Effect of bile salt hydrolase inhibitors on Clostridium difficile infection

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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.