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

摘要：越来越多的证据表明，阴道和肠道微生物的组成是 在暴露于实验性应激源的怀孕小鼠中发生了显著变化。此外，我们以前和 初步研究表明，肠道微生物从肠道转移到内脏， 它们导致细胞因子产生增加。应激诱导的细菌移位到胎盘会 对后代发育有重要意义，因为子宫内的细胞因子影响神经发育， 以及后代的行为因此，这个R21的目标是询问 产前应激、子宫内微生物和子宫内炎症，并研究它们对子宫内膜异位症的影响。 暴露后代出现异常行为。有证据表明，母亲的压力， 怀孕会破坏后代中枢神经系统（CNS）的发育，并增加 精神病迄今为止，研究主要集中在产前压力影响的机制上， 发育中的下丘脑-垂体-肾上腺（HPA）轴和婴儿的表观遗传调节， 最近关注母体炎症和母体微生物组改变的作用。啮齿动物研究 模型显示，产前压力通过母体肠道的改变影响后代 怀孕期间的微生物组成和出生时将异常微生物传播给后代。在 此外，应激暴露导致肠道微生物转移到身体内部，在那里它们有助于 应激诱导趋化因子和细胞因子释放。产前压力是否会导致微生物增加 易位到胎盘，在那里它可以触发细胞因子的释放，能够进入胎儿 循环和影响神经发育是未知的。我们建立了一个产前基因突变的小鼠模型， 压力，这会导致胎盘微生物的改变以及炎症和大脑的伴随变化 子宫内衍生的神经营养因子，导致女性焦虑和认知变化增加， 男性的社会行为减少，以及两性微生物组的长期变化。因此，该模型 将被用来测试高度新颖的，综合假设，在产前压力增加， 肠道微生物易位到胎盘，在那里它们触发CCL 2趋化因子依赖性的 组织巨噬细胞和中性粒细胞的胎盘和随后的细胞因子释放，影响 发展CNS。这一假设将通过追求这些目标进行检验：1）阐明子宫内的作用， CCL 2在产前应激后行为变化中的作用; 2）确定哪些细胞产生能够 影响发育中的CNS; 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.