Alterations in the intrauterine environment with prenatal stress: Novel role for commensal microbes

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Summary: There is increasing evidence that the compositions of the vaginal and gut microbiomes are significantly changed in pregnant mice exposed to experimental stressors. Moreover, our previous and preliminary studies demonstrate that commensal microbes translocate from the gut to internal organs where they lead to increased cytokine production. Stressor-induced bacterial translocation to the placenta would have important implications for offspring development, because cytokines in utero impact neurodevelopment and subsequent offspring behavior. Thus, the goal of this R21 is to interrogate the relationship between prenatal stress, commensal microbes, and intrauterine inflammation, and to investigate their influence on the development of aberrant behavior in exposed offspring. Evidence suggests that maternal stress during pregnancy disrupts the development of the offspring's central nervous system (CNS) and increases the risk of psychiatric illness. To date, research has largely focused on mechanisms by which prenatal stress influences the developing Hypothalamic-Pituitary-Adrenal (HPA) Axis and epigenetic regulation in the infant, with more recent focus on a role for maternal inflammation and alterations in the maternal microbiome. Studies in rodent models have shown that prenatal stress influences the offspring through modifications of maternal gut microbial composition during pregnancy and transmission of aberrant microbes to the offspring at birth. In addition, stressor exposure leads to translocation of gut microbes to the body interior, where they contribute to stressor induced chemokine and cytokine release. Whether prenatal stress leads to increased microbe translocation to the placenta, where it could trigger the release of cytokines capable of crossing into fetal circulation and influence neurodevelopment is unknown. We have established a mouse model of prenatal stress, which induces alterations in placental microbes and concomitant changes in inflammation and brain derived neurotrophic factor in utero, resulting in increased anxiety and cognitive changes in females, decreased social behavior in males, and longstanding changes in microbiome in both sexes. Thus, this model will be used to test the highly novel, and integrative hypothesis that during prenatal stress there is increased translocation of gut microbes to the placenta, where they trigger a CCL2 chemokine dependent recruitment of tissue macrophages and neutrophils to the placenta and subsequent cytokine release, influencing the developing CNS. This hypothesis will be tested by pursuing these aims: 1) Elucidate a role for intrauterine CCL2 in behavioral changes following prenatal stress; 2) Determine which cells produce cytokines capable of influencing the developing CNS; 3) Define whether the cytokine producing cells contain bacterial RNA.