Deficiency in intestinal epithelial O‐GlcNAcylation predisposes to gut inflammation

• DOI: 10.15252/emmm.201708736
• Publication Date: 2018-06-25T15:45:19Z
• Authors: Ming Zhao; Xiwen Xiong; Kaiqun Ren; Bing Xu; Meng Cheng; Chinmayi Sahu; Kaichun Wu; Yongzhan Nie; Zan Huang; Richard S Blumberg; Xiaonan Han; Hai‐Bin Ruan
• Keywords: Male; 0301 basic medicine; Medicine (General); Paneth Cells; QH426-470; N-Acetylglucosaminyltransferases; Acetylglucosamine; Mice; 03 medical and health sciences; R5-920; inflammatory bowel disease; Genetics; Animals; Homeostasis; Humans; Intestinal Mucosa; Research Articles; Pyrans; epithelial barrier function; gut microbiota; Epithelial Cells; Fecal Microbiota Transplantation; Paneth cells; Colitis; Inflammatory Bowel Diseases; beta-N-Acetylhexosaminidases; STAT signaling; STAT Transcription Factors; Thiazoles; Dysbiosis; Female; Protein Processing, Post-Translational

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.