BACKGROUND Gankyrin (GK) is an oncoprotein which regulates inflammatory responses and its inhibition is considered as a possible anti-inflammatory therapy for inflammatory bowel disease (IBD). METHODS In this study, we investigated the role of GK in epithelial cells using mice with intestinal epithelial cell-specific GK deletion in (i) the entire small intestine and colon (Villin-Cre;Gankyrinf/f) and (ii) the distal intestine and colon (Cdx2-Cre;Gankyrinf/f). RESULT Unexpectedly, GK-deficiency in the upper small bowel augmented inflammatory activity compared with control mice when colitis was induced with dextran sodium sulfate. Biochemical analyses have revealed GK-deficiency to have caused reduction in the expression of antimicrobial peptides, α-Defensin-5 and -6, in the upper small bowel. Examination of human samples have further confirmed that the reduction of GK expression in the small bowel is associated with colonic involvement in human Crohn's disease. Through the sequencing of bacterial 16S rRNA gene amplicons, bacteria potentially deleterious to intestinal homeostasis such as Helicobacter japonicum and Bilophila were found to be over-represented in colitis induced Villin-Cre;Gankyrinf/f mice when compared to Gankyrinf/f control mice under the same condition. CONCLUSION These results highlight the distinct site dependence of the pro- and anti-inflammatory functions of GK and provide important insights into the pathogenesis of IBD.

中文翻译：

---

小肠中gankyrin的缺乏与结肠炎加重相关，并伴有肠道菌群细菌组成的改变。

背景技术gankyrin（GK）是一种调节炎症反应的癌蛋白，其抑制作用被认为是炎症性肠病（IBD）的一种可能的抗炎疗法。方法在这项研究中，我们使用（i）小肠和结肠（Villin-Cre; Gankyrinf / f）和（ii）远端小肠中具有肠上皮细胞特异性GK缺失的小鼠，研究了GK在上皮细胞中的作用。和结肠（Cdx2-Cre; Gankyrinf / f）。结果出乎意料的是，当右旋糖酐硫酸钠诱发结肠炎时，与对照小鼠相比，小肠上部的GK缺乏增强了炎症活动。生化分析表明，GK缺乏症导致上部小肠中抗菌肽α-防御素5和-6的表达降低。对人体样品的检查进一步证实，小肠中GK表达的降低与结肠克罗恩病的侵袭有关。通过对细菌16S rRNA基因扩增子进行测序，发现结肠炎诱导的Villin-Cre; Gankyrinf / f小鼠与在以下条件下的Gankyrinf / f对照小鼠相比，在肠道内稳态中可能有害的细菌（例如日本Helicobacter japonicum和Bilophila）过量表达。同样的条件。结论这些结果突出了GK的促炎和抗炎功能的独特部位依赖性，并为IBD的发病机理提供了重要的见识。与相同条件下的Gankyrinf / f对照小鼠相比，在结肠炎诱导的Villin-Cre; Gankyrinf / f小鼠中发现了对肠道稳态可能有害的细菌，例如日本Helicobacter japonicum和Bilophila过量存在。结论这些结果突出了GK的促炎和抗炎功能的独特部位依赖性，并为IBD的发病机理提供了重要的见识。与相同条件下的Gankyrinf / f对照小鼠相比，在结肠炎诱导的Villin-Cre; Gankyrinf / f小鼠中发现了对肠道稳态可能有害的细菌，例如日本Helicobacter japonicum和Bilophila过量存在。结论这些结果突出了GK的促炎和抗炎功能的独特部位依赖性，并为IBD的发病机理提供了重要的见识。