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: 10468700
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468700
• 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; 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; 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.

项目概要 炎症性肠病 (IBD) 和结肠恶性肿瘤是异质性疾病状态，由以下原因引起： 宿主遗传和环境因素之间复杂的相互作用。越来越明显的是，早期事件 结肠微生物群的发育会影响宿主的免疫力、营养和疾病易感性。 脆弱拟杆菌占人体微生物群的 2.5%，通常在第一个月内感染 的生活。脆弱拟杆菌的一个亚种，称为产肠毒素脆弱拟杆菌 (ETBF)，可释放脆弱拟杆菌毒素 （BFT），一种锌依赖性金属蛋白酶，可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 在儿童中。 ETBF 定植于高达 20% 的无症状人群中，这表明这些人可能会出现 长期携带造成的长期健康风险未被充分认识。我们已经证明，竞争 结肠内的脆弱拟杆菌生态位由菌株特异性决定因素（包括 VI 型细菌）控制 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。通过综合分析 ETBF 结肠生态位建立的遗传决定因素以及 BFT 的机制 表达并释放以作用于宿主细胞，这项研究将定义其背后的基本机制 ETBF 介导的疾病。这些研究将受益于新型脆弱拟杆菌垂直模型的使用 其中脆弱拟杆菌初始生态位定殖的时间和遗传决定因素是 在新生小鼠中进行了检查。预计这些研究将揭示战略机遇 基于基因的益生菌方法通过菌株特异性生态位调节结肠疾病 竞争，防止有害地获得 ETBF，从而使宿主容易患病。

项目成果

Bacteroides fragilis toxin expression enables lamina propria niche acquisition in the developing mouse gut.

脆弱拟杆菌毒素的表达能够在发育中的小鼠肠道中获得固有层生态位。

• 发表时间: 2024-01
• 影响因子: 28.3
• 作者: Hill, Craig A;Casterline, Benjamin W;Valguarnera, Ezequiel;Hecht, Aaron L;Shepherd, Elizabeth Stanley;Sonnenburg, Justin L;Bubeck Wardenburg, Juliane
• 通讯作者: Bubeck Wardenburg, Juliane