The Microbiota in a Novel Mouse Model of Ulcerative Colitis

溃疡性结肠炎新型小鼠模型中的微生物群

• 批准号: 8385102
• 负责人: DANIEL A PETERSON
• 金额: $ 25.83万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385102
• 关键词: Address; Animals; Antibodies; Archaea; Area; Bacteria; Bacteroides; Bacteroides thetaiotaomicron; Biochemical; Chemicals; Colitis; Colon; Communities; Complex; Crohn' s disease; Defect; Development; Disease; Distal; Epithelial Cells; Etiology; Family; Future; Gastrointestinal tract structure; Gene Targeting; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Genomics; Germ-Free; Glycoproteins; Gnotobiotic; Goals; Goblet Cells; Health; Homeostasis; Human; Immune; Immune response; Immune system; Immunoglobulin A; Immunologic Factors; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Integration Host Factors; Interleukin-10; Interleukin-2; Intestines; Knock-out; Laboratories; Life; Measures; Mediating; Metabolic; Metabolism; Metagenomics; Microbe; Microbial Genetics; Modeling; Molecular Weight; Morbidity - disease rate; Mucins; Mucous body substance; Mus; Mutate; Pathogenesis; Pathway interactions; Patients; Polysaccharides; Production; Protozoa; Publishing; Rag1 Mouse; Research; Rest; Role; Ruminococcus; Severity of illness; Signal Transduction; Tamoxifen; Technology; Testing; Time; Torque; Ulcerative Colitis; Virus; adaptive immunity; arm; base; comparative genomics; knockout gene; microbial; microbial community; microbiome; microorganism interaction; mortality; mouse model; mutant; novel; prevent; rRNA Genes; tool

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. PUBLIC HEALTH RELEVANCE: Ulcerative Colitis (UC) is an inflammatory disease of the colon that has significant morbidity and mortality. Its etiology likely involves a complex interaction between the patient's genetic predisposition and specific microbes that live in the gut. The proposed research examines potential causative bacteria using a novel mouse model that contains a defect in the mucus barrier. The goal is to identify both the microbial genetic components that trigger disease and host immune factors that help make decrease disease severity.

描述（由申请人提供）：我们建议研究特定肠道细菌在新型溃疡性结肠炎模型中的影响。该模型由夏立军实验室创建，当结肠粘液的 2 个主要核心聚糖（核心 1）之一的产生被基因敲除技术 (TM-IEC C1galt1-/-) 破坏时，就会产生自发性结肠炎。在诱导敲除后 2 周观察到传统 TM-IEC C1galt1-/- 小鼠微生物群的具体变化后，我们建议随着时间的推移检查微生物群，以识别在结肠炎发作之前和之后粘液产生丧失后发生的变化。我们将检查已知能够降解粘液的肠道微生物（Bacteroides thetaiotaomicronsm、Akkermansia muciniphila、Ruminococcus gnavus 和 R. Torks）、已在其他小鼠模型中证明与结肠炎有关的细菌，以及通过基于 16s rRNA 基因焦磷酸测序的微生物分析在我们自己的模型中鉴定出的微生物 社区。我们将比较所测试的各种微生物的基因组组成，以确定与结肠炎发展相关的代谢途径和其他途径。我们将通过在无菌小鼠设施中将 TM-IEC C1galt1-/- 小鼠与 Rag1-/- 杂交来检查 IgA 和其余适应性免疫系统对结肠炎的影响。使用我们之前建立的工具（例如共生体特异性 IgA），我们将研究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奠定基础，这些研究将检查有助于结肠炎发展的特定宿主微生物相互作用。该项目有潜力识别在结肠中 O-聚糖丢失的情况下调节溃疡性结肠炎的微生物成分和宿主适应性免疫成分。 公众健康相关性：溃疡性结肠炎 (UC) 是一种结肠炎性疾病，具有显着的发病率和死亡率。其病因可能涉及患者的遗传倾向和肠道中特定微生物之间的复杂相互作用。拟议的研究使用一种粘液屏障存在缺陷的新型小鼠模型来检查潜在的致病细菌。目标是确定引发疾病的微生物遗传成分和有助于降低疾病严重程度的宿主免疫因子。