Microbiome and E. coli O157:H7 infection of human gut tissue

人体肠道组织的微生物组和大肠杆菌 O157:H7 感染

• 批准号: 9764263
• 负责人: Alison A. Weiss
• 金额: $ 40.13万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764263
• 关键词: Actins; Acute Kidney Failure; Adult; Animal Model; Animals; Antibiotic Therapy; Antibiotics; Bacteria; Bacteriophages; Biological Models; Child; Clustered Regularly Interspaced Short Palindromic Repeats; Complication; DNA; Disease; Disease Outcome; Disease Progression; Environment; Epithelial; Escherichia coli; Escherichia coli EHEC; Escherichia coli Infections; Escherichia coli O157:H7; F-Actin; Genetic Engineering; Germ-Free; Health; Hemolytic-Uremic Syndrome; Hemorrhagic colitis; Hour; Human; In Vitro; Incidence; Individual; Infection; Inflammation; Injections; Integration Host Factors; Intestines; Knowledge; Life; Lytic Phase; Modeling; Mucous body substance; Mus; Organoids; Outcome; Pathogenicity; Patients; Pre-Clinical Model; Predisposition; Process; Production; Rage; Reporting; Resistance; Role; Safety; Severity of illness; Shiga Toxin; Source; Stains; Stem cells; Surface Antigens; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Tissue Model; Tissue Sample; Tissues; Translating; Up-Regulation; Virulence Factors; commensal bacteria; embryonic stem cell; experience; foodborne illness; gut microbiota; human disease; human pathogen; human tissue; microbial; microbial host; microbiome; microbiome alteration; microorganism interaction; pathogen; pathogenic Escherichia coli; pathogenic bacteria; prevent; resident commensals; response; stem cell biology; Actins; Acute Kidney Failure; Adult; Animal Model; Animals; Antibiotic Therapy; Antibiotics; Bacteria; Bacteriophages; Biological Models; Child; Clustered Regularly Interspaced Short Palindromic Repeats; Complication; DNA; Disease; Disease Outcome; Disease Progression; Environment; Epithelial; Escherichia coli; Escherichia coli EHEC; Escherichia coli Infections; Escherichia coli O157:H7; F-Actin; Genetic Engineering; Germ-Free; Health; Hemolytic-Uremic Syndrome; Hemorrhagic colitis; Hour; Human; In Vitro; Incidence; Individual; Infection; Inflammation; Injections; Integration Host Factors; Intestines; Knowledge; Life; Lytic Phase; Modeling; Mucous body substance; Mus; Organoids; Outcome; Pathogenicity; Patients; Pre-Clinical Model; Predisposition; Process; Production; Rage; Reporting; Resistance; Role; Safety; Severity of illness; Shiga Toxin; Source; Stains; Stem cells; Surface Antigens; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Tissue Model; Tissue Sample; Tissues; Translating; Up-Regulation; Virulence Factors; commensal bacteria; embryonic stem cell; experience; foodborne illness; gut microbiota; human disease; human pathogen; human tissue; microbial; microbial host; microbiome; microbiome alteration; microorganism interaction; pathogen; pathogenic Escherichia coli; pathogenic bacteria; prevent; resident commensals; response; stem cell biology

Project Summary/Abstract Shiga toxin producing E. coli (STEC), including O157:H7, are a leading cause of food-borne illnesses, causing about 100,000 cases of watery and bloody diarrhea annually in the US. About 10% of cases progress to the life-threatening complication, hemolytic uremic syndrome (HUS). For reasons that are not clear, young children are more likely to develop HUS than adults, and HUS is the most common cause of acute kidney failure in children. Currently there is no treatment for STEC. Furthermore, antibiotics induce STEC to produce higher quantities of Shiga toxin, and antibiotic treatment is associated with increased incidence of severe disease. A serious limitation has been the lack of good animal models. Mice are not susceptible to STEC or Shiga toxin when introduced into the intestinal tract. We have now shown that stem cell derived ‘induced human intestinal organoids’ (iHIOs) are sensitive to E. coli O157:H7 and Shiga toxin, and thus represents the first tractable model system to study human disease. This proposal will test the hypotheses that iHIOs can be used to identify microbial and host factors that influence infection by STEC: Aim 1 will test role of antibiotics in preventing or enhancing disease. Aim 2 will examine the role of the microbiome in influencing disease progression. Aim 3 will determine if agents reported to down-regulate O157:H7 virulence factor expression can impact disease outcome by preventing intestinal damage. These studies will increase our understanding of human STEC infection and could provide a simple experimental system to assess potential therapeutic interventions for safety and efficacy in humans.

项目摘要/摘要 包括O157：H7在内的志贺毒素产生大肠杆菌（STEC）是饮食传播疾病的主要原因， 在美国，每年引起约100,000例水和血腥的腹泻。大约10％的案件进展 为了威胁生命的并发症，溶血性尿毒症综合征（HUS）。由于不清楚的原因，年轻 儿童比成年人更有可能发展HUS，而HUS是急性肾脏的最常见原因 儿童失败。目前尚无针对STEC的治疗方法。此外，抗生素诱导STEC产生 较高量的志贺毒素和抗生素治疗与严重的发生率增加有关 疾病。 严重的限制是缺乏好的动物模型。小鼠不容易受到STEC或 志加毒素引入肠道时。现在我们已经表明，干细胞得出了' 人肠癌（IHIOS）对大肠杆菌O157：H7和Shiga毒素敏感，因此代表 研究人类疾病的第一个可处理模型系统。该建议将检验IHIOS可能是 用于识别影响STEC感染的微生物和宿主因素： AIM 1将测试抗生素在预防或增强疾病中的作用。 AIM 2将检查影响疾病进展的微生物组的作用。 AIM 3将确定是否报告了向下调节O157的药物：H7病毒因子表达可以 通过预防肠道损伤来影响疾病的结果。 这些研究将增加我们对人类STEC感染的理解，并可以提供一个简单的 实验系统评估人类安全性和效率的潜在治疗干预措施。