Enterotoxigenic B. fragilis Acquisition in Disease Susceptibility

产肠毒素脆弱拟杆菌的获得与疾病易感性

• 批准号: 10228659
• 负责人: Juliane Bubeck Wardenburg
• 金额: $ 39.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-13 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228659
• 关键词: Acute; Acute Diarrhea; Acute Disease; Animal Model; Bacteroides fragilis; Benign; Cells; Child; Chronic; Chronic Disease; Clinical; Colitis; Colon; Colon Carcinoma; Colonic Diseases; Colonic Neoplasms; Complex; Coupled; Development; Disease; Disease susceptibility; Enteral; Environment; Environmental Risk Factor; Escherichia coli; Evaluation; Event; Exclusion; Familial Adenomatous Polyposis Syndrome; Feces; Genetic; Genetic Determinism; Goals; Health; Human; Human Microbiome; Immunity; Individual; Infant; Inflammatory; Inflammatory Bowel Diseases; Intestinal Diseases; Intestines; Investigation; Knowledge; Laboratories; Lesion; Libraries; Life; Light; Link; Malignant Neoplasms; Malnutrition; Measures; Mediating; Metabolism; Metalloproteases; Microbe; Microbial Biofilms; Microbial Genetics; Modeling; Mus; Neonatal; Nutritional; Pathogenesis; Pathogenicity; Predisposition; Probiotics; Regulation; Resistance; Risk; Shapes; Signal Transduction; System; Time; Tissues; Toxic effect; Toxin; Vertical Disease Transmission; Zinc; base; colon microbiome; colon microbiota; colon tumorigenesis; disease phenotype; epithelial injury; gene function; genetic analysis; genetic approach; germ free condition; host microbiota; host-microbe interactions; human disease; human microbiota; infancy; intestinal epithelium; intestinal injury; malignant colon tumor; microbiome; microbiota; neonatal mice; novel; nutrition; pathobiont; pathogenic bacteria; residence; resilience; symbiont; trafficking

PROJECT SUMMARY Inflammatory bowel disease (IBD) and colonic malignancy are heterogeneous disease states that result from a complex interplay of host genetic and environmental factors. It is becoming increasingly clear that early events in development of the colonic microbiota influence host immunity, nutrition, and susceptibility to disease. Bacteroides fragilis comprises up to 2.5% of the human microbiota, and is often acquired within the first month of life. A subspecies of Bacteroides fragilis termed enterotoxigenic B. fragilis (ETBF) releases B. fragilis toxin (BFT), a zinc-dependent metalloprotease that causes a pro-inflammatory injury of the intestinal epithelium. ETBF has been implicated in the pathogenesis of IBD, colon tumorigenesis, acute diarrhea, and undernutrition in children. ETBF colonizes up to 20% of asymptomatic humans, suggesting that these individuals may incur an underappreciated long-term health risk from chronic carriage. We have demonstrated that competition for the B. fragilis niche within the colon is governed by strain-specific determinants including the Type VI bacterial secretion system. Further, the acquisition of protective strains of NTBF that restrict ETBF acquisition blunt the toxic effects of ETBF and thereby mitigate disease. The primary goal of this proposal is to examine neonatal acquisition of ETBF as a determinant of host susceptibility to disease. Through a comprehensive analysis of the genetic determinants of ETBF colonic niche establishment and the mechanisms by which BFT is expressed and released to act upon host cells, this study will define fundamental mechanisms that underlie ETBF-mediated disease. These studies will benefit from the use of a novel model of B. fragilis vertical transmission in which the temporal and genetic determinants of initial niche colonization by B. fragilis is examined in neonatal mice. It is anticipated that these studies will shed light on strategic opportunities for genetically informed probiotic-based approaches to modulate colonic disease through strain-specific niche competition, precluding the deleterious acquisition of ETBF that renders a host susceptible to disease.

项目摘要 炎症性肠病（IBD）和结肠恶性肿瘤是由炎症引起的异质性疾病状态。 宿主遗传和环境因素的复杂相互作用。越来越明显的是，早期事件 在结肠微生物群的发展中，影响宿主的免疫力、营养和对疾病的易感性。 脆弱拟杆菌占人体微生物群的2.5%，通常在第一个月内获得 生命脆弱拟杆菌的一个亚种，称为肠致病性B。fragilis（ETBF）释放B。脆壁毒素 (BFT)是一种锌依赖性金属蛋白酶，引起肠上皮的促炎性损伤。 ETBF与IBD、结肠肿瘤发生、急性腹泻和营养不良的发病机制有关 小儿ETBF在20%的无症状人群中定植，这表明这些人可能会引起 长期携带的长期健康风险被低估了。我们已经证明， B。结肠内的fragilis生态位由菌株特异性决定因素控制，包括VI型细菌 分泌系统此外，限制ETBF获得的NTBF保护性菌株的获得削弱了ETBF的表达。 ETBF的毒性作用，从而减轻疾病。该提案的主要目标是检查新生儿 获得ETBF作为宿主对疾病易感性的决定因素。通过全面分析 ETBF结肠生态位建立的遗传决定因素和BFT是 表达并释放以作用于宿主细胞，这项研究将定义其基础的基本机制 ETBF介导的疾病。这些研究将受益于一种新的B模型的使用。垂直脆弱 传播，其中的时间和遗传决定因素的初始生态位殖民由B。脆弱群岛 在新生小鼠中检测。预计这些研究将揭示以下方面的战略机遇： 通过菌株特异性生态位调节结肠疾病的基于遗传信息的益生菌的方法 竞争，排除了ETBF的有害获得，ETBF使宿主对疾病易感。