The Impact of Bile Salt Hydrolase on Intestinal T Cells in Colitis

About This Grant

PROJECT SUMMARY/ABSTRACT Inflammatory bowel disease (IBD) affects up to 3.1 million adults in the U.S. Bile acids are recognized as key signaling molecules in microbe-immune communication and may therefore be new therapeutic targets for IBD. Microbes deconjugate bile acids with bile salt hydrolases (BSHs), which can produce a variety of bacterial bile acid amidates (BBAAs). However, whether the microbiome affects the immune system through BBAAs remains a gap in knowledge. To investigate this, there is a critical need for a research tool that allows us to overexpress specific BSHs in the gut microbiota to manipulate the BBAA pool. The innovation of this proposal is the use of engineered native bacteria, which allow the stable overexpression of single BSH enzymes in the lumen without disrupting the native microbiota. Preliminary data show that an engineered native bacteria expressing BSH is protective against colitis. The overall goal of this study is to determine how BSH has this effect. The candidate will colonize mice with BSH-expressing engineered native bacteria to test the central hypothesis that BSH protects against colitis through the production of specific BBAAs. In the next three years, the candidate will pursue this hypothesis with two specific aims. The first aim will determine if BBAA production is necessary for BSH to protect against colitis. The candidate will administer engineered native bacteria that produce different BSHs to mice in the dextran sodium sulfate colitis model and determine whether only BSHs that produce BBAAs reduce colitis severity. The second aim will determine if BBAAs are sufficient to recapitulate the effects of BSH. The candidate will administer synthesized BBAAs to mice in the dextran sodium sulfate colitis model and determine if BBAAs alone are protective against colitis. The expected outcome of this study is a mechanistic understanding of how BSH activity ameliorates colitis, and clarity as to whether the production of certain BBAAs mediates this effect. These findings will have a positive translational impact, since characterizing microbial metabolites that ameliorate colitis could provide new therapeutic targets for the development of IBD treatments. The candidate is an outstanding scientist with a clear goal of establishing herself as an independent researcher specializing in the host-microbiome interface in inflammatory disease. Her training objectives include: designing experiments with engineered native bacteria, conducting microbiome and metabolomics studies, gaining expertise in animal models of inflammatory bowel disease, acquiring the skills necessary for independent research, and expanding her professional network. To achieve these objectives, she has developed a comprehensive plan that integrates hands-on bench research, targeted coursework, seminars, participation in national meetings, and other career development activities. This plan will be carried out under the guidance of a mentorship committee led by Drs. Amir Zarrinpar and Pieter Dorrestein.