Sex disparate gut microbiome and metabolome perturbations precede disease progression in a mouse model of Rett syndrome

Abstract Rett syndrome (RTT) is a severe regressive neurodevelopmental disorder in girls, characterized by multisystem complications including gut dysbiosis and altered metabolism. While RTT is known to be caused by mutations in the X-linked gene MECP2, the intermediate molecular pathways of progressive disease phenotypes are unknown. Mecp2 knockout rodents used to model RTT pathophysiology in most prior studies have been male. Thus, we utilized a patient-relevant mouse model of RTT to longitudinally profile the gut microbiome and metabolome across disease progression in both sexes. Fecal metabolite alterations in Mecp2e1 mutant females occurred prior to onset of neuromotor phenotypes and correlated with lipid deficiencies in brain, results not observed in males. Females also displayed altered gut microbial communities, including those belonging to Clostridia, that were more consistent with RTT patients than males. These findings suggest new potential therapeutic targets for RTT and demonstrate the importance of further study in female animal models.