期刊
INFECTION AND IMMUNITY
卷 87, 期 11, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/IAI.00587-19
关键词
fibrosis; AIEC; Crohn's disease; colitis; microbiome; yersiniabactin; intestinal inflammation; microbiota
资金
- NIH [P30DK34987, P40 OD01995]
- NCI [P30-CA016086-40]
- NIEHS [P30ES010126-15A1]
- NCBT [2015-IDG-1007]
- NSF [CHE-1726291]
- UNC-CH School of Medicine Office of Research
- NIH/NIDDK [K01 DK103952]
- Kenneth Rainin Foundation Innovator Award
- CGIBD (NIH) [P30DK34987]
- American Gastroenterological Association Augustyn Award in Digestive Cancer
- Lineberger Comprehensive Cancer Center Pilot Grant
- North Carolina Translational and Clinical Sciences Institute (NC TraCS) pilot grant
- American Cancer Society postdoctoral fellowship
- UNC dissertation completion fellowship
- Microbiome Initiative
- Crohn's and Colitis Foundation of America (CCFA)
- CCFA
- UCRF
- [P30DK097948]
- [K08DK110415]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [K08DK110415] Funding Source: NIH RePORTER
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 monoassociated with adherent/invasive Escherichia coli (AIEC) that harbors 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 subepithelial 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 profibrotic environment in the host in the absence of binding to its cognate receptor and indicate a direct link between intestinal AIEC and the induction of inflammation-associated fibrosis.
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