妊娠期糖尿病与肠道菌群动态变化的关系及宿主-肠道菌群共代谢机制研究

Gestational Diabetes Mellitus (GDM) is a common metabolic disorder during pregnancy, with a prevalence of 16%, which tends to increase annually. GDM can not only increase the morbidity of adverse gestational outcomes of mothers and infants, but also increase the risk of postpartum type 2 Diabetes Mellitus (T2DM), cardiovascular disease as well as other diseases. Similar to T2DM, GDM is related to insulin resistance and dysfunctional incretion of β islets cells. However, the explicit mechanism of its onset has not been elaborated, still, there has not been a reliable early predictive model. Current studies have found dynamic changes in pregnant women’s gut microbiome, meanwhile, solid interplays have been found between the effects of gut microbiome and T2DM as well as T1DM. Yet, studies focusing on the relationship between GDM and gut microbiome have rarely been reported, the published ones have just studied the changes in gut microbiome of GDM patients, without dynamic monitoring, which makes it hard to elaborate the explicit relationship and mechanism. The hypothesis is that gut microbiome might have an effect on the host’s metabolism and thus participate in the onset and development of GDM. Thus, this study intends to adopt a nest case-control study, combined with epidemiological survey and techniques of 16S rRNA, metagenome sequencing, metabolomics analysis, to investigate the relationship between dynamic changes of gut microbiome and the development of GDM, meanwhile probing the host- gut microbiome co-metabolism mechanism, which in turn will project light on the relationship between the development of GDM and the dynamics of gut microbiome. In addition, to build an early diagnostic model for GDM based on the changes of gut microbiome as bio-markers, which might provide fundamental evidence for new strategies for the prevention and diagnosis of GDM, with significant theoretical and practical values.

妊娠期糖尿病（GDM）是常见的孕期代谢性疾病，发病率约为16%，并呈逐年升高趋势。GDM不仅会增加母儿不良妊娠结局的发生率，而且还会增加孕妇产后患2型糖尿病（T2DM）、心血管等疾病的风险。GDM和T2DM类似，主要和胰岛素抵抗及胰岛β细胞分泌功能降低有关，但其具体发病机制仍未完全阐明，也无可靠的早期预测模型。现有研究发现孕期肠道菌群会动态改变，且肠道菌群与T2DM及T1DM密切关联；但关于GDM与肠道菌群关系的研究较少，且报告的都是发病时的肠道菌群情况，其确切关系及机理尚难明确。我们假设，肠道菌群可能通过调控宿主代谢，参与GDM的发病与进展。本研究拟通过巢式病例对照研究设计，通过扩增子、宏基因组测序和代谢组学分析技术，探讨GDM发生和发展与肠道菌群动态变化的关系，以及宿主-肠道菌群可能的共代谢机制，以明晰GDM与肠道菌群的关系和机制，并建立以肠道菌群为主要生物标志的GDM早期诊断模型。

妊娠期糖尿病是常见的孕期代谢性疾病。按照研究计划，本研究建立了一个872人的孕早期随访队列，收集了研究对象孕期的问卷调查和临床检测数据，并构建了队列生物样本库。采用前瞻性队列研究设计，基于全队列数据，重点探讨GDM发病的危险因素，并据此建立了基于孕早期空腹血糖、BMI、年龄和甘油三脂的GDM早期预测模型，发现集和验证集的AUC分别为0.777和0.803，模型预测效能较好。采用巢式病例对照研究设计，对98例GDM病例和98例匹配对照的粪便样本16S rRNA测序数据分析显示，GDM病例孕早期肠道菌群α多样性显著降低，而β多样性显著升高。在属水平上共有12种组间差异菌属，7条组间有显著差异的代谢通路，提示妊娠早期GDM组肠道菌群失调，可能通过影响机体代谢和炎症反应参与GDM的发生。GDM病例与对照的血清代谢谱差异分析鉴定了99种候选差异代谢物，涉及30条差异代谢通路。组间差异临床因子、肠道菌群差异物种和血清差异代谢产物关联分析发现4个差异菌属丰度分别与2种差异代谢物的丰度变化相关，进一步实现了宿主-肠道菌群共代谢机制的探索。此外，借助孕期动态收集的数据和样本，分析了GDM病例和对照的常规监测/检测指标、RBP4、vaspin和肠道菌群在孕期的动态变化。研究发现Vaspin 在 GDM发展的早期可能存在代偿性升高，RBP4可能是GDM 的一个独立危险因素。不同孕期时点的菌属差异分析发现，孕早、中、晚期三个时点相对丰度有统计学差异的菌属有：Alloprevotella、Collinsella、Hungatella、Moraxella、Paraprevotella、Prevotella 2、Prevotella 9，肠道菌群功能预测分析发现，GDM病例与对照间，孕早期肠道菌群功能有统计学差异的模块是醚脂类代谢和RIG-I样受体信号通路，中晚期有差异的功能模块分别是柠檬烯/蒎烯降解途径和糖胺聚糖生物合成-硫酸软骨素通路，提示肠道菌群的动态变化参与GDM的发生发展。本课题研究目标已达标，多组学检测数据仍在挖掘，拟进一步申请项目，采用细胞实验和动物实验方法探索其可能的作用机制。