肠道微生物代谢产物短链脂肪酸（SCFAs）在妊娠期糖尿病发生中的作用及机制探讨

研究表明，肠道微生物代谢产物短链脂肪酸（SCFAs）和2型糖尿病发生关系密切。在孕期，肠道微生物组成发生重构，但SCFAs和妊娠期糖尿病（GDM)的关系尚不清楚。课题组前期动物实验发现SCFAs的FFRA2受体贡献了妊娠期糖稳态；基于前期研究及其他证据， 课题组提出如下假说：在孕期，肠道微生物代谢紊乱，产生SCFAs减少，通过其FFAR2受体激活下游NF-kB通路，调控炎症反应，介导了GDM的发生。我们拟采用人群队列研究，招募孕早期女性，动态留取血清及粪便标本，随访妊娠结局；对确定的GDM患者及正常孕妇检测SCFAs、脂肪组织中胰岛素抵抗（IR)、FFAR2、NFkB活化及相关炎症反应因子表达情况；对剖宫产孕妇脂肪细胞原代培养，诱导IR同时给予SCFAs、FFAR2激动或抑制及利用Ffar2基因敲除孕鼠实验等对假说进行验证，以期进一步阐明GDM的发生机制，为其防治寻找关键干预靶点。

Short chain fatty acid (SCFAs), which is produced by gut microbiota, has been increasingly shown to play a key role in the development of Type 2 diabetes mellitus. During pregnancy, there is a significant remodeling of the gut microbiota. However, the role of SCFAs in the gestational diabetes (GDM) is not clear. Our mouse study has demonstrated that free fatty acid receptor 2 (FFAR2), the specific receptor for SCFAs, contributes to glucose homeostasis during pregnancy. Based on our previous studies and other evidence, we hypothesize that aberrant change in gut microbiota during pregnancy leads to decreased level of SCFAs, resulting in activation of the downstream NF-kB pathway and subsequent modulation of various inflammatory responses via FFAR2 and eventually causing GDM. We aim to initiate a cohort study to enroll pregnant women during their early pregnancy. In both control subjects and women diagnosed with GDM, we propose to assess their metabolic profile for Week 8-12 and Week 24-28 of pregnancy by measuring serum and cecum SCFA levels, index of insulin resistance (IR), and expression of FFAR2, NF-kB pathway, adipokines and cytokines in white fat tissues (obtained from selected subjects who undergo C-sections). Additionally, we will generate an IR model in primary adipocytes derived from these subjects and challenge the primary adipocytes with SCFAs, selective agonist or siRNA for FFAR2 to further investigate the role of adipose SCFAs-FFAR2 pathway in the development of GDM. Finally, we seek to utilize Ffar2 knockout mouse model to further test our hypothesis. The overarching goal of our study is to elucidate the role of SCFAs-FFAR2 pathway in the pathogenesis of GDM and explore potential targets for prevention and treatment of GDM.