The Role And Mechanism Of Inhibition Of Histone Histone Deacetylation By MS-275 Alleviates Ulcerative Colits

Background and aims:Ulcerative colitis(UC)is a common chronic inflammatory bowel disease without curative treatment.Methods:We first conducted gene set enrichment analysis to explore potential therapeutic agent for UC.Human colon tissue samples were collected to test H3 acetylation in UC.Both in vivo and in vitro colitis models were constructed to verify the role and mechanism of H3 acetylation modification in UC.Intestine-specific vitamin D receptor(VDR)-/-mice and VD-deficient diet-fed mice were used to explore downstream molecular mechanism accordingly.Results:According to the Connectivity Map database,MS-275(class I histone deacetylase inhibitor)was the top-ranked agent,indicating potential importance of histone acetylation in UC.We then found that histone H3 acetylation was significantly decreased in the colon epithelium of UC patients and negatively associated with disease severity.MS-275 treatment inhibited histone H3 deacetylation,and subsequently attenuated NF-KB-induced inflammation,reduced cellular apoptosis,maintained epithelial barrier function,and thereby reduced colitis activity in a mouse model of colitis.We also identified vitamin D receptor(VDR)to be a downstream effector of MS-275.The curative effect of MS-275 on colitis was abolished in intestine-specific VDR-/-mice and in VD-deficient diet-fed mice and VDR directly targeted p65.In UC patients,histone H3 acetylation,VDR and ZO-1 expression showed similar downregulation patterns and were negatively associated with disease severity.Conclusion:We demonstrate that MS-275 inhibits histone deacetylation and alleviates colitis by ameliorating inflammation,reducing apoptosis and maintaining intestinal epithelial barrier via VDR,providing new strategies for colitis treatment.