Newborns are colonized by maternal microbiota that is essential for offspring health and development. The composition of these pioneer communities exhibits individual differences, but the importance of this early-life heterogeneity to health outcomes is not understood. Here we validate a human microbiota-associated model in which fetal mice are cesarean delivered and gavaged with defined human vaginal microbial communities. This model replicates the inoculation that occurs during vaginal birth and reveals lasting effects on offspring metabolism, immunity, and the brain in a community-specific manner. This microbial effect is amplified by prior gestation in a maternal obesogenic or vaginal dysbiotic environment where placental and fetal ileum development are altered, and an augmented immune response increases rates of offspring mortality. Collectively, we describe a translationally relevant model to examine the defined role of specific human microbial communities on offspring health outcomes, and demonstrate that the prenatal environment dramatically shapes the postnatal response to inoculation.
Women who have experienced adverse childhood events (ACEs) around puberty are at the greatest risk for neuropsychiatric disorders across the lifespan. This population is exceptionally vulnerable to neuropsychiatric disease presentation during the hormonally dynamic state of pregnancy. We previously established that chronic adversity around puberty in female mice significantly altered their HPA axis function specifically during pregnancy, modeling the effects of pubertal ACEs we also reported in women. We hypothesized that the pregnancy hormone, allopregnanolone, was involved in presentation of the blunted stress response phenotype by its interaction with the molecular programming that had occurred during pubertal adversity experience. Here, in adult mice previously stressed during puberty, allopregnanolone administration was sufficient to reproduce the decreased corticosterone response after acute stress. Examination of neuronal activation and the electrophysiological properties of CRF neurons in the paraventricular nucleus of the hypothalamus (PVN) found no significant changes in synaptic function that corresponded with the blunted HPA axis reactivity. However, at the chromatin level, utilization of ATAC-Seq profiling demonstrated a dramatic remodeling of DNA accessibility in the PVN following pubertal adversity. Altogether, these data establish a potential molecular mechanism whereby adversity during puberty can enact lasting transcriptional control that manifests only during a unique period of the lifespan where dynamic hormonal changes occur. These results highlight a biological process that may impart an increased risk for a highly vulnerable population, whereby pubertal programming of the PVN results in aberrant HPA axis responsiveness when exposed to the hormonal changes unique to pregnancy.
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