PDF(Pubmed)
Abstract：
Dysregulation of gut homeostasis is associated with irritable bowel syndrome (IBS), a chronic functional gastrointestinal disorder affecting approximately 11.2% of the global population. The poorly understood pathogenesis of IBS has impeded its treatment. Here, we report that the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) is weakly expressed in IBS but highly expressed in inflammatory bowel disease (IBD), a frequent chronic organic gastrointestinal disorder. Accordingly, knockout of Trim27 in mice causes spontaneously occurring IBS-like symptoms, including increased visceral hyperalgesia and abnormal stool features, as observed in IBS patients. Mechanistically, TRIM27 stabilizes β-catenin and thus activates Wnt/β-catenin signaling to promote intestinal stem cell (ISC) self-renewal. Consistent with these findings, Trim27 deficiency disrupts organoid formation, which is rescued by reintroducing TRIM27 or β-catenin. Furthermore, Wnt/β-catenin signaling activator treatment ameliorates IBS symptoms by promoting ISC self-renewal. Taken together, these data indicate that TRIM27 is critical for maintaining gut homeostasis, suggesting that targeting the TRIM27/Wnt/β-catenin axis could be a potential treatment strategy for IBS. Our study also indicates that TRIM27 might serve as a potential biomarker for differentiating IBS from IBD.
摘要：
肠道稳态失调与肠易激综合征（IBS）有关，影响全球约11.2%人口的慢性功能性胃肠病。对IBS的发病机制知之甚少阻碍了其治疗。这里,我们报道，E3泛素连接酶三部分基序27（TRIM27）在IBS中弱表达，但在炎症性肠病（IBD）中高表达，一种常见的慢性器质性胃肠病。因此，敲除小鼠Trim27会导致自发发生的IBS样症状，包括内脏痛觉过敏增加和大便异常特征，在IBS患者中观察到。机械上,TRIM27稳定β-连环蛋白并因此激活Wnt/β-连环蛋白信号传导以促进肠干细胞(ISC)自我更新。与这些发现一致，Trim27缺乏会破坏类器官的形成，通过重新引入TRIM27或β-catenin来挽救。此外，Wnt/β-连环蛋白信号转导激活剂治疗通过促进ISC自我更新改善IBS症状。一起来看,这些数据表明TRIM27对于维持肠道稳态至关重要，提示靶向TRIM27/Wnt/β-catenin轴可能是IBS的潜在治疗策略。我们的研究还表明，TRIM27可能是区分IBS和IBD的潜在生物标志物。
