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.

项目总结 炎症性肠病(IBD)和结肠恶性肿瘤是由 寄主遗传和环境因素的复杂相互作用。越来越清楚的是，早期事件 结肠微生物区系的发育影响宿主免疫、营养和对疾病的易感性。 脆弱类杆菌占人类微生物群的2.5%，通常在第一个月内获得 生活的一部分。脆弱类杆菌的一个亚种，称为产肠毒素脆弱杆菌(ETBF)，释放脆弱杆菌毒素 (BFT)，一种锌依赖的金属蛋白酶，导致肠道上皮的促炎损伤。 ETBF与IBD、结肠肿瘤、急性腹泻和营养不良的发病机制有关。 在孩子们身上。ETBF在高达20%的无症状人类中定居，这表明这些人可能会导致 长期运输造成的长期健康风险未得到充分认识。我们已经证明了这一竞争 结肠内的脆弱杆菌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收购的NTBF保护性菌株的获得削弱了 ETBF的毒性效应，从而减轻疾病。这项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。通过综合分析 ETBF结肠生态位建立的遗传决定因素及BFT形成机制 表达和释放作用于宿主细胞，这项研究将定义基础的基本机制 ETBF介导的疾病。这些研究将受益于一种新的脆弱芽孢杆菌垂直模型的使用。 脆弱杆菌初始生态位定植的时间和遗传决定因素是 在新生小鼠身上进行了检测。预计这些研究将揭示以下战略机遇 基于基因信息的益生菌通过菌株特异性生态位调节结肠疾病的方法 竞争，排除了有害的ETBF收购，使宿主容易感染疾病。