Effect of bile salt hydrolase inhibitors on Clostridium difficile infection

胆盐水解酶抑制剂对艰难梭菌感染的影响

• 批准号: 10495265
• 负责人: JUN LIN
• 金额: $ 18.43万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10495265
• 关键词: Affect; Anaerobic Bacteria; Animal Model; Animals; Antibiotic Therapy; Antibiotics; Back; Bile Acid Biosynthesis Pathway; Bile Acids; Biological Models; Blood; Body Weight; Caffeic Acids; Cells; Chenodeoxycholic Acid; Chicken Model; Clostridium difficile; Complex; Cues; Development; Diarrhea; Enteral; Enterohepatic Circulation; Enzymes; Event; Exhibits; Experimental Designs; Feces; Gastrointestinal tract structure; Genes; Genomics; Germination; Glycine; Harvest; Histopathology; Human; Hydrolase; Immune response; In Vitro; Incidence; Infection; Inflammation; Intestines; Knowledge; Lipids; Liver; Measurement; Mediating; Metabolic; Metabolism; Microbiology; Modification; Molecular; Mus; Names; Nature; Oral Administration; Pathogenesis; Play; Process; Production; Public Health; Publishing; Reproduction spores; Research; Riboflavin; Risk Factors; Role; Sampling; Series; Severities; System; Taurine; Taurocholic Acid; Testing; Time; Tissues; Toxin; base; bile acid metabolism; bile salts; cell growth; cell injury; design; gut bacteria; gut microbiota; in vivo; inhibitor; innovation; insight; lipid metabolism; liver metabolism; metabolomics; microbial; microbiome; microbiome analysis; mouse model; pathogenic bacteria; prevent; response; salvin; tool; transcriptome; transcriptome sequencing; transcriptomics

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.

项目摘要 艰难梭菌感染（CDI）是医院腹泻的主要原因，随着增加 全球发病率。孢子的发芽，通过感测特定的提示介导的肠道（命名 发芽剂），是艰难梭菌和CDI发育发育的必要早期要求。 胆汁酸（BAS）已被认为是肠中主要的发芽剂。但是，是 仍然未知哪些特定的肠道BA特征在体内艰难梭菌发芽和 CDI开发主要是由于缺乏受控系统中动物研究的适当工具。这 细菌胆汁盐水解酶（BSH）是一种门户酶，显着影响BA代谢和BA 肠道中的轮廓。最近，我们发现并验证了三个有效和广泛的光谱 BSH抑制剂都使用体外和体内系统，这为我们提供了检查C的绝佳工具。 艰难的发芽响应于CDI发育的肠道碱。我们假设那个口头 BSH抑制剂的给药会改变肠中的BA轮廓，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 鼠标模型中的CDI。我们将全面研究哪些特定肠道BA签名 在体内艰难梭菌发芽，细胞生长和毒素产生中影响CDI发育。通过 代谢组学，基因组学，分子，微生物和转录组学的强大组合 与建立良好的鼠标模型结合使用的方法，我们希望这个项目将填充重要的 艰难梭菌发病机理中的知识差距，并提供了有效发展的见解 预防和控制CDI的策略。