幽门螺杆菌感染与2型糖尿病发生的关系及其炎症致病机制研究

The relationship between Helicobacter pylori (Hp) infection and extragastric diseases has been a hot area of research recently. Emerging data now indicate that a higher prevalence of Hp infection in people with type 2 diabetes (T2DM), and a prospective cohort study further demonstrates that Hp infection leads to an increased rate of incident diabetes. Our preliminary study revealed that Hp infection induced inflammation of gastric mucosa and the abnormal secretion of inflammatory cytokines in the Mongolian gerbils. Meanwhile, the level of glycated hemoglobin and HbA1c in Hp infected Mongolian gerbils is significantly higher than control which further support that the inflammation caused by Hp is associated with the incidence of T2DM. Accordingly, based on the inflammation pathogenic theory of T2DM, we speculate that Hp infection could probably be an important inflammatory pathogenic factor of T2DM. The possible mechanisms are the low grade inflammation caused by Hp infection and the abnormal secretion of inflammatory cytokines, which could induce disorder of intracellular signaling network of pancreas islet and peripheral insulin sensitive tissues, and eventually lead to insulin resistance and insulin secretion disability. Therefore, this project will set up Hp-infected Mongolian gerbils model, investigate the impact of Hp-infected chronic inflammation on glucose metabolism and the IRS/PI3K/Akt signaling pathways of islet and peripheral insulin sensitive tissues. Besides, we will study the reversion effect after Hp eradication to further characterize the relationship between Hp infection and T2DM and the underlying mechanisms. The resolution of this issue will provide new rational for the prevention of T2DM and the formulation of Hp eradication guideline.

Hp感染与胃肠外疾病的关系是近年研究热点。新近研究示T2DM的Hp感染率明显升高，前瞻性研究证实Hp感染可能增加T2DM的发生风险。我们前期研究发现Hp感染在引起蒙古沙鼠胃黏膜炎症反应和炎症因子异常的同时，血清糖化血红蛋白和血红蛋白A1c水平明显升高，进一步支持Hp引起的炎症反应与T2DM的发生相关。根据T2DM的炎症致病学说，我们推测Hp感染可能是T2DM重要的炎症致病因子，其通过引起胃黏膜炎症反应和炎症因子异常，诱导胰腺和外周胰岛素敏感组织的相关细胞信号网络的紊乱，最终导致胰岛素抵抗和分泌障碍。因此，本课题拟通过建立Hp感染蒙古沙鼠动物模型，研究Hp感染引起的慢性炎症对糖代谢及胰腺和外周胰岛素敏感组织中IRS/PI3K/Akt信号通路的影响，以及根除Hp后的逆转效应，进一步深入探讨Hp感染与T2DM的关系及可能的致病机制，为T2DM的预防提供新思路，为Hp根除适应症的制定提供理论依据。

新近研究发现Hp感染可增加代谢性疾病的发生风险，但机制不明。作为人体第二大基因组的肠道菌群已被证实参与肥胖、糖尿病等代谢性疾病的发生发展。本研究围绕Hp感染对代谢性疾病的影响及其与肠道菌群的相关性进行系统探讨。首先建立Hp感染动物模型，发现短期高脂饮食联合Hp感染可促进小鼠内脏脂肪重分布，促进腹型肥胖的发生，糖耐量试验显示Hp感染可加重高脂饮食诱导的胰岛素抵抗，肝脏胰岛素信号通路IRS1/PI3K/Akt传导障碍，单纯Hp感染对小鼠代谢无明显影响；而长期高脂饮食下Hp感染对代谢的影响减弱，高脂饮食本身进一步加重小鼠肥胖和糖耐量异常。接着我们应用16S rRNA测序法分析不同饮食结构下Hp感染对小鼠肠道菌群的影响，结果显示短期高脂饮食后Hp感染组与未感染组肠道菌群结构存在显著差异，Hp感染组α多样性增加、厚壁菌门和变形菌门相对丰度增加而拟杆菌门和疣微菌门减少，Desulfovibrionaceae菌科增加而Akkermansia菌属减少，而且Desulfovibrionaceae菌和Akkermansia菌的丰度和胰岛素抵抗指数有显著相关性，其中前者呈正相关而后者呈负相关。进一步检测小鼠肠屏障相关指标发现感染组肠黏膜紧密连接蛋白表达明显低于未感染组。长期高脂饮食后高脂饮食组和普通饮食组肠道菌群结构具有显著差异，而Hp感染组与未感染组无明显差异，这种肠道菌群改变与代谢表型变化一致。以上结果提示，Hp感染对代谢性疾病的影响与饮食结构和作用时间密切相关，高脂饮食早期Hp感染可能通过诱导肠道菌群失衡加重胰岛素抵抗，促进代谢性疾病的发生，后期高脂饮食本身对代谢的影响占主导地位，Hp作用逐渐减弱。本研究阐述Hp感染、饮食和代谢性疾病的相关性，为合理膳食和根除Hp预防代谢性疾病提供一定的依据。

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