Department of Gastroenterology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Department of Gastroenterology, Ningbo First Hospital, Ningbo, China.
J Crohns Colitis. 2020 Sep 7;14(8):1103-1118. doi: 10.1093/ecco-jcc/jjaa016.
Ulcerative colitis [UC] is a common chronic inflammatory bowel disease without curative treatment.
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.
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 downregulation patterns and were negatively associated with disease severity.
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 UC treatment.
溃疡性结肠炎（UC）是一种常见的慢性炎症性肠病，目前尚无治愈方法。
我们进行了基因集富集分析，以探索治疗 UC 的潜在治疗药物。收集人结肠组织样本以检测 UC 中的 H3 乙酰化。构建体内和体外结肠炎模型以验证 H3 乙酰化修饰在 UC 中的作用和机制。使用肠道特异性维生素 D 受体（VDR）缺失小鼠和维生素 D 缺乏饮食喂养小鼠来相应地探索下游分子机制。
根据 Connectivity Map 数据库，MS-275（I 类组蛋白去乙酰化酶抑制剂）是排名最高的药物，表明组蛋白乙酰化在 UC 的发病机制中具有潜在的重要性。我们发现 UC 患者结肠上皮中的组蛋白 H3 乙酰化明显降低，且与疾病严重程度呈负相关。MS-275 治疗抑制组蛋白 H3 去乙酰化，从而减弱核因子 kappa B（NF-κB）诱导的炎症，减少细胞凋亡，维持上皮屏障功能，从而减轻结肠炎模型中的结肠炎活动。我们还确定 VDR 是 MS-275 的下游效应因子。在 VDR 缺失小鼠和维生素 D 缺乏饮食喂养小鼠中，MS-275 对结肠炎的疗效被消除，并且 VDR 直接靶向 p65。在 UC 患者中，组蛋白 H3 乙酰化、VDR 和紧密连接蛋白-1 的表达呈相似的下调模式，且与疾病严重程度呈负相关。
我们证明 MS-275 通过改善炎症、减少凋亡和维持肠道上皮屏障来抑制组蛋白去乙酰化并缓解结肠炎，为 UC 治疗提供了新的策略。
