The composition of human vaginal microbiota transferred at birth affects offspring health in a mouse model

Abstract

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.

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“…On the other hand, maternal gut strains are more enduring in the baby’s gut and are better ecologically adapted [ 38 , 39 ]. During pregnancy, the bacterial diversity in the vagina is low but stable.…”

“…Offspring born from vaginal delivery and whose mothers were vaginally colonized with Lactobacillus during pregnancy had increased ratios of CD45RO+ cells and lower IL-12 levels in cord blood, indicating that lactobacilli in the vagina impacted fetal immune development. It is a possibility that this influence could be attributable to bacterial metabolites, ascending organisms, or the dependence of the vaginal microbiome on the gut microbiota [ 38 , 39 ].…”

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“…We used our C-section and oral gavage protocol to inoculate mouse pups with either CST I or CST IV and assessed outcomes across development and into adulthood. Birth-associated exposure to CST I and CST IV resulted in transient colonization of the intestinal tract in C-section delivered mice and was sufficient to elicit CST-specific transcriptional signatures in the neonatal ileum, as well as sex-specific differences in adulthood [ 57 ]. Epidemiological studies demonstrated that maternal obesity and presence of vaginal G. vaginalis are two common risk factors associated with increased risk for adverse obstetric outcomes [ 58 – 63 ].…”

“…Epidemiological studies demonstrated that maternal obesity and presence of vaginal G. vaginalis are two common risk factors associated with increased risk for adverse obstetric outcomes [ 58 – 63 ]. We established a two-hit model to determine whether maternal obesity and presence of vaginal G. vaginalis , alone or in combination, would affect the offspring postnatal response to CST I or CST IV exposure at birth [ 57 ]. Surprisingly, neonates that gestated in a two-hit environment showed a pathological immune response and decreased survival following exposure to CST IV, a pattern that was not observed in CST I exposed offspring.…”

“…Surprisingly, neonates that gestated in a two-hit environment showed a pathological immune response and decreased survival following exposure to CST IV, a pattern that was not observed in CST I exposed offspring. This pathological response to the postnatal microbiota was associated with disruption to the development of the placenta and fetal ileum in the two-hit neonates [ 57 ]. If these results bear any translational relevance, they underscore that prenatal exposures directly shape how offspring respond to their postnatal microbial environment and that one unforeseen consequence of high-risk pregnancies may be a pathological response to the colonizing microbiota and increased neonatal morbidity.…”