母代肠菌在孕期应激损伤子代中的作用及其胎盘 11β-HSD2调控机制研究

Gestational stress can significantly affect the offspring. Up to date, no drug is available for the clinical treatment of gestational stress. Our Preliminary data have shown that transplanting gut microbiome from gestational restraint-stressed rats to the control pregnant rats can reproduce the effects of gestational stress on birth weight and adulthood behaviors of offspring, and the selective inhibition of 11β-HSD2 expression in placenta. Probiotic treatment from stress beginning to offspring adulthood significantly alleviated the effects of gestational stress on offspring. In addition, previous studies have shown that metabolites of gut microbiome can regulate the activity of HDACs and the levels of blood inflammatory factors. And HDACs and IL-1β both can modulate 11β-HSD2 expression. Thus we think that during the offspring damage of gestational stress, maternal gut microbiome plays an important role. And the inhibition of gut microbiome metabolites on placenta11β-HSD2 expression via HDACs and IL-1β is a critical molecular mechanism. Here we will further investigate the mechanisms that maternal gut microbiome modulates placenta 11β-HSD2 expression, screen out the strains of maternal gut microbiome with a critical role during gestational stress, and detect the effect of probiotic treatment on Gestational stress of pregnant women. These results will provide new information for the prevention and treatment of gestational stress.

孕期应激对子代影响深远，但其临床防治目前仍是无药可用。我们前期发现：应激孕鼠的肠菌移植给非应激孕鼠可复制出孕期应激对子代出生体重和成年期行为的影响，也可复制出孕期应激对胎盘11β-HSD2的选择性抑制；而从孕期应激开始喂养益生菌可减轻孕期应激对子代的影响。结合文献中肠菌代谢产物可抑制HDACs活性和调节外周血炎症因子水平；HDACs和IL-1β都可调节11β-HSD2表达。我们推断：在孕期应激损伤子代过程中，母代肠菌是关键的调控环节；而肠菌代谢物通过HDACs和IL-1β抑制胎盘11β-HSD2表达是其重要分子机制。本项目中我们将进一步：1.探索在孕期应激损伤子代过程中母代肠菌对胎盘11β-HSD2的调控机制以及起关键作用的肠菌菌种；2.检测益生菌干预对孕期应激孕妇的保护作用。这些结果有望为孕期应激的防治提供新的方法和新的依据。

孕期应激对子代影响深远，可导致流产、早产及妊娠合并症等，但其临床防治目前仍是无药可用。本项目在孕期应激损伤模型下，应用肠菌移植和饲喂益生菌两种干预手段，明确了母代肠菌为母代孕期应激损伤的重要靶点。为进一步明确母代肠菌的作用机制，我们利用高通量测序筛查出特定菌，阐明了益生菌通过对胎盘11β-HSD2调控、抑制炎症因子TNF-α，IL-1β等途径，从而抑制子代脑中海马小胶质细胞的活化，下调组蛋白去乙酰化酶（HDAC2）表达，降低了海马神经元的凋亡，对子代海马神经元具有保护作用，进而改善子代认知功能。本项目中我们使用动物行为学、测序分析、分子生物学等多种方法探索了在孕期应激损伤子代过程中，母代肠菌对胎盘11β-HSD2的调控机制以及起关键作用的肠菌菌种，并探索了益生菌干预对孕期应激子代的保护作用，这些结果有望为孕期应激的防治提供新的方法和依据。