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

摘要：越来越多的证据表明，阴道和肠道微生物群的组成是 暴露在实验应激源下的怀孕小鼠发生了显著的变化。而且，我们以前的和 初步研究表明，共生微生物从肠道转移到内脏器官， 它们会导致细胞因子的产生增加。应激源诱导的细菌移位到胎盘将 对后代发育有重要影响，因为子宫内的细胞因子影响神经发育 以及随后的后代行为。因此，这一R21的目标是询问 产前应激、共生微生物和宫内炎症，并调查它们对 暴露于环境中的后代异常行为的发展。有证据表明，母性压力在 怀孕会扰乱后代的中枢神经系统(CNS)的发育，并增加患 精神疾病。到目前为止，研究主要集中在产前应激影响的机制上。 婴儿发育中的下丘脑-垂体-肾上腺(HPA)轴和表观遗传调节 最近的重点是母体炎症和母体微生物群变化的作用。关于啮齿动物的研究 模型表明，产前应激通过改变母亲的肠道来影响后代。 怀孕期间的微生物组成和异常微生物在出生时传播给后代。在……里面 此外，应激源暴露会导致肠道微生物移位到身体内部，在那里它们有助于 应激源诱导趋化因子和细胞因子的释放。产前应激是否导致微生物增加 移位到胎盘，在那里它可以触发能够进入胎儿体内的细胞因子的释放 循环和对神经发育的影响尚不清楚。我们已经建立了一种胎儿期小鼠模型。 应激，引起胎盘微生物的改变，以及伴随而来的炎症和大脑的变化 子宫中的衍生神经营养因子，导致女性焦虑和认知变化增加， 男性的社会行为减少，以及两性微生物群的长期变化。因此，该模型 将被用来检验这一高度新颖的综合假设，即在产前应激期间 肠道微生物移位到胎盘，在那里它们触发CCL2趋化因子依赖的 组织巨噬细胞和中性粒细胞到胎盘和随后的细胞因子释放，影响 发展中枢神经系统。这一假说将通过追求以下目标来检验：1)阐明宫内的作用 CCL2在产前应激后的行为变化中的作用；2)确定哪些细胞产生能够 影响发育中的中枢神经系统；3)确定产生细胞因子的细胞是否含有细菌RNA。

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.