TY - JOUR T1 - Yersiniabactin producing AIEC promote inflammation-associated fibrosis in gnotobiotic <em>Il10<sup>−/−</sup></em> mice JF - bioRxiv DO - 10.1101/723148 SP - 723148 AU - Melissa Ellermann AU - Raad Z Gharaibeh AU - Laura Fulbright AU - Belgin Dogan AU - Lyndsey N Moore AU - Christopher A. Broberg AU - Lacey R. Lopez AU - Aaron M. Rothemich AU - Jeremy W Herzog AU - Allison Rogala AU - Ilyssa O. Gordon AU - Florian Rieder AU - Cory R. Brouwer AU - Kenneth W. Simpson AU - Christian Jobin AU - R Balfour Sartor AU - Janelle C Arthur Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/08/02/723148.abstract N2 - 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 that colitis susceptible Il10-deficient mice develop inflammation-associated fibrosis when mono-associated with adherent/invasive Escherichia coli (AIEC) that harbor the yersiniabactin (Ybt) pathogenicity island. Inactivation of Ybt siderophore production in AIEC nearly abrogated fibrosis development in inflamed mice. In contrast, inactivation of Ybt import through its cognate receptor FyuA enhanced fibrosis severity. This corresponded with increased colonic expression of profibrogenic genes prior to the development of histological disease, therefore suggesting causality. FyuA-deficient AIEC also exhibited greater localization within sub-epithelial tissues and fibrotic lesions that was dependent on Ybt biosynthesis and corresponded with increased fibroblast activation in vitro. Together, these findings suggest that Ybt establishes a pro-fibrotic environment in the host in the absence of binding to its cognate receptor and indicates a direct link between intestinal AIEC and the induction of inflammation-associated fibrosis. ER -