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

Abstract

Rett syndrome (RTT) is a 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 deficient 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 metabolites were altered in Mecp2e1 mutant females before onset of neuromotor phenotypes and correlated with lipid deficiencies in brain, results not observed in males. Females also displayed altered gut microbial communities and an inflammatory profile that were more consistent with RTT patients than males. These findings identify new molecular pathways of RTT disease progression and demonstrate the relevance of further study in female Mecp2 animal models.

Exogenous Players in Mitochondria-Related CNS Disorders: Viral Pathogens and Unbalanced Microbiota in the Gut-Brain Axis

“…In addition, in a representative female mouse model of RTT, mutants had higher fecal levels of butyrate, iso-valerate, and propionate than wild-type females. Genotype-related differences are not shared by age-matched male mutant mice and occur prior to the onset of neuromotor phenotypes, suggesting that gut dysbiosis might be the earliest phenotypic manifestation of RTT and play a role in disease pathology [91].…”

“…Microglia play critical roles in synapse pruning, clearance of apoptotic bodies, and signaling to neurons in the brain in health and neurological diseases. Of note, chronic neuroinflammation has been documented in many progressive brain disorders either with multifactorial (e.g., Alzheimer Disease [88], Parkinson disease [89], and autism spectrum disorders (ASD) [90]) or monogenic origin (e.g., Rett syndrome (RTT) [91]).…”

“…Microglia play critical roles in synapse pruning, clearance of apoptotic bodies signaling to neurons in the brain in health and neurological diseases. Of note, ch neuroinflammation has been documented in many progressive brain disorders eithe multifactorial (e.g., Alzheimer Disease [88], Parkinson disease [89], and autism spec disorders (ASD) [90]) or monogenic origin (e.g., Rett syndrome (RTT) [91]). Neurotransmitters and their precursors, as well as metabolites, produced directly by the gut microbiota and/or through dietary metabolism can cross the gut-blood barrier and enter the bloodstream.…”

The microbiota–gut–brain axis and neurodevelopmental disorders

“…RTT is observed in girls and is characterized by progressive mental decline, motor dysfunction, and ASD-like behaviors. Dysbiosis in the gut has been observed in patients with RTT, suggesting that the gut microbiota plays a role in this NDD ( Neier et al ., 2021 ). Specifically, reduced richness in certain microbial taxa in Bifidobacterium , Anaerostipes , Clostridium XIVa, Clostridium XIVb, Erysipelotrichaceae , Actinomyces , Lactobacillus , Enterococcus , as well as Eggerthella , has been identified in RTT patients ( Strati et al ., 2016 ), while an enrichment was found in Bacteroidaceae , Clostridium spp., and Sutterella spp.…”

“…( Borghi et al ., 2017 ). It should be noted that an inflammatory profile is seen in female mouse models of RTT, suggesting that the immune pathway is possibly involved ( Neier et al ., 2021 ). Indeed, microglia have been found to play a part since activated microglia and loss of microglia through apoptosis are associated with the development of the condition ( Lukens and Eyo, 2022 ).…”