Abstract The intestinal microbiota maintains mucosal homeostasis through dynamic host–microbe interactions. When this balance is disrupted, gut dysbiosis drives inappropriate immune activation, leading to dysregulated inflammation that contributes to the pathogenesis of chronic inflammatory diseases, including inflammatory bowel diseases (IBD). Chronic inflammation in patients with IBD increases the risk of intestinal fibrosis and colorectal cancer. However, therapeutic options for patients with IBD with fibrosis or neoplasia remain limited and challenging. Adherent-invasive Escherichia coli (AIEC) have emerged as key metabolic drivers of disease in IBD. We previously demonstrated that the AIEC-derived genotoxin colibactin and the siderophore yersiniabactin (Ybt) promote tumorigenesis through DNA damage and fibrosis via pro-fibrotic macrophage–fibroblast interactions, respectively. Because fibrosis and tumorigenesis involve overlapping pathways such as extracellular matrix remodeling, transforming growth factor-beta signaling, angiogenesis, and epithelial-to-mesenchymal transition, AIEC-derived metabolites may be functionally interconnected and could drive distinct pathological outcomes depending on the context of the disease. This Review highlights how AIEC-derived metabolites amplify inflammation, fibrosis, and neoplasia, outlines potential crosstalk between colibactin and Ybt, and discusses therapeutic opportunities targeting AIEC metabolite production in parallel with host-directed antifibrotic and cancer-prevention strategies.
Ahn et al. (Tue,) studied this question.