Abstract
Post‐translational modifications in intestinal epithelial cells (IECs) allow for precise control in intestinal homeostasis, the breakdown of which may precipitate the pathological damage and inflammation in inflammatory bowel disease. The O‐linked β‐N‐acetylglucosamine (O‐GlcNAc) modification on intracellular proteins controls diverse biological processes; however, its roles in intestinal homeostasis are still largely unexplored. Here, we found that levels of protein O‐GlcNAcylation and the expression of O‐GlcNAc transferase (OGT), the enzyme adding the O‐GlcNAc moiety, were reduced in IECs in human IBD patients. Deletion of OGT specifically in IECs resulted in disrupted epithelial barrier, microbial dysbiosis, Paneth cell dysfunction, and intestinal inflammation in mice. Using fecal microbiota transplantation in mice, we demonstrated that microbial dysbiosis although was insufficient to induce spontaneous inflammation but exacerbated chemical‐induced colitis. Paneth cell‐specific deletion of OGT led to Paneth cell dysfunction, which might predispose mice to chemical‐induced colitis. On the other hand, the augmentation of O‐GlcNAc signaling by inhibiting O‐GlcNAcase, the enzyme removing O‐GlcNAcylation, alleviated chemical‐induced colitis. Our data reveal that protein O‐GlcNAcylation in IECs controls key regulatory mechanisms to maintain mucosal homeostasis.
Highlights
Post-translational modifications in intestinal epithelial cells (IECs) allow for precise control in intestinal homeostasis, the breakdown of which may precipitate the pathological damage and inflammation in inflammatory bowel disease
To further evaluate whether there was any correlation between disease severity and levels of O-GlcNAc transferase (OGT) and O-GlcNAcylation, we performed the immunohistochemistry staining on another set of intestine biopsies (Appendix Table S2) and confirmed the reduction in OGT and O-GlcNAcylation levels in IECs of both ulcerative colitis (UC) and Crohn’s disease (CD) (Fig 1C)
Intensities of both OGT and O-GlcNAcylation were negatively correlated with histological disease activities in UC and CD that were determined by Geboes and global histological activity (GHA) scores, respectively (Fig 1D and E, and Dataset EV1; van Loosdregt & Coffer, 2014)
Summary
Post-translational modifications in intestinal epithelial cells (IECs) allow for precise control in intestinal homeostasis, the breakdown of which may precipitate the pathological damage and inflammation in inflammatory bowel disease. The O-linked b-N-acetylglucosamine (O-GlcNAc) modification on intracellular proteins controls diverse biological processes; its roles in intestinal homeostasis are still largely unexplored. Deletion of OGT in IECs resulted in disrupted epithelial barrier, microbial dysbiosis, Paneth cell dysfunction, and intestinal inflammation in mice. Using fecal microbiota transplantation in mice, we demonstrated that microbial dysbiosis was insufficient to induce spontaneous inflammation but exacerbated chemical-induced colitis. Paneth cell-specific deletion of OGT led to Paneth cell dysfunction, which might predispose mice to chemical-induced colitis. The augmentation of O-GlcNAc signaling by inhibiting O-GlcNAcase, the enzyme removing O-GlcNAcylation, alleviated chemical-induced colitis. Our data reveal that protein O-GlcNAcylation in IECs controls key regulatory mechanisms to maintain mucosal homeostasis
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