT) reversed these alterations. More importantly, the effects of androgen on glucose metabolism were largely abolished when the gut microbiome was depleted. Our study identifies the effects of androgen in deteriorating glucose homeostasis by modulating the gut microbiome, thereby contributing to the glucose metabolism difference between the sexes.

Males are generally more susceptible to impaired glucose metabolism and type 2 diabetes (T2D) than females. However, the underlying mechanisms remain to be determined. Here, we revealed that gut microbiome depletion abolished sexual dimorphism in glucose tolerance and insulin resistance. The transfer of male donor microbiota into antibiotic-treated female mice led the recipients to be more insulin resistant. Depleting androgen via castration changed the gut microbiome of male mice to be more similar to that of females and improved glucose metabolism, while reintroducing dihydrotestosterone (DHT) reversed these alterations. More importantly, the effects of androgen on glucose metabolism were largely abolished when the gut microbiome was depleted. Next, we demonstrated that the sex differences in the circulating glutamine and glutamine/glutamate ratio (Gln/Glu), which are associated with insulin resistance, are modulated by androgen, depending on the gut microbiome. Our study identifies the novel effects of androgen in deteriorating glucose homeostasis by modulating the gut microbiome and glutamine/glutamate ratio (Gln/Glu) levels, thereby contributing to the glucose metabolism difference between the sexes.