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During vaginal birth, a newborn is exposed to its mother's vaginal microbes, known as the microbiota. This microbiota importantly colonizes the newborn's gut, helping its immune system mature and influencing baby's metabolism. These effects also take place during a critical window of brain development.

Stressed moms alter babys' gut and brain

Stress during the first trimester of pregnancy alters the population of microbes living in a woman's vagina. Those changes are passed on to newborns during birth and are associated with differences in their gut microbiome as well as their brain development, according to a new study from the University of Pennsylvania.

During a vaginal birth, a newborn is exposed to its mother's vaginal microbes, collectively known as the microbiota. This microbiota importantly colonizes the newborn's gut, helping its immune system mature and influencing its metabolism. These effects also take place during a critical window of brain development.

Babies born by C-section miss out on this initial exposure and are more likely to be exposed to and their guts then colonized by other bacteria in the local environment, including the mother's skin and potential pathogens in the hospital.

The new work, published in Endocrinology, suggests that the maternal vaginal microbiome is one of the ways that a mother's stress during pregnancy can 'reprogram' the developing brains of her children.

One implication is that these changes could put the offspring at an increased risk of neurodevelopment disorders such as autism and schizophrenia, neurodevelopmental disorders where disruption of gut microbiota and gastrointestinal dysfunction are increasingly reported.

"Mom's stress during pregnancy can impact her offspring's development, including the brain, through changes in the vaginal microbiome that are passed on during vaginal birth. As the neonate's gut is initially populated by the maternal vaginal microbiota, changes produced by maternal stress can alter this initial microbial population as well as determine many aspects of the host's immune system that are also established during this early period."

Tracy Bale PhD, senior author on the study and a professor of neuroscience in Penn's School of Veterinary Medicine and Perelman School of Medicine.

In addition to Bale, the study was conducted by postdoctoral researchers Eldin Jašarevi? and Christopher Howerton and research specialist Christopher Howard, all from Penn Vet.

To conduct the study, researchers used a mouse model of early maternal stress that Bale's lab had previously developed. An experimental group of pregnant mice were periodically exposed to stressors, such as predator odors, restraint and novel noises, early in gestation, the equivalent of their 'first trimester.' The day following birth, the team assessed the microbiota from the mothers' vaginas and from the offsprings' colons. In addition, the offsprings' brains were examined to measure transport of amino acids, a proxy for brain metabolism and development.

Bale's team found that stress during early pregnancy had surprising long-lasting effects on the mother's vaginal microbiota. They observed that these changes were reflected in their offspring's gut microbiota and were associated with alterations in the offspring's metabolism and amino acid processing in the brain. The neurodevelopmental effects were particularly pronounced in male mice, which is the sex that the Bale lab has previously demonstrated shows a stress-sensitive phenotype later in life.

Taken together, these findings not only underscore the important role that the mother's vaginal microbiome has in populating her offspring's gut at birth but also the profound effect of maternal stress experience on this microbial population and on early gut and brain development. The fact that male offspring appeared most affected may have implications for the development of disorders such as autism and schizophrenia, both of which disproportionately affect males.

Interestingly, a subset of offspring that were delivered by C-section and then had their mother's vaginal microbiota introduced to their gut ultimately had gut microbiota that resembled that of vaginally-delivered offspring.

"These studies have enormous translational potential," Bale said. "Many countries are already administering oral application of vaginal lavages to C-section delivered babies to ensure appropriate microbial exposure occurs. Knowledge of how maternal experiences such as stress during pregnancy can alter the vaginal microbiome is critical in determination of at-risk populations."

Abstract
The neonate is exposed to the maternal vaginal microbiota during parturition, providing the primary source for normal gut colonization, host immune maturation, and metabolism. These early interactions between the host and microbiota occur during a critical window of neurodevelopment, suggesting early life as an important period of cross talk between the developing gut and brain. Because perturbations in the prenatal environment such as maternal stress increase neurodevelopmental disease risk, disruptions to the vaginal ecosystem could be a contributing factor in significant and long-term consequences for the offspring. Therefore, to examine the hypothesis that changes in the vaginal microbiome are associated with effects on the offspring gut microbiota and on the developing brain, we used genomic, proteomic and metabolomic technologies to examine outcomes in our mouse model of early prenatal stress. Multivariate modeling identified broad proteomic changes to the maternal vaginal environment that influence offspring microbiota composition and metabolic processes essential for normal neurodevelopment. Maternal stress altered proteins related to vaginal immunity and abundance of Lactobacillus, the prominent taxa in the maternal vagina. Loss of maternal vaginal Lactobacillus resulted in decreased transmission of this bacterium to offspring. Further, altered microbiota composition in the neonate gut corresponded with changes in metabolite profiles involved in energy balance, and with region- and sex-specific disruptions of amino acid profiles in the developing brain. Taken together, these results identify the vaginal microbiota as a novel factor by which maternal stress may contribute to reprogramming of the developing brain that may predispose individuals to neurodevelopmental disorders.

The research was supported by the Penn Vet Center for Host-Microbial Interactions, the National Institute of Mental Health, the CHOP Metabolomics Core, Perelman School of Medicine Proteomics and Systems Biology Core, and the Next Generation Sequencing Core.

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