The Microbiota in a Novel Mouse Model of Ulcerative Colitis

描述(由申请人提供)：我们建议研究特定肠道细菌在一种新的溃疡性结肠炎模型中的影响。该模型由夏丽君实验室建立，当结肠粘液的两个主要核心多糖之一(核心1)的产生被基因敲除技术(TM-IEC C1galt1-/-)干扰时，会发生自发性结肠炎。在观察到传统TM-IEC C1galt1-/-小鼠在基因敲除诱导2周后微生物区系的特定变化后，我们建议随着时间的推移检查微生物区系，以确定在粘液产生丧失后发生的变化，包括结肠炎发作之前和之后。我们将检查已知能够降解粘液的肠道微生物(拟杆菌、粘液阿克曼杆菌、侏儒瘤球菌和扭矩杆菌)，以及在其他小鼠模型中被证明参与结肠炎的细菌，以及在我们自己的模型中通过基于16S rRNA基因焦磷酸测序的微生物群落分析确定的微生物。我们将比较各种被测试微生物的基因组组成，以确定与结肠炎发展相关的代谢和其他途径。我们将在无菌小鼠设施中将TM-IEC C1galt1-/-小鼠与Rag1-/-小鼠杂交，以检查IgA和其他适应性免疫系统对结肠炎的影响。使用我们以前建立的工具(如共生体特异性IgA)，我们将检查这种免疫反应如何影响结肠炎的发展。这些研究的结果将为未来的研究提供基础，这些研究将检查有助于结肠炎发育的特定宿主微生物相互作用。该项目有可能识别微生物成分和宿主适应性免疫成分，这些成分在结肠中O-葡聚糖丢失的情况下调节溃疡性结肠炎。

DESCRIPTION (provided by applicant): We propose to study the influence of specific gut bacteria in a novel model of Ulcerative Colitis. The model was created by the Lijun Xia laboratory and develops spontaneous colitis when the production of one of the 2 main core glycans (Core 1) of colonic mucus is disrupted by gene knockout technology (TM-IEC C1galt1-/-). Having observed specific changes in the microbiota of the conventional TM-IEC C1galt1-/- mice 2 weeks after the induction of the knockout we propose to examine the microbiota over time to identify changes that occur after mucus production is lost, both before and after the onset of colitis. We will examine gut microbes that are known to be able to degrade mucus (Bacteroides thetaiotaomicronsm, Akkermansia muciniphila, Ruminococcus gnavus, and R. torques), bacteria that have demonstrated to be involved in colitis in other mouse models, and microbes identified in our own model by 16s rRNA gene pyrosequencing based analysis of the microbial communities. We will compare the genomic composition of the various microbes tested to define the metabolic and other pathways associated with colitis development. We will examine the impact of IgA and the rest of the adaptive immune system on colitis by crossing the TM-IEC C1galt1-/- mice with Rag1-/- in the germ-free mouse facility. Using tools that we have previously established (such as a symbiont specific IgA) we will examine how this immune response can influence colitis development. The results of these studies will provide the basis of future studies that will examine the specific host microbial interactions that contribute to coliti development. The project has the potential to identify the microbial components and host adaptive immune components that modulate Ulcerative Colitis in the context of O-glycans loss in the colon.