EVALUATION OF ESCHERICHIA COLI SPECIALIZED METABOLITES IMPLICATED IN INFLAMMATORY BOWEL DISEASE COMPLICATIONS

Inflammatory bowel disease (IBD) is defined by painful and chronic intestinal inflammation that can lead to life-threatening complications, including intestinal fibrosis and colorectal cancer (CRC). IBD is a rising global health threat with no cure and limited therapeutic options for affected patients. Gut resident adherent-invasive Escherichia coli (AIEC) are strongly linked to IBD development and are a key target for microbiota-directed IBD therapies. Despite decades of research, there is no genetic definition for AIEC – this suggests it is the functional response of AIEC to the host environment that alters disease development. E. coli impact IBD via production of pro-inflammatory and pro-carcinogenic molecules. Two key E. coli-derived specialized metabolites that drive IBD pathology are yersiniabactin (Ybt) and colibactin. Ybt promotes IBD-associated intestinal fibrosis and colibactin is a CRC-promoting genotoxin. Like many specialized metabolites, the production of Ybt and colibactin is finely tuned based on environmental signals, many of which remain undefined. In my dissertation, I define relevant host factors that regulate production of E. coli specialized metabolites. Further, I evaluate how Ybt and colibactin may drive IBD complications, including intestinal fibrosis and inflammation-associated CRC. Through this body of work, I illustrate some of the many diverse mechanisms for how seemingly innocuous intestinal microbes respond to stress and induce disease. My findings are expected to inform novel microbiota-targeted interventions for IBD and related complications, like intestinal fibrosis and CRC.Doctor of Philosoph