Metagenome profiles identified to cause neuroinflammation during prenatal stress
With maternal stress universally presenting and increasing, many researchers are expanding knowledge of its implications on the developing fetus. High levels of stress may lead to complications such as premature birth, low birthweight or long-term mental disorders. More so, growing evidence indicates that maternal stress may impose long-term consequences on infant immune system development.
Psychological stress in mothers has been linked to many adverse immune outcomes, including intrauterine immune homeostasis disruption and changes in the fetal-stress pathway hypothalamic-pituitary-adrenal (HPA)-axis. While the relationship between maternal stress and fetal immune development is not entirely defined, much research is geared toward the effect of psychological stress on maternal-fetal immune profiles. Recent studies are finding that the maternal-fetal immune system barrier is more nuanced and complex than anticipated.
One of these studies is led by Tamar Gur, MD, PhD, assistant professor of Psychiatry at The Ohio State University College of Medicine. She explores a variety of factors that may foster gestational immune-profile shifts: stress-activated signal pathways, CCL2-mediated leukocyte recruitment, GI microbial community disruption and stressor-induced glucocorticoid signals.
“The unique maternal immune and microbial profiles unveiled in our study indicate that repeated restraint stress imparts complex immunomodulatory effects during the mid- to late gestational period,” says Dr. Gur.
Noting the importance of balanced inflammatory signaling for a healthy pregnancy, Dr. Gur finds that stress-activated signal pathways such as alterations in maternal microbes are possible triggers for monocytosis and neutrophilia. “To our knowledge, this is the first time that neutrophils and monocytes have been assessed in circulation and at reproductive sites during prenatal restraint stress,” she says.
Interestingly, she discovered that increased stress resulted in no significant percentile changes in monocytes and neutrophils. Her study indicates that repeated psychological stress activates glucocorticoid circuits, which in turn induce systemic immunosuppression. This suggests that glucocorticoid signals may foment immune profile aberrations systemically and within the placenta.
Delving into the relationship between psychological stress and GI microbial communities, Dr. Gur notes the potential role the microbe Parasutterella excrementihominis has on maintaining intestinal barrier integrity. Dr. Gur finds that stressed animal models present lower levels of fumarate reductase gene subunit A, which is known for expressing the enzyme fumarate reductase (frdA). In converting fumarate to succinate, this enzyme may contribute to inflammation. However, succinate may also serve a role in microbe proliferation.
As Parasutterella excrementihominis is the only known microbe to contain the frdA gene, Dr. Gur surmises a connection between psychological stress and microbial gene abundance. As microbes are primary mediators of immune profiles and infant neurodevelopment, this connection provides another clue about the interrelation between stress and maternal-fetal immune mechanisms.
“Disrupted Parasutterella excrementihominis appears to be integral to inflammatory and metabolic dysregulation during prenatal stress,” she says.
Dr. Gur also finds a connection between CCL2 and inflammation. Models with altered levels of chemokine CCL2 exhibit differing immune profiles, indicating a more intricate inflammatory signaling pathway than anticipated. Dr. Gur’s future studies aim to better understand the integral role CCL2- signaling has in prenatal stress mediation.
“Overall, our data reveal a unique maternal immune phenotype during prenatal stress that does not mirror the inflammatory responses elicited in the fetal brain and placenta, indicating that the intrauterine immune signaling patterns driving fetal outcomes are more intricate and nuanced in this context.” Dr. Gur credits the efforts of Adrienne Antonson, PhD, a postdoctoral fellow in her lab, and Jeffrey Galley, PhD, a research scientist in the lab, for designing and analyzing the experiments in the study.
Dedicated to homing in on psychiatric and women’s health issues, Dr. Gur’s work seeks to holistically define the impact of maternal mental illness on offspring development. Her clinical research at The Ohio State University College of Medicine concentrates on perinatal and postnatal depression and anxiety. Blending molecular, biochemical, epigenetic and behavioral lab techniques, Dr. Gur has garnered various awards, including the Henry A. and Amelia T. Nasrallah Award for Research Excellence in Psychiatry.
“During residency, I saw the incredible ability that intervention during pregnancy has on helping both mother and developing infant. There are a myriad of fascinating neuroscientific questions that can be addressed in this area,” she says.
Dr. Gur will continue to analyze gestational immunomodulatory mechanisms, aiming to eventually proceed with clinical interventions that benefit both mother and infant.
“These exciting findings expand our understanding of the potential impacts of prenatal psychological stress on the developing fetus, and also provide several avenues for developing non-invasive therapeutic strategies that could be applied prenatally.”