肠道菌群代谢物TMAO与子痫前期发病风险的关联及其机制研究

Preeclampsia (PE) is a serious complication of pregnancy. Recent researches found that the intestinal microbiota plays an important role in the development of PE, however, it is still unclear how intestinal microbiota participates in the pathogenesis of PE. Intestinal microbiota-generated metabolite trimethylaine-N-oxide (TMAO) as a signal molecule is one of the ways that intestinal microbiota affecting the health of human beings which is associated with atherosclerotic cardiovascular disease (ASCVD) and an independent predictor of ASCVD. Considering common mechanisms and risk factors have been shared between PE and ASCVD. We therefore, speculated that TMAO might be associated with an increased risk of PE. Moreover, endothelial dysfunction plays an essential role in both of the pathogenesis of PE and ASCVD；TMAO could accelerate endothelial dysfunction and participant in the development of ASCVD. We therefore, planned to conduct a prospective cohort study which is based on previously built cohort and partly new participants enrollment, and combined with cell experiment, with hoping to systemically answer whether there is association and dose respond relationship between TMAO in different gestational age and PE; what is the role of endothelial dysfunction in the process of increased PE risk induced by TMAO exposure. The proposed study will provide information on potential prevention and therapeutic target for PE based on intestinal microbiota.

子痫前期（PE）严重影响母婴健康。肠道菌群失调参与了PE的发生，但机制尚未完全阐明。近来发现，肠道菌群代谢产物氧化三甲胺（TMAO）作为信号分子是肠道菌群对健康产生影响的途径之一，它与粥样硬化性心血管病（ASCVD）相关且是心血管事件预测的独立因子。研究表明，PE与ASCVD存在相似的危险因素和部分共同的发病机制，结合当前的最新进展及本课题组的前期研究结果，我们认为TMAO极有可能参与了PE的发生发展。此外，血管内皮细胞损伤是PE与ASCVD发生的共同核心环节，TMAO还可损伤内皮细胞参与ASCVD。因此，本项目拟依托前期妊娠队列并继续招募部分研究对象，同时结合细胞实验，以期系统的回答孕早、中、晚期血浆TMAO与PE的关联，并探索血管内皮细胞损伤在TMAO致PE中的作用。本项目将进一步阐释肠道菌群参与PE的机制，为以肠道菌群为靶点的PE预防及治疗提供依据。

子痫前期（Preeclampsia, PE）是常见的妊娠期特有疾病，指妊娠20周后新出现的高血压、蛋白尿及全身多脏器损害，严重时可出现抽搐、昏迷、甚至母婴死亡。尽管有研究表明肠道菌群与PE存在关联，但由于微生物群落的复杂性，肠道菌群是如何参与PE的发病机制尚不十分清楚。为探讨肠道菌群的代谢产物氧化三甲胺（Trimethylamine N-Oxide，TMAO）作为信号分子如何参与的PE发生发展，我们首先建立了妊娠队列，收集了孕中、孕晚期产妇的血浆、临床资料。将队列中患有子痫前期患者组成病例组，通过倾向性评分选取与之相匹配的健康产妇组成对照组。两组人群孕中期及分娩期的血浆均进行了TMAO检测和分析，结果发现在妊娠过程中，血浆TMAO的水平会发生改变，孕中期产妇的TMAO水平与其孕晚期的TMAO水平并不存在具有统计学意义的关联（r=0.09，p= 0.157）；孕中期的TMAO水平与PE无统计学关联（OR=1.23，95%CI：0.90, 1.68，每增加50μg/m3）；仅孕晚期的TMAO水平与PE存在显著相关，TMAO每增加50μg/m3发生PE的风险增加0.24倍(OR=1.24, 95% CI:1.09, 1.40)。同时我们还在人绒毛膜滋养层细胞HTR-8/SVneo中初步探讨了TMAO的效应，研究发现在体外TMAO <500μmmol/L（6.67ng/dl）的情况下，其对HTR-8/SVneo无明显的毒性作用，TMAO可能并非PE发生的始动因子。