Bacterial Siderophores and Inflammatory Bowel Diseases-Associated Fibrosis.

Intestinal scarring and thickening, also called fibrosis, afflicts >30% of inflammatory bowel diseases (IBD) patients, yet there is no cure and few treatment options. The fundamental processes underlying IBD-fibrosis are unknown, partly due to the absence of relevant animal models. This lack of basic understanding has prevented therapeutic development. Accordingly, our lab has developed a novel IBD-fibrosis mouse model. The community of microbes residing in our gut — the microbiota — strongly influences health and disease. IBD patients exhibit microbiota alterations, but it is unknown which specific microbial products incite pro-fibrotic host responses. Our data suggest that excessive quantities of a microbial small molecule secreted from intestinal bacteria, yersiniabactin, promotes intestinal fibrosis. Bacteria expressing yersiniabactin are over-represented in the intestines of IBD patients, which may drive fibrosis in these patients. In this proposal, we will characterize the pro-fibrotic immune cells induced by yersiniabactin, quantify secreted yersiniabactin levels, and determine how this microbial product causes fibrosis in a new mouse model of IBD. Together these studies will reveal host and bacterial mechanisms that promote fibrosis in IBD patients, and identify a potential drug target within the bacteria of our gut that could prevent fibrosis in IBD patients.