肠道菌群及代谢产物短链脂肪酸在产前抑郁发生中的作用及机制研究

Prenatal depression seriously harms the health of pregnant women and their children. According to the theory of gut microbiota - intestinal - brain axis, gut microbiota and metabolites may play an important role in the occurrence of prenatal depression, but the specific role and mechanism are still unclear. Based on the available literature, we hypothesized that the gut microbiota of pregnant women, spore-forming bacteria and the metabolite butyrate affect the enterocromafin cells to regulate the level of serotonin in the blood, thus leading to depressive symptoms in pregnant women. This study will be divided into two stages. The first stage is population study. Feces and blood samples of pregnant women with and without prenatal depression will be collected through a case-control study design, and gut microbiota diversity, metabolite short-chain fatty acids and serotonin levels in platelets were analyzed to understand the role of spore-forming bacteria and metabolite butyrate in the occurrence of prenatal depression. The second phase is to establish a germ-free pregnant mice model of depression. The germ- free mice will be implanted with feces from prenatal depression women and non-depression pregnant women. We willl analyze two groups of germ-free mice's depression behavior, gut microbiota , metabolites, serotonin in the brain tissue and enterocromafin cells' number and function. According to these two stages, we will explore the influence and mechanism of gut microbiota and metabolites on enterocromafin cells to regulates serotonin levels result in the depression. The results will provide new ideas for understanding the mechanism and intervention of prenatal depression.

产前抑郁严重危害孕妇及子代健康。根据肠道菌群-肠-脑轴学说，肠道菌群及代谢产物可能在产前抑郁发生中发挥重要作用，但具体作用及机制尚不清楚。根据现有文献我们假设孕妇肠道菌群中产芽孢菌和代谢产物丁酸盐通过影响肠嗜铬细胞来调节血液中五羟色胺水平从而导致孕妇出现抑郁症状。本研究分2个阶段，第一阶段为人群研究。通过病例对照研究设计，收集产前抑郁孕妇和非抑郁孕妇的粪便和血液样本，分析肠道菌群多样性、代谢产物短链脂肪酸以及血小板中五羟色胺水平，了解产芽孢菌和代谢产物丁酸盐在产前抑郁发生中的作用。第二阶段通过建立无菌孕小鼠抑郁模型，将产前抑郁孕妇与非抑郁孕妇粪便植入无菌孕鼠体内，分析两组无菌孕鼠抑郁样行为、肠道菌群、代谢产物、脑组织中五羟色胺含量以及肠嗜铬细胞数量和功能。以此探明肠道菌群和代谢产物通过影响肠嗜铬细胞调节五羟色胺水平导致抑郁症状的肠脑轴机制。研究结果将为了解产前抑郁发生机制及干预提供新思路。

产前抑郁是一种较难察觉、易被忽视的心理疾病，其患病率近年来逐渐升高，且严重危害母婴健康。根据肠道菌群-肠-脑轴学说，肠道菌群及代谢产物可能在产前抑郁发生中发挥重要作用，但具体作用及机制尚不清楚。申请人前期提出科学假设：孕晚期妇女肠道细菌及其代谢产物短链脂肪酸通过影响肠嗜铬细胞调节血液中5-羟色胺水平进而导致产前抑郁的发生。为验证这一科学假设，申请人团队经过三年的流行病学调查和生物样本收集，以43例产前抑郁组孕妇和43例对照组孕妇为研究对象，比较产前抑郁组与对照组孕妇肠道菌群及其代谢产物短链脂肪酸和血液中5-羟色胺和色氨酸等代谢产物差异，并采用中介效应模型明确血液中5-羟色胺和色氨酸在肠道菌群及其代谢产物短链脂肪酸和产前抑郁关系中的作用。研究结果发现产前抑郁组和对照组孕妇肠道菌群及其代谢产物短链脂肪酸如乙酸（P=0.023）、丙酸（P=0.005）和丁酸（P=0.047）存在统计学差异。控制相关协变量后（孕次和收集血液与问卷的间隔时间），研究结果发现Candidatus_Soleaferrea是产前抑郁的保护因素（OR=0.370, 95% CI=[0.185, 0.738]）；丙酸是产前抑郁的危险因素（OR=8.035, 95% CI=[1.287, 50.164]）。产前抑郁组的5-羟色胺低于对照组的5-羟色胺的含量（P=0.032），且5-羟色胺是产前抑郁的保护因素，其含量越低，孕妇患产前抑郁风险越高（OR=0.946, 95% CI=[0.899, 0.995]）；且肠道菌群NK4A214_group和unclassified_c_Clostridia 会影响血液中5-羟色胺的含量。在结合肠道菌群、短链脂肪酸和5-羟色胺的回归模型中，研究结果发现发现5-羟色胺对产前抑郁的影响不显著（OR=0.963, 95% CI= [0.912, 1.017]）；这可能源于复杂的肠-脑轴与 5-羟色胺的相互作用。因此，基于上述研究结果的基础上，申请人进一步探究5-HT相关代谢产物-色氨酸在肠道菌群与产前抑郁中的作用；研究结果发现色氨酸在孕妇肠道菌群和产前抑郁关系中的部分中介作用，即色氨酸在Enterococcus菌属与产前抑郁之间起部分中介作用。综上所述，本项目从一个新角度探索了产前抑郁的发病机制，研究结果为基于饮食或益生菌对孕期抑郁症状的干预提供了新的思路。