菌群代谢产物短链脂肪酸在炎症性早产巨噬细胞的免疫调节效应研究

Inflammatory response is the vital process of preterm birth (PTB), and controlling the inflammatory response is an urgent problem to be solved. Based on our previous study on the cervical microflora of preterm pregnancies and the metabolism analysis of fetal cord blood, the significant decrease of the microbial metabolites short chain fatty acids (SCFAs) was noticed in both cervical secretions and umbilical cord blood from preterm group. Since the SCFAs have immune-modulatory effect on macrophages, and macrophages function as the essential antigen presentation in the inflammatory response, we further investigated the polarization effect of the decidual macrophage (dMφ) in the PTB placenta. The results indicated that there was an apparent disorder between M1 / M2 balance. Therefore, we hypothesized that SCFAs were relevant to PTB, and that SCFAs had immune regulation on the maternal fetal interface of inflammation-related PTB. This project aims to establish a sample library for inflammatory PTB, to explore the M1/M2 balance in preterm dMφ cells, to detect SCFAs levels in various tissues, and to evaluate the correlation and its predictive value of PTB; to set up a vitro polarization model for preterm dMφ cells at cellular level, to discuss the mechanism of SCFAs regulation on dMφ differentiation with RNA-Seq and other techniques, and to reveal the regulation of relevant signal paths and molecules. Further, the findings would be verified in the LPS-induced PTB mice model. Our study might provide new evidences for the PTB prevention.

诱发炎症反应是早产发生的关键环节，控制感染相关炎症反应是早产预防亟待解决的问题。我们前期对早产孕妇宫颈微生物群和胎儿脐血代谢组的研究显示，菌群代谢物短链脂肪酸(SCFAs)在早产组宫颈分泌物和脐静脉血中均显著下降。鉴于SCFAs对巨噬细胞存在免疫调节能力，且后者在炎症反应中发挥关键的抗原提呈作用，我们进一步研究早产组胎盘蜕膜巨噬细胞(dMφ)的极化作用，发现存在明显的M1/M2平衡失调。据此我们提出假设：SCFAs下调与早产发生相关，SCFAs对炎症性早产母胎界面dMφ免疫调控。课题拟建立炎症性早产样本库，探讨早产者dMφ细胞M1/M2平衡，检测各组织SCFAs水平，评估其早产相关性及预测价值；在细胞水平建立早产dMφ体外极化模型，利用RNA-Seq等技术探讨SCFAs调控dMφ分化的机制，揭示调控相关信号通路和分子机制；在LPS诱导炎症性早产小鼠模型上加以验证，以期为早产防治提供新依据。

研究背景：诱发炎症反应是早产发生的关键环节，控制感染相关炎症反应是早产预防亟待解决的问题。我们前期对早产孕妇宫颈微生物群和胎儿脐血代谢组的研究显示，菌群代谢物短链脂肪酸(S CFAs)在早产组宫颈分泌物和脐静脉血中均显著下降。.研究内容：队列研究中检测菌群组成及SCFAs的差异；检测孕早期、孕晚期胎盘组织FFAR2受体表达差异；检测SCFAs对人胎盘滋养层细胞生物学行为的影响并进一步探究具体机制；动物实验验证SCFAs与妊娠结局的关系及其机制，进一步阐明SCFAs与胎盘功能障碍的相关性。.重要结果及关键数据：1. 组织学水平显示,SCFAs受体FFAR2均表达于胎盘,滋养细胞系。2. 细胞功能实验显示，10mM SCFAs抑制胎盘滋养层细胞的增殖、迁移、侵袭能力；细胞的迁移和小管形成能力；大麻素受体抑制剂可以部分拮抗THC损伤胎盘细胞功能的作用。3. 临床样本检测结果显示早产组乙酸含量明显高于足月产组。.科学意义：胎盘作为连接母体和胎儿的桥梁，滋养层细胞的功能影响胎盘发育以及妊娠的维持，通过上述研究阐明了孕期SCFAs暴露通过影响胎盘滋养层细胞生物学行为，从而导致影响妊娠结局。