Effect of bile salt hydrolase inhibitors on Clostridium difficile infection

项目摘要 艰难梭菌感染(CDI)是引起医院内腹泻的主要原因，且呈逐年上升趋势。 世界范围内的发病率。孢子的萌发，通过感知肠道中的特定线索(称为 芽胞杆菌)，是艰难梭菌致病和CDI发展的重要早期要求。 胆汁酸(BAs)已被公认为肠道中的主要发芽物质。然而，它是 目前尚不清楚哪些特定的肠道BA信号以及如何影响艰难梭菌体内的萌发和 CDI的发展，主要是由于在受控系统中缺乏适当的动物研究工具。这个 细菌胆盐水解酶(BSH)是影响BA代谢和BA的重要通道酶 肠子里的侧写。最近，我们发现并验证了三种有效的广谱 BSH抑制剂使用体外和体内系统，这为我们提供了一个很好的工具来检测C. 艰难杆菌的萌发对CDI发展的肠道反应。我们假设口头的 给予BSH抑制剂会改变肠道中BA的分布，从而影响 CDI的发展和严重程度。为了测试这一点，我们计划评估BSH抑制剂对 CDI在小鼠模型中的表达。我们将全面检查哪些特定的肠道BA签名以及如何 在体内影响艰难梭菌的萌发、细胞生长和毒素产生对CDI发展的影响。穿过 代谢组学、基因组学、分子、微生物和转录组学的强大组合 结合一个成熟的鼠标模型，我们预计这个项目将填补一个重要的 对艰难梭菌致病机制的认识差距，并为有效的发展提供了见解 预防和控制CDI的策略。

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.