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: 8497618
• 负责人: DANIEL A PETERSON
• 金额: $ 19.02万
• 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/8497618
• 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; pyrosequencing; 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.

描述（由申请人提供）：我们建议研究特定肠道细菌对溃疡性结肠炎新模型的影响。该模型由夏丽君实验室创建，当结肠粘液的两种主要核心聚糖之一（core 1）的产生被基因敲除技术（TM-IEC C1galt1-/-）破坏时，发生自发性结肠炎。在观察到常规TM-IEC C1galt1-/-小鼠在诱导基因敲除2周后微生物群的特异性变化后，我们建议随着时间的推移检查微生物群，以确定粘液产生丢失后发生的变化，无论是在结肠炎发作之前还是之后。我们将研究已知能够降解粘液的肠道微生物（拟杆菌、嗜粘杆菌、瘤球菌和托克氏杆菌），在其他小鼠模型中已被证明与结肠炎有关的细菌，以及通过基于微生物群落分析的16s rRNA基因焦磷酸测序在我们自己的模型中鉴定出的微生物。我们将比较不同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，通过将TM-IEC C1galt1-/-小鼠与Rag1-/-小鼠杂交，研究IgA和适应性免疫系统的其余部分对结肠炎的影响。使用我们之前建立的工具（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，这些研究将检查促进结肠炎发展的特定宿主微生物相互作用。该项目有潜力确定在结肠中o -聚糖损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。

项目成果

Discordance between changes in the gut microbiota and pathogenicity in a mouse model of spontaneous colitis.

自发性结肠炎小鼠模型中肠道微生物群的变化与致病性之间的不一致。

• DOI: 10.4161/gmic.28622
• 发表时间: 2014-05
• 期刊: Gut microbes
• 影响因子: 12.2
• 作者: Perez-Muñoz ME;Bergstrom K;Peng V;Schmaltz R;Jimenez-Cardona R;Marsteller N;McGee S;Clavel T;Ley R;Fu J;Xia L;Peterson DA
• 通讯作者: Peterson DA

Identification and Phylogeny of the First T Cell Epitope Identified from a Human Gut Bacteroides Species.

• DOI: 10.1371/journal.pone.0144382
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Perez-Muñoz ME;Joglekar P;Shen YJ;Chang KY;Peterson DA
• 通讯作者: Peterson DA