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疾病 宿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 结肠菌群的发展影响宿主免疫，营养和对疾病的易感性。 细菌脆弱的脆弱性占人类微生物群的2.5％，通常在第一个月内获得 生活。菌属的亚种，称为肠毒素B. fragilis（ETBF）释放B. fragilis毒素 （BFT）是一种依赖锌的金属蛋白酶，会导致肠上皮的促炎性损伤。 ETBF与IBD的发病机理有关，结肠肿瘤发生，急性腹泻和营养不良 在儿童中。 ETBF殖民多达20％的无症状人类，表明这些人可能会发生 慢性运输的长期健康风险不足。我们已经证明了争夺 结肠内的B. fragilis like the族受菌株特异性决定因素（包括VI型细菌）的控制 分泌系统。此外，收购了限制ETBF收购的NTBF保护性菌株 ETBF的毒性作用，从而减轻疾病。该提议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。通过对 ETBF结肠生态位建立的遗传决定因素和BFT的机制 该研究表达并释放以对宿主细胞作用，将定义基本机制 ETBF介导的疾病。这些研究将受益于使用新型B. fragilis垂直模型 fragilis的初始生态位定植的时间和遗传决定因素的传播是 在新生小鼠中检查。预计这些研究将阐明 基于益生菌的基于遗传知情的方法，通过菌株特异性利基调节结肠疾病 竞争，排除了对ETBF的有害习得，这使宿主容易受到疾病的影响。