肠道菌群移植对母体高雌二醇所致子代摄食调节紊乱及下丘脑神经干细胞分化异常的纠正作用及机制研究

There are growing concern about the safety of descendants of assisted reproductive technology (ART). We have proved that fresh embryo transfer leads to high maternal estradiol during early pregnancy, which induces food intake disorder in offspring, but the mechanisms are not well understood. We plan to use the established maternal high estradiol mouse model to explore the influence of this abnormal intrauterine environment on hypothalamic neural stem cell (NSC) differentiation and intestinal flora composition. The hypothalamic NSCs are labeled and intracerebrally transplanted to track the destiny of differentiation, and the rescue effect of flora transplantation will be confirmed by phenotype detection and histological analysis during development after combined transplantation of NSCs and intestinal flora in newborn mouse. Finally the critical metabolite through which flora transplantation functions is going to be identified by metabolome assay with validation experiments in vivo. We explore the mechanism of feeding disorder with abnormal hypothalamic neurogenesis resulted from maternal high extradiol, and seak for feassible interference, expecting to provide new idea for reducing occurrence of development origined adult disease and improving descendants'safety of ART.

辅助生殖技术子代安全性日益受到关注。已有研究提示新鲜胚胎移植引起早孕期母体高雌二醇，后者可导致子代出现摄食调节紊乱，但深入的机制未明。本研究拟使用母体高雌二醇小鼠模型，探究母体高雌对子代下丘脑神经干细胞分化功能及肠道菌群组成的影响；通过脑内移植荧光标记的下丘脑神经干细胞追踪其分化命运；对新生小鼠进行下丘脑神经干细胞与肠道菌群共移植，通过发育过程中表型监测及组织学实验探究菌群移植对摄食紊乱和下丘脑神经干细胞分化异常的纠正作用；最后利用代谢组分析明确菌群移植发挥效应的关键代谢产物并予以体内验证。本研究从多学科融合的角度探究母体高雌对子代摄食调节和神经发生的影响机制，并探索有效的干预方法，为减少发育源性疾病的发生、提高辅助生殖子代安全性提供新的思路。

随着辅助生殖技术的广泛应用，其子代安全性问题愈发受到关注。本项目聚焦于辅助生殖技术引起的母体早孕期高雌二醇对子代神经发育及糖代谢功能的早期及远期影响，探究可能的调节机制及干预方法。我们的研究发现，母体早孕期高雌二醇的子代胎鼠下丘脑神经干细胞体外增殖能力减弱，但向神经元分化的比例增加。这些干细胞的mRNA测序及相关生信分析提示，高雌组神经干细胞中下调的基因富集于神经发生功能，而上调的基因富集于雌二醇应答功能。此两类基因中的Hub mRNA与差异表达lncRNA有潜在相关性，形成了母体高雌对胚胎下丘脑神经发育的lncRNA-mRNA调控网络。高雌组子代小鼠成年后表现出摄食增加、体重增加及胰岛素抵抗，其肠道菌群组成与对照组形成显著差异，它们的粪便短链脂肪酸浓度及血清肠道激素水平降低，而下丘脑神经肽NPY表达量增加。将新生高雌组子代小鼠转移至对照组的母鼠进行抚养后，它们成年后不再出现胰岛素抵抗相关表型，其肠道菌群的组成及代谢指标的异常也被纠正。我们的研究结果揭示了母体高雌影响子代下丘脑早期发育的可能机制及其介导子代远期糖代谢功能障碍的微生物-肠-脑调控轴，将慢性病的循因与防控研究相结合，为发育源性慢性疾病探寻可行的早期干预方法。