The Influence Of Gut Microbiota Stability In Inflammatory Bowel Disease

肠道微生物群稳定性对炎症性肠病的影响

• 批准号: 9764766
• 负责人: Jeremiah James Faith
• 金额: $ 66.99万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-04 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764766
• 关键词: Acute; Affect; Animals; Automobile Driving; Bacteria; Cell Compartmentation; Characteristics; Chronic; Clinical Research; Colitis; Collection; Communities; Crohn' s disease; Data; Disease; Environmental Risk Factor; Escherichia coli; Gastrointestinal tract structure; Genetic; Gnotobiotic; Goals; Human; Human Genome; IL2RA gene; Immune; Immune response; Immune system; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestinal Diseases; Intestines; Metagenomics; Methods; Microbe; Minor; Monozygotic twins; Mucous Membrane; Mus; Nature; Organism; Pathogenicity; Pathology; Patients; Prevention; Role; Sampling; Serum; Severities; Severity of illness; System; T-Lymphocyte; Testing; Therapeutic; Therapeutic Studies; Ulcerative Colitis; commensal bacteria; experimental study; fecal microbiota; genome sequencing; genome wide association study; gut microbes; gut microbiota; human disease; immunogenicity; member; metagenomic sequencing; microbial; microbiome; microbiota; mouse model; novel; novel therapeutic intervention; pathogen; pathogenic bacteria; targeted treatment; tool; virtual

PROJECT SUMMARY Inflammatory Bowel Diseases (IBD), consisting of Ulcerative colitis (UC) and Crohn's disease (CD), are chronic progressive inflammatory conditions of the intestine. Numerous lines of evidence suggest their origins lie in an overaggressive response of the host immune system towards the gut microbiota in a genetically susceptible host. We hypothesize a key feature of IBD is the persistent colonization by colitogenic microbial strains that over years to decades can drive the progressive inflammation and damage associated with IBD. To test this hypothesis we propose three Aims. In Aim 1, we will sample, every six months for four years, the fecal microbiota of individuals with Inflammatory Bowel Disease (UC or CD) whose gut microbiota induces disease when colonized in the gnotobiotic T-cell transfer mouse model of colitis. We will use metagenomics combined with high throughput microbial isolation and genome sequencing to identify the stable and transient microbes in each individual's microbiota and determine if individuals with IBD have significantly altered gut microbiota stability. In Aim 2, we will use gnotobiotic T-cell transfer colitis mice colonized with subsets of each microbiota to identify colitogenic and colitoprotective microbial strains and to determine if colitogenic or colitoprotective organisms are preferentially found in the stably colonized community members. Finally in Aim 3, we will determine if colitogenic and colitoprotective strains drive unique baseline immune tones when colonized in unchallenged gnotobiotic mice. Together these aims will help us determine if individuals with Inflammatory Bowel Disease are enriched in stably colonized colitogenic organisms whose elimination might form a novel therapeutic intervention for the treatment or prevention of Inflammatory Bowel Disease and if healthy individuals are enriched in stably colonized colitoprotective organisms that might form the basis of a novel IBD therapeutic.

项目摘要 炎症性肠病（IBD），包括溃疡性结肠炎（UC）和克罗恩病（CD）， 是肠道的慢性进行性炎症。大量证据表明 它们的起源在于宿主免疫系统对肠道微生物群的过度攻击性反应 在一个基因易感的宿主中我们假设IBD的一个关键特征是持续的定植 由大肠杆菌微生物菌株，在数年至数十年内可以驱动进行性炎症， 与IBD相关的损伤。为了验证这个假设，我们提出了三个目标。在目标1中，我们 样本，每六个月一次，持续四年，患有炎症性肠病的个体的粪便微生物群 当肠道微生物群在特定菌T细胞中定殖时诱导疾病的疾病（UC或CD） 转移小鼠结肠炎模型。我们将使用宏基因组学结合高通量微生物 分离和基因组测序，以确定稳定和短暂的微生物在每个 个体的微生物群，并确定患有IBD的个体是否具有显著改变的肠道 微生物群稳定性在目标2中，我们将使用以亚群定殖的非生物性T细胞转移结肠炎小鼠， 以鉴定致大肠杆菌和保护大肠杆菌的微生物菌株，并确定 产大肠杆菌或大肠杆菌保护性微生物优先存在于稳定定殖的 社区成员。最后，在目标3中，我们将确定是否具有致大肠杆菌性和大肠杆菌保护性。 当在未挑战的非病原菌中定殖时，菌株驱动独特的基线免疫音调 小鼠这些目标将有助于我们确定炎症性肠病患者是否 富含稳定定殖的大肠杆菌微生物，其消除可能形成新的治疗方法， 治疗或预防炎症性肠病的干预，如果健康个体 富含稳定定植的大肠杆菌保护性微生物，这些微生物可能形成新型IBD的基础 有治疗作用的