GUT MICROBIAL INTERPLAY WITH SEX HORMONE HOMEOSTASIS

The gut microbiome plays a pivotal role in host health through both its composition and metabolic functions. Notably, emerging evidence suggests a bi-directional relationship between the gut microbiome and sex steroid homeostasis. Studies have documented shifts in gut microbial communities following gonadectomy, and menopause, and additional research indicates that gut microbes can directly modify sex steroids through deconjugation and sterol conversions. However, the interplay between the gut microbiome and the hypothalamic-pituitary-gonadal (HPG) axis - the central regulator of sex steroid homeostasis - along with the microbiome's response to exogenous sex steroids, remains poorly understood. Moreover, the causal role of the microbiome in regulating sex steroid homeostasis has yet to be fully elucidated. Herein, we present evidence from both conventional and gnotobiotic mouse models demonstrating that the gut microbiome not only responds to changes in sex steroid homeostasis but can also influence hypothalamic-pituitary-gonadal (HPG) axis signaling, potentially through its impact on the host metabolome. We further show that upstream suppression of the HPG axis leads to rapid perturbations in the gut microbiota, and that this altered microbiome can, in turn, affect reproductive parameters governed by sex steroid homeostasis. Additionally, we provide evidence that exogenous sex steroids, delivered as oral contraceptives, induce time- and intestinal segment-specific alterations in the gut microbiome - changes that may contribute to oral contraceptive-associated metabolic stress. Given the gut microbiome’s highly responsive nature to external factors such as diet, environment, and lifestyle factors, understanding its interaction with sex steroid homeostasis could offer promising targets for the development of novel therapeutics and precision medicine strategies.