Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is caused by complex environment-host interactions1). It is well-recognized that commensal microbiota-derived signals help maintain barrier function and restrain gut inflammation. In IBD patients, intestinal inflammation is strongly associated with microbial dysbiosis and barrier dysfunction. Defining the mechanisms by which intestinal epithelium senses and integrates microbial signals in health and disease will facilitate the understanding of the etiology of IBD and the development of novel therapeutics.Our funded projected aimed to define O-linked N-acetylglucosamine (O-GlcNAc) modification in microbial sensing and intestinal homeostasis. The O-GlcNAc glycosylation on intracellular proteins has been widely accepted as a sensor of cellular metabolic status (Figure 1), because levels of the Figure 1. Hexosamine biosynthetic pathway (HBP) and Protein O-GlcNAcylationdonor substrate UDP-GlcNAc fluctuate with the availability of glucose, fatty acids, uridine, and glutamine2). The role of O-GlcNAc in microbiota-host interactions was unexplored. The overarching hypothesis we tested was that epithelial O-GlcNAc links the metabolism of microbiota-derived short-chain fatty acids (SCFAs) to barrier integrity and intestinal homeostasis.We found that both the levels of global O-GlcNAc modification and O-GlcNAc transferase (OGT, the enzyme adding O-GlcNAc to proteins) were significantly downregulated in IBD epithelial cells. In mice that were deprived of gut microbiota, intestinal epithelial O-GlcNAc was impaired; and supplementation of SCFAs, a group of metabolites mainly produced by commensal bacteria, rescued epithelial O-GlcNAc levels. The Mizutani grant allowed us to further investigate the following two specific aims: 1) how microbial dysbiosis is caused by OGT deficiency and contributes to IBD progression and 2) if elevation of O-GlcNAc levels protects from intestinal inflammation. A multi-hit model of O-GlcNAc in IBD pathogenesisThe induction and perpetuation of intestinal inflammation require the convergence of several abnormalities that affect overlapping layers of homeostatic modules including genetic predisposition, barrier dysfunction, microbial dysbiosis, and immune over-activation. A multi-hit model has been proposed (Figure 2). We generated intestinal epithelial cell (IEC)-specific OGT deletion mice, and observed IBD-like symptoms progressively, including weight loss, rectal prolapse, and bleeding. The early-onset spontaneous intestinal damages observed in these IECΔOGT mice suggested that protein O-GlcNAcylation is a regulator of multiple homeostatic modules in the epithelium. We demonstrated that O-GlcNAc deficiency results in disruptive epithelial barrier, Paneth cell dysfunction, and microbial dysbiosis. Only inducing OGT deficiency in Paneth cells or transplanting fecal microbiota from IECΔOGT mice did not sufficiently cause intestinal inflammation, supporting the multi-hit model of IBD. Nevertheless, microbial dysbiosis and Paneth cell dysfunction together potentiated chemical-induced gut inflammation. Mechanistically, we identified STAT 53Gut microbiota-sensitive O-GlcNAc signaling protects intestinal inflammationHai-Bin RuanUniversity of Minnesota
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