Yersiniabactin producing AIEC promote inflammation-associated fibrosis in gnotobiotic Il10-/- mice

Ellermann, M.; Gharaibeh, R.; Fulbright, L.; Dogan, B.; Moore, L. N.; Broberg, C. A.; Lopez, L. R.; Rothemich, A. M.; Herzog, J.; Rogala, A.; Gordon, I. O.; Rieder, F.; Brouwer, C. R.; Simpson, K. W.; Jobin, C.; Sartor, R. B.; Arthur, J. C.

doi:10.1101/723148

bioRxiv · 10.1101/723148

Yersiniabactin producing AIEC promote inflammation-associated fibrosis in gnotobiotic Il10-/- mice

Ellermann, M.·Gharaibeh, R.·Fulbright, L.·Dogan, B.·Moore, L. N.·Broberg, C. A.·Lopez, L. R.·Rothemich, A. M.·Herzog, J.·Rogala, A.·Gordon, I. O.·Rieder, F.·Brouwer, C. R.·Simpson, K. W.·Jobin, C.·Sartor, R. B.·Arthur, J. C.

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Abstract

Fibrosis is a significant complication of intestinal disorders associated with microbial dysbiosis and pathobiont expansion, notably Crohns 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.

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Ellermann, M., Gharaibeh, R., Fulbright, L., Dogan, B., Moore, L. N., Broberg, C. A., Lopez, L. R., Rothemich, A. M., Herzog, J., Rogala, A., Gordon, I. O., Rieder, F., Brouwer, C. R., Simpson, K. W., Jobin, C., Sartor, R. B., Arthur, J. C.. 2019-08-02. Yersiniabactin producing AIEC promote inflammation-associated fibrosis in gnotobiotic Il10-/- mice. https://doi.org/10.1101/723148

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