Mom’s Stress Alters Babies’ Gut and Brain through Vaginal Microbiome

 

Stress during the first trimester of pregnancy alters the population of microbes living in a mother’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 by University of Pennsylvania researchers.
During a vaginal birth, a newborn is exposed to its mother’s vaginal microbes, collectively known as the microbiota, which importantly colonizes the newborn’s gut, helping its immune system mature and influencing its metabolism. These effects 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,” said Tracy Bale, senior author on the study and a professor of neuroscience in Penn’s School of Veterinary Medicine and Perelman School of Medicine. “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.”
In addition to Bale, the study was conducted by postdoctoral researchers Eldin Jašarević 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.”
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.

A growing body of research suggests that prenatal stress has a long-lasting impact on an infant's development. A new study adds to the evidence, showing that prenatal stress can negatively affect the child well into adulthood, through a connection via the maternal gut bacteria.

Stress-induced changes in the maternal gut bacteria may affect the child for life, according to new research.

According to an analysis conducted by the Centers for Disease Control and Prevention (CDC), prenatal stress is associated with preterm birth, low birth weight, as well as prenatal and postpartum depression and anxiety in the mother.
An overview of existing research further supports the "fetal origins hypothesis," according to which prenatal environmental factors can have lifelong effects on the brain development and behavior of offspring.
Pregnant women's exposure to a variety of stressors, ranging from common to traumatic, have been linked to significant modifications in the children's neurodevelopment. Stressors such as the loss of a loved one, daily hassles, or financial worries have been connected to autism, affective disorders, and reduced cognitive ability in children.
New research in mice suggests that prenatal exposure to a mother's stress may change the microbiome in a way that negatively affects the baby.

Gut bacteria and mental health

Tamar Gur, assistant professor of psychiatry, behavioral health, neuroscience, and obstetrics and gynecology at Ohio State University, believes the bacteria to be a particularly good medium for researching the connection between a mother and her fetus.
This is why she led a team of researchers to examine exactly how maternal stress affects the offspring. "We already understand that prenatal stress can be bad for offspring, but the mystery is how," says Gur, who is also a member of Ohio State Wexner Medical Center's Institute for Behavioral Medicine Research.
Gur explains that the microbes from a mother's gastrointestinal and reproductive tracts are the first ones to spread to the developing fetus and the newborn. As a result, gut bacteria might provide an explanation for why and how maternal stress can affect a person's mental health for their entire life.
"More and more, doctors and researchers understand that naturally occurring bacteria are not just a silent presence in our body, but that they contribute to our health," says Gur.

How prenatal stress affects offspring in mice

For the study, researchers compared two groups of pregnant mice. One group was subjected to 2 hours of stress-inducing restraint per day for 7 days. The other group was left undisturbed during pregnancy. The gut bacteria of both groups assessed by taking fecal samples.
Researchers found increased markers of inflammation in the placenta, the fetal brain, and the adult brain of the mice's offspring. The scientists also found a decrease in a supportive protein called the "brain-derived neurotrophic factor."
When stressed, pregnant mice displayed a change in their bacterial makeup. These changes could be observed both in the mothers' guts and in the placentas, as well as in the intestines of their female offspring. Bacterial changes lasted all the way into adulthood.
Affected adult mice "were more anxious, they spent more time in dark, closed spaces and they had a harder time learning cognitive tasks even though they were never stressed after birth," Gur explains.
Researchers found a lower ability to learn and behavior indicative of higher levels of anxiety among the female offspring of the mice. According to Gur, the team found alterations in the behavior of male offspring as well, but the details of that part of the study are still a work in progress.
Gur recently presented the study at Neuroscience 2016 - the annual meeting of the Society for Neuroscience, held in San Diego, CA.

Future research to uncover link between brain and bacteria

The author emphasizes that by no means do the findings suggests mothers should be blamed for their children's adult mental health. Rather, the results of the study highlight the importance of having a discussion about mental health for both the pregnant mother and the baby.

"As a psychiatrist who treats pregnant women, if you're stressed, anxious or depressed, I think pregnancy is a prime time for intervention. And what's good for mom is good for the baby."

Tamar Gur

In the future, Gur and team hope to further study the link between the brain and the gut bacteria by examining pregnant women and their babies.
Ultimately, Gur hopes to investigate the role of probiotics in alleviating the negative effects of stress.