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

项目摘要/摘要 产生志贺毒素的大肠杆菌(STEC)，包括O157：H7，是导致食源性疾病的主要原因， 每年在美国造成大约10万例水样和血性腹泻。约10%的案件进展 对于危及生命的并发症--溶血性尿毒症综合征(HUS)。原因不清楚，年轻人 儿童比成人更容易患上HUS，HUS是急性肾脏病最常见的原因 孩子们的失败。目前还没有治疗STEC的方法。此外，抗生素诱导STEC产生 较高数量的志贺毒素，和抗生素治疗与增加严重的 疾病。 一个严重的限制是缺乏好的动物模型。小鼠不容易感染STEC或 志贺毒素进入肠道时。我们现在已经证明了干细胞来源的‘诱导 人类肠道有机化合物(IHIO)对O157：H7和志贺毒素敏感，因此代表了 第一个研究人类疾病的易于处理的模型系统。这项提议将检验iHIO可以是 用于确定影响STEC感染的微生物和宿主因素： 目标1将测试抗生素在预防或增强疾病方面的作用。 目标2将研究微生物组在影响疾病进展中的作用。 AIM 3将确定被报道下调O157：H7毒力因子表达的药物是否可以 通过预防肠道损伤来影响疾病结局。 这些研究将增加我们对人类STEC感染的了解，并可能提供一种简单的 评估潜在的治疗干预措施对人类的安全性和有效性的实验系统。

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.