基于无菌小鼠模型研究肠道菌群在胃转流手术治疗糖尿病中的作用

Gastric bypass is a effective clinical surgical treatment on T2DM (type 2 diabetes mellitus),however,the mechanism is not clear.It's well known that T2DM is closely associated with gut microbiota, more ever, gut microbiota is reported to be significantly altered by gastric bypass on both patients and experimental animals. Which maybe involved in improvement of Inflammatory state and metabolic phenotype in T2DM patients.So, we hypothesis that the gastric bypass treatment of T2DM carries out by changing gut microbiota. To clarify this problem,the gut microbiota is studied as a target, GF (germ free) mice are used as an essential animal model,"knockout" and "transplantation" of gut microbiota are applied as basic tools.The following experiments will be concluded: the effect of gastric bypass on GF and SPF T2DM mice; the changes of microbiota in both T2DM mice and patients; the metabolic phenotype changes of GF mice by transplanted with microbiota collected from mice or patients experiencing gastric bypass treatment. In this way, following questions will be answered: the relationship between abssence of microbiota and host response to gastric bypass;before and after surgery, the relationship between changes of metabolic phenotype, inflammation and changes of microbiota; before and after surgery, the relationship between different microbiota types microbiota and different host metabolic phenotypes, imflammation states by microbiota transplantation.Finally,if gastric bypass surgery on host metabolic phenotypes alter through changing microbiota will be clarified, proof in mechanism role of microbiota on treatment of T2DM by gastric bypass willed be provided, new target, way for describing it's mechanism will be provied.

基于胃转流治疗糖尿病手术机理不清、肠道菌群与代谢性疾病关系密切、胃转流所致肠道菌群改变与宿主炎症反应及糖代谢表型有关文献报道，提出肠道菌群在胃转流手术治疗糖尿病机理中发挥关键作用的假设。以肠道菌群为靶标，以无菌小鼠模型为核心，通过菌群"敲除"（小鼠无菌化）、菌群"敲入"（菌群植入）两种技术途径，研究无菌糖尿病小鼠与普通带菌糖尿病小鼠对胃转流手术反应性的差异、糖尿病小鼠以及糖尿病人胃转流手术前、后菌群差异分析及其移植无菌小鼠所致代谢表型的差异；通过检验机体胃转流手术反应性是否与其菌群存在与否具有相关性、通过检验胃转流手术前后菌群是否存在变化及其与手术前后代谢参数及炎性指标改善的相关性、通过手术前后不同菌群的移植是否可转移其不同代谢表型及炎性变化，研究胃转流手术导致的菌群改变可否导致机体的代谢表型改变，力图证实肠道菌群在胃转流手术治疗糖尿病机制中的核心作用，为阐明其机理提供新途径、新靶点。

基于胃转流治疗糖尿病手术机理不清、肠道菌群与代谢性疾病关系密切、胃转流所致肠道菌群改变与宿主炎症反应及糖代谢表型有关文献报道，提出肠道菌群在胃转流手术治疗糖尿病机理中发挥关键作用的假设。本课题无菌小鼠与普通小鼠（SPF）胃转流手术后进行比较研究，发现二者OGTT、胰岛素分泌差异显著。 糖尿病小鼠的胃转流手术后菌群显著改变，糖耐受、胰岛素分泌显著变化。证明肠道菌群通过调控溶菌酶分拣、LRRC19等途径影响宿主炎症反应。 对糖尿病人胃转流手术前、后粪便，进行菌群差异分析，实施了菌群移植实验，并比较其代谢表性差异。还利用无菌小鼠进行菌群移植实验，进行移植模型基本参数摸索建立C57BL/6J 、KM的HFA小鼠模型。通过一系列研究证明，证明肠道菌群在胃转流手术治疗糖尿病机制中的具有重要作用。