Inhibition of Histone Deacetylation by MS-275 Alleviates Colitis by Activating the Vitamin D Receptor

作者：Chunxiao Li, Yi Chen, Hua-Tuo Zhu, Xiuming Zhang, Lu Han, Zuodong Zhao, Jinghua Wang, Longgui Ning, Weihua Zhou, Chao Lü, Lei Xu, Jianzhong Sang, Zemin Feng, Yuwei Zhang, Xinhe Lou, Xiaochen Bo, Bing Zhu, Chaohui Yu, Min Zheng, Youming Li, Jing Ping Sun, Zhe Shen · 发表于：Journal of Crohn s and Colitis · 年份：2020 · DOI：10.1093/ecco-jcc/jjaa016 · 被引用次数：35 · 研究领域：Vitamin D Research Studies、Inflammatory Bowel Disease、Gut microbiota and health

BACKGROUND: Ulcerative colitis [UC] is a common chronic inflammatory bowel disease without curative treatment. METHODS: We conducted gene set enrichment analysis to explore potential therapeutic agents 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 [vitamin D]-deficient diet-fed mice were used to explore downstream molecular mechanisms accordingly. RESULTS: According to the Connectivity Map database, MS-275 [class I histone deacetylase inhibitor] was the top-ranked agent, indicating the potential importance of histone acetylation in the pathogenesis of UC. We then found that histone H3 acetylation was significantly lower in the colon epithelium of UC patients and negatively associated with disease severity. MS-275 treatment inhibited histone H3 deacetylation, subsequently attenuating nuclear factor kappa B [NF-κB]-induced inflammation, reducing cellular apoptosis, maintaining epithelial barrier function, and thereby reducing colitis activity in a mouse model of colitis. We also identified VDR as be a downstream effector of MS-275. The curative effect of MS-275 on colitis was abolished in VDR-/- mice and in VD-deficient diet-fed mice and VDR directly targeted p65. In UC patients, histone H3 acetylation, VDR and zonulin-1 expression showed similar downregulatio...