Future perspectiveThe gastrointestinal (GI) tract is an organ system not only absorbing nutrients from food, but also secreting a large body of endocrine hormones, and possessing a rich defensive arsenal of immune cells. Inability of the GI tract in adapting to environmental changes leads to diseases such as obesity, malabsorption, autoimmune, and inflammation. We aim to characterize how O-GlcNAc signaling in the gut relays signals from food, microbiota and parasites to regulate body weight, glucose metabolism, and immune responses. For examples, we have shown that optimal O-GlcNAc signaling is required for the control of enteroendocrine lineage development and function4) and type 2 immune responses to helminth infections5).Figure 2. A multi-hit model of O-GlcNAc in IBD pathogenesis Modified from Maloy and Powrie, 2011. “X” indicates a hit, while “O” indicates a non-hit. ND, not determined in this study.Gut microbiota-sensitive O-GlcNAc signaling protects intestinal inflammationHai-Bin Ruanproteins, particularly STAT1, as a downstream target of protein O-GlcNAcylation and mediator of intestinal damage in IECΔOGT mice.To determine whether pharmacologically elevated protein O-GlcNAcylation strengthens barrier function and protects mice from chemical-induced acute colitis, we administered an O-GlcNAcase inhibitor to increase O-GlcNAc levels in mice and found that treated animals showed improved intestinal integrity, lower expression of inflammatory cytokines, and alleviated colitis overall. In summary, our research established that O-GlcNAc signaling controls multiple regulatory mechanisms including epithelial junction, Paneth cell autophagy, and gut microbiota to maintain overlapping layers of intestinal homeostasis3). Our study helps determine the etiology of IBD and informs the development of new treatments.References1) N. Kamada, S. U. Seo, G. Y. Chen and G. Nunez: Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol, 13(5), 321-35 (2013) doi:10.1038/nri34302) X. Yang and K. Qian: Protein O-GlcNAcylation: emerging mechanisms and functions. Nat Rev Mol Cell Biol, 18(7), 452-465 (2017) doi:10.1038/nrm.2017.223) M. Zhao, X. Xiong, K. Ren, B. Xu, M. Cheng, C. Sahu, K. Wu, Y. Nie, Z. Huang, R. S. Blumberg, X. Han and H. B. Ruan: Deficiency in intestinal epithelial O-GlcNAcylation predisposes to gut inflammation. EMBO Mol Med, 10(8) (2018) doi:10.15252/emmm.2017087364) M. Zhao, K. Ren, X. Xiong, M. Cheng, Z. Zhang, Z. Huang, X. Han, X. Yang, E. U. Alejandro and H. B. Ruan: Protein O-GlcNAc Modification Links Dietary and Gut Microbial Cues to the Differentiation of Enteroendocrine L Cells. Cell Rep, 32(6), 108013 (2020) doi:10.1016/j.celrep.2020.1080135) M. Zhao, K. Ren, X. Xiong, Y. Xin, Y. Zou, J. C. Maynard, A. Kim, A. P. Battist, N. Koneripalli, Y. Wang, Q. Chen, R. Xin, C. Yang, R. Huang, J. Yu, Z. Huang, Z. Zhang, H. Wang, D. Wang, Y. Xiao, O. C. Salgado, N. N. Jarjour, K. A. Hogquist, X. S. Revelo, A. L. Burlingame, X. Gao, J. von Moltke, Z. Lin and H. B. Ruan: Epithelial STAT6 O-GlcNAcylation drives a concerted anti-helminth alarmin response dependent on tuft cell hyperplasia and Gasdermin C. Immunity, 55(4), 623-638 e5 (2022) doi:10.1016/j.immuni.2022.03.00954
元のページ ../index.html#54