肠道菌群代谢产物TMAO在早产胎儿炎症反应中作用及机制研究

Fetal inflammatory response significantly contributes to the occurrence of preterm birth and perinatal morbidity and mortality. The maternal bacterial metabolites could flow into the fetal circulation and shape the fetal immune response. Based on the placental and umbilical cord pathology, 40 cases were included (20 cases in control group and 20 cases in study group with fetal inflammatory response). LC-MS was performed to screen the different bacterial metabolites in the plasma of cord blood between control group and study group. 11 metabolites were found to be higher in the plasma of the study group. Gene-reporting experiment showed that phosphatidylcholine-derived TMAO stimulated the expression of IL-6 in dendritic cells. In vitro, TMAO enhanced the maturation of dendritic cells. Based on these findings, we will conduct the following studies: (1) to investigate the mechanisms by which TMAO promotes the maturation of dendritic cells and the expression of IL-6; (2) to build pregnant mice model with high phosphatidylcholine diet to reveal the change in TMAO-related bacteria and the feasibility of fecal transplantation for the reduction of TMAO and associated fetal inflammatory response; (3) to conduct a prospective cohort trial to evaluate the predictive value of maternal TMAO for preterm birth and fetal inflammatory response. This study is beneficial to the prevention and treatment for fetal inflammatory response and preterm birth.

胎儿炎症反应导致早产等不良围产结局。前期研究应用LC-MS技术和报告基因实验筛查脐带血浆中胎儿炎症反应相关的肠道菌群代谢产物，我们发现卵磷脂来源的氧化三甲胺（TMAO）在胎儿炎症组的脐带血浆中明显升高，且上调胎儿树突状细胞IL-6的表达。体外诱导实验显示TMAO促进胎儿树突状细胞成熟，进一步生物信息学分析和RT-PCR验证提示TCF4/miRNA-20a-5p/E2F1轴为可能的分子机制。在此基础上，本课题拟进行以下研究：（1）应用RNAi等技术阐释TMAO通过TCF4/miRNA-20a-5p/E2F1轴促进树突状细胞成熟和IL-6表达的分子机制；（2）建立高卵磷脂饮食孕鼠模型；16SrRNA测序分析高卵磷脂饮食介导的肠道菌群变化并探讨粪便移植干预的可行性；（3）开展前瞻性队列研究评估母体TMAO对胎儿炎症反应的预测价值。本研究为胎儿炎症反应及早产的预防和治疗提供理论依据和新靶点。

胎儿炎症反应导致早产等不良围产结局。前期研究应用LC-MS技术和报告基因实验筛查脐带血浆中胎儿炎症反应相关的肠道菌群代谢产物，我们发现卵磷脂来源的氧化三甲胺（TMAO）在胎儿炎症组的脐带血浆中明显升高，且上调胎儿树突状细胞IL-6的表达。体外诱导实验显示TMAO促进胎儿树突状细胞成熟，进一步生物信息学分析和RT-PCR验证提示TCF4/miRNA-20a-5p/E2F1轴为可能的分子机制。本课题应用RNAi等技术阐释了TMAO通过TCF4/miRNA-20a-5p/E2F1轴促进树突状细胞成熟和IL-6表达的分子机制；（2）高卵磷脂饮食孕鼠子代血浆中TMAO及IL-6水平显著升高，同时TMAO水平与仔鼠发生胎儿炎症（FIR）的风险显著相关，R=0.845。本研究为胎儿炎症反应及早产的预防和治疗提供理论依据和新靶点。