期刊
EMBO MOLECULAR MEDICINE
卷 10, 期 8, 页码 -出版社
WILEY
DOI: 10.15252/emmm.201708736
关键词
epithelial barrier function; gut microbiota; inflammatory bowel disease; Paneth cells; STAT signaling
资金
- National Natural and Science Foundation of China [81770543]
- American Heart Association [14SDG20120052]
- Mizutani Foundation for Glycoscience Grant [170133]
- University of Minnesota Medical School
- Key Science and Technology Project of Henan Province [182102310107]
- Natural Science Foundation of Jiangsu Province [BK20150687]
- NIH [DK088199]
- Crohn's Colitis Foundation of America [426234]
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 beta-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.
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