SATB2 Defect Promotes Colitis and Colitis-associated Colorectal Cancer by Impairing Cl-/HCO3- Exchange and Homeostasis of Gut Microbiota
SATB2 Defect Promotes Colitis and Colitis-associated Colorectal Cancer by Impairing Cl-/HCO3- Exchange and Homeostasis of Gut Microbiota
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DOI：
10.1093/ecco-jcc/jjab094
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发表时间：
2021-05-21
影响因子：
8
通讯作者：
Li, Jianming
中科院分区：
文献类型：
--
作者：
Ni, Hengli;Chen, Yongyu;Li, Jianming
背景资料：SATB 2是一种诊断性生物标志物和结直肠癌[CRC]的有利预后标志物，但其在结肠炎和结肠炎相关的结直肠癌[CAC]中的作用是未知的。方法：使用葡聚糖硫酸钠[DSS]在肠上皮特异性Satb 2敲除[Satb 2 IEC-KO]和对照小鼠中诱导结肠炎。对来自Satb 2 IEC-KO和对照小鼠的结肠组织进行RNA-seq分析，并对粪便细菌DNA进行16 S rDNA-Seq分析。免疫组化和流式细胞术显示不同免疫细胞的比例。染色质免疫沉淀（ChIP）和荧光素酶报告基因检测SATB 2对SLC 26 A3的调控作用，并采用pH敏感染料荧光法检测SLC 26 A3的Cl-/HCO 3-交换活性。结果：Satb 2 IEC-KO小鼠自发性肠上皮损伤，结肠炎和CAC发生率明显增高。SLC 26 A3的表达与RNA-seq和癌症基因组图谱[TCGA]数据显示的SATB 2相关性良好，并且由ChIP和荧光素酶报告基因实验证实的SATB 2控制。在Satb 2 IEC-KO小鼠中观察到肠道植物群多样性降低。类杆菌在Satb 2 IEC-KO小鼠结肠黏膜中数量较多，并能定植于结肠黏膜内层。结论：SATB 2在维持肠道内环境稳定中起重要作用，其缺乏通过影响肠道内环境和肠道植物群促进结肠炎和CAC的发生。
Background: SATB2 is a diagnostic biomarker and a favourable prognostic marker for colorectal cancer [CRC], but its role in colitis and colitis-associated colorectal cancer [CAC] is unknown.Methods: Colitis was induced in intestinal epithelial-specific Satb2 knockout [Satb2 IEC-KO] and control mice using dextran sulphate sodium [DSS]. RNA-seq analysis was performed on colonic tissues, and 16S rDNA-Seq on faecal bacterial DNA from Satb2 IEC-KO and control mice. Immunohistochemistry and flow cytometry were performed to reveal the proportions of different immune cells. Chromatin immunoprecipitation [ChIP] and luciferase reporter were applied to show the regulatory role of SATB2 on SLC26A3, of which the Cl-/HCO3- exchange activity was measured fluorometrically by the pHi-sensitive dye. Bacteroides were detected by fluorescence in situ hybridisation [FISH] on colonic tissue.Results: Satb2 IEC-KO mice suffered from intestinal epithelial damage spontaneously, and developed more severe colitis and CAC. The expression of SLC26A3 correlated well with SATB2 revealed by RNA-seq and The Cancer Genome Atlas [TCGA] data, and was governed by SATB2 confirmed by ChIP and luciferase reporter experiments. Decreased intestinal flora diversity was seen in Satb2 IEC-KO mice. Bacteroides were more abundant and could colonise into the inner layer of colonic mucosa in Satb2 IEC-KO mice. Faecal microbiome transplantation from Satb2 IEC-KO mice aggravated colitis and M1 macrophages infiltration.Conclusions: SATB2 plays a vital role in maintaining intestinal homeostasis, and its deficiency promotes the development of colitis and CAC by influencing the intestinal luminal environment and gut flora.