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.
Bibliographical noteFunding Information:
We thank Dr. Xiaoyong Yang for providing the Ogt-floxed mouse line, Dr. David Vocadlo for providing Ac45S-GlcNAc, and Dr. Daniel Vallera for providing Caco-2 cells. We thank Dr. Tim Starr for providing the Karl Storz Coloview system and Patrick Blaney for assisting with the colonoscopy. We thank Dr. Dan Knights and Trevor Gould for assisting the analysis of 16S sequencing data. We thank Dr. Weiqi He and Huashan Li for providing the technical assistance in organoid culture. This work was supported by National Natural and Science Foundation of China (81770543), American Heart Association Scientist Development Grant (14SDG20120052), Mizutani Foundation for Glycoscience Grant (170133), and University of Minnesota Medical School 2017 Innovation Grant to H.-B.R, Key Science and Technology Project of Henan Province (182102310107) to X. X, Natural Science Foundation of Jiangsu Province (BK20150687) to Z. H, NIH DK088199 to R.S.B, and Crohn’s Colitis Foundation of America Senior Research Award (426234) to X.H.
- Paneth cells
- STAT signaling
- epithelial barrier function
- gut microbiota
- inflammatory bowel disease