Inflammation-associated intestinal fibrosis is driven by a pathobiont-derived small molecule of the microbiota

Fibrosis is a significant complication of intestinal disorders associated with microbial dysbiosis and pathobiont expansion, notably Crohn's disease (CD). Mechanisms that favor fibrosis are not well understood and therapeutic strategies are limited. Here we demonstrate inflammation-associated fibrosis driven by pathobiont Escherichia coli production of the siderophore yersiniabactin (Ybt). Inactivating the import of Ybt through its cognate receptor FyuA in E. coli NC101 promotes fibrosis in mono-associated colitis-susceptible Il10-deficient mice. Inactivation of Ybt biosynthesis in fyuA-deficient E. coli nearly abrogates fibrosis. RNAseq revealed profibrogenic gene signatures in proximal colon tissue before histological disease, suggesting a causative role. FyuA-deficient Ybt+ E. coli are detected in sub-epithelial tissue. When modeled in vitro, Ybt+ but not Ybt-deficient E. coli induce pro-fibrotic gene expression in fibroblasts. This suggests that Ybt establishes a pro-fibrotic environment in the host and indicates a direct link between intestinal pathobiont bacteria and the induction of inflammation-associated fibrosis.