Abstract
Maternal stress during pregnancy is widespread and is associated with poor offspring outcomes, including long-term mental health issues. Prenatal stress-induced fetal neuroinflammation is thought to underlie aberrant neurodevelopment and to derive from a disruption in intrauterine immune homeostasis, though the exact origins are incompletely defined. We aimed to identify divergent immune and microbial metagenome profiles of stressed gestating mice that may trigger detrimental inflammatory signaling at the maternal–fetal interface. In response to stress, maternal glucocorticoid circuit activation corresponded with indicators of systemic immunosuppression. At the maternal–fetal interface, density of placental mononuclear leukocytes decreased with stress, yet maternal whole blood leukocyte analysis indicated monocytosis and classical M1 phenotypic shifts. Genome-resolved microbial metagenomic analyses revealed reductions in genes, microbial strains, and metabolic pathways in stressed dams that are primarily associated with pro-inflammatory function. In particular, disrupted Parasutterella excrementihominis appears to be integral to inflammatory and metabolic dysregulation during prenatal stress. Overall, these perturbations in maternal immunological and microbial regulation during pregnancy may displace immune equilibrium at the maternal–fetal interface. Notably, the absence of and reduction in overt maternal inflammation during stress indicates that the signaling patterns driving fetal outcomes in this context are more nuanced and complex than originally anticipated.
Highlights
Is much more complex than a physical barrier between maternal and fetal tissues[6]
While there is a potential for bacterial signaling, directly or indirectly, to potentiate leukocyte trafficking and pro-inflammatory activation at the maternal–fetal interface, this has not been examined during prenatal stress
Pregnant dams were subjected to repeated restraint stress (2 h/day) from gestational day (GD) 10 to GD16, and tissues were collected on GD17 (Fig. 1a)
Summary
Is much more complex than a physical barrier between maternal and fetal tissues[6]. Communication between placental trophoblast cells and uterine immune and endometrial cells provides an intricate regulation of the inflammatory microenvironment throughout pregnancy[4]. In cases of intrauterine infection, the presence of microorganisms elicits leukocyte trafficking first from maternal blood and subsequently from fetal circulation, resulting in localized release of inflammatory cytokines and c hemokines[38]. Microbes or their components are detected through pattern recognition receptors (such as Toll-like receptors, TLRs) expressed by immune cells and by non-immune cells of the uterus (e.g. endometrial epithelial cells) and placenta (e.g. trophoblast cells), which in turn release their own cytokines and c hemokines[4,39]. We examined maternal endocrine and immune outcomes in order to establish a comprehensive gestational stress phenotype and to determine whether leukocyte trafficking to the maternal–fetal interface augments detrimental intrauterine inflammation
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