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.

项目总结

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。

• DOI: 10.1038/s41564-023-01559-9
• 发表时间: 2024
• 期刊: Nature microbiology
• 影响因子: 28.3
• 作者: Hill,CraigA;Casterline,BenjaminW;Valguarnera,Ezequiel;Hecht,AaronL;Shepherd,ElizabethStanley;Sonnenburg,JustinL;BubeckWardenburg,Juliane
• 通讯作者: BubeckWardenburg,Juliane