ADHERENT-INVASIVEE. COLI PROMOTE ER STRESS TO SUPPORT IL23R-DRIVEN AGR2-DEPENDENT ILEOCOLITIS. (22nd January 2022)

• Record Type: Journal Article
• Authors: Viladomiu, Monica; Khounlotham, Manirath; Dogan, Belgin; Lima, Svetlana; Elsaadi, Ahmed; Herzog, Jeremy; Schoenborn, Alexi; Ellermann, Melissa; Liu, Bo; Zhang, Shiying; Gulati, Ajay; Sartor, R Balfour; Simpson, Kenneth; Lipkin, Steve; Longman, Randy
• Is Part Of: Inflammatory bowel diseases. Volume 28(2022)Supplement 1
• Page Start: S56
• Page End: S56
• Publication Date: 2022-01-22
• Subjects: Inflammatory bowel diseases -- Periodicals; Colitis, Ulcerative -- Periodicals; Crohn Disease -- Periodicals; Inflammatory Bowel Diseases -- Periodicals; 616.344
• DOI: 10.1093/ibd/izac015.087
• Languages: English
• ISSNs: 1078-0998

Abstract

Abstract: Anterior gradient 2 (AGR2) is an epithelial protein disulfide isomerase critical for mucus production and endoplasmic reticulum (ER) homeostasis. Loss-of-function genetic variants in AGR2 are associated with Crohn's disease (CD), and AGR2-deficient mice develop spontaneous ileocolitis, but the specificity of its impact on the host-microbe interaction driving disease is not well understood. Our new data reveals that AGR2 deficiency results in intestinal dysbiosis characterized by the expansion of adherent-invasive E. coli (AIEC). By re-deriving mice germ-free, we show that spontaneous ileocolitis is microbe-dependent and that AIEC isolates, but not other mucosa-associated microbes such as SFB, are sufficient to drive inflammatory disease in the absence of AGR2. AIEC induction of ER stress in AGR2-deficient mice enables further expansion of mucosal Enterobacteriaceae and is required for IL-23R-dependent Th17 cell ileocolitis. These findings reveal a central role for epithelial cell AGR2 in restraining ER stress induced by AIEC to prevent dysbiosis and inflammation in CD.