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

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.

项目总结/摘要 产滋贺毒素E.大肠杆菌（STEC），包括O 157：H7，是食源性疾病的主要原因， 每年在美国造成大约10万例水样腹泻和血性腹泻。大约10%的病例进展 危及生命的并发症，溶血性尿毒综合征（HUS）。由于不清楚的原因，年轻人 儿童比成人更容易患上溶血尿毒综合征，溶血尿毒综合征是急性肾衰竭最常见的原因。 孩子的失败。目前还没有针对STEC的治疗方法。此外，抗生素诱导STEC产生 较高量的滋贺毒素和抗生素治疗与严重 疾病 一个严重的限制是缺乏良好的动物模型。小鼠对STEC不敏感， 滋贺毒素进入肠道。我们现在已经表明，干细胞衍生的诱导 人肠类器官（iHIO）对E. coli O 157：H7和滋贺毒素，因此代表了 第一个研究人类疾病的易处理模型系统。该提案将测试iHIOs可以 用于确定影响STEC感染的微生物和宿主因素： 目的1将测试抗生素在预防或增强疾病中的作用。 目标2将研究微生物组在影响疾病进展中的作用。 目的3将确定是否代理报告下调O 157：H7毒力因子表达， 通过防止肠道损伤影响疾病结果。 这些研究将增加我们对人类STEC感染的了解，并提供一个简单的方法。 实验系统，以评估潜在的治疗干预的安全性和有效性在人类。