Effect of bile salt hydrolase inhibitors on Clostridium difficile infection

项目摘要 艰难梭菌感染（CDI）是医院获得性腹泻的主要原因， 全球发病率。孢子的萌发，通过在肠道中感知特定的线索来介导（称为 萌发剂）是C. difficile和CDI开发。 胆汁酸（BA）已被认为是肠道中的主要萌发剂。但据 仍不清楚具体肠BA特征在体内影响哪些以及如何影响C。难以萌发， CDI开发，主要是由于在受控系统中缺乏适当的动物研究工具。的 细菌胆盐水解酶（BSH）是影响BA代谢的重要门户酶， 肠中的轮廓。最近，我们发现并验证了三种有效的广谱 BSH抑制剂的研究为我们提供了一个很好的检测C。 艰难的萌发响应肠BA的CDI发展。我们假设口腔 BSH抑制剂的给药将改变肠中的BA分布，从而影响肠中的BA浓度。 CDI的发展和严重程度。为了验证这一点，我们计划评估BSH抑制剂对 小鼠模型中的CDI。我们将全面研究哪些和如何具体的肠道BA签名 体内影响C.艰难杆菌萌发、细胞生长和毒素产生以用于CDI发育。通过 代谢组学、基因组学、分子学、微生物学和转录组学的强大组合 方法结合一个完善的小鼠模型，我们预计这个项目将填补一个重要的 C.知识差距艰难的发病机制，并提供见解的发展，有效的 预防和控制CDI。

Project Summary Clostridium difficile infection (CDI) is the major cause of nosocomial diarrhea with increasing incidence rates worldwide. Germination of spores, mediated by sensing specific cues in the gut (named germinants), is an essential early requirement for the pathogenesis of C. difficile and CDI development. Bile acids (BAs) have been recognized as the major group of germinants in the intestine. However, it is still unknown which and how specific intestinal BA signature influence in vivo C. difficile germination and CDI development, primarily due to lack of appropriate tools for animal study in a controlled system. The bacterial bile salt hydrolase (BSH) is a gateway enzyme significantly influencing BA metabolism and BA profile in the intestine. Recently, we have discovered and validated three potent and broad-spectrum BSH inhibitors using both in vitro and in vivo systems, which provides us an excellent tool to examine C. difficile germination in response to intestinal BAs for CDI development. We hypothesize that oral administration of the BSH inhibitors would alter BA profile in the intestine, consequently affecting the development and severity of CDI. To test this, we plan to evaluate the effects of the BSH inhibitors on CDI in a mouse model. We will comprehensively examine which and how specific intestinal BA signatures influence in vivo C. difficile germination, cell growth, and toxin production for CDI development. Through a powerful combination of metabolomics, genomics, molecular, microbiological, and transcriptomics approaches in conjunction with a well-established mouse model, we expect this project will fill a significant knowledge gap in C. difficile pathogenesis, and provide insights into the development of effective strategies to prevent and control CDI.