Zhu Yuhua, Wang Wei, Yuan Taolin, Fu Liangliang, Zhou Lian, Lin Gang, Zhao Shuhong, Zhou Huaijun, Wu Guoyao, Wang Junjun
State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China, Agricultural University, Beijing, China.
Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction, Huazhong Agricultural University, Wuhan, Hubei, China.
Am J Physiol Gastrointest Liver Physiol. 2017 May 1;312(5):G434-G442. doi: 10.1152/ajpgi.00020.2017. Epub 2017 Mar 9.
An important characteristic of intrauterine growth restricted (IUGR) neonate is the impaired intestinal barrier function. With the use of a pig model, this study was conducted to identify the responsible microRNA (miRNA) for the intestinal damage in IUGR neonates through comparing the miRNA profile of IUGR and normal porcine neonates and to investigate the regulation mechanism. Compared with the normal ones, we identified 83 upregulated and 76 downregulated miRNAs in the jejunum of IUGR pigs. Notably, IUGR is associated with profoundly increasesd miR-29 family and decreased expression of extracellular matrix (ECM) and tight junction (TJ) proteins in the jejunum. Furthermore, in vitro study using theporcine intestinal epithelial cell line (IPEC-1) showed that inhibition of miR-29a expression could improve the monolayer integrity by increasing cell proliferation and transepithelial resistance. Also, overexpression/inhibition of miR-29a in IPEC-1 cells can suppress/increase the expression of integrin-β1, collagen I, collagen IV, fibronectin, and claudin 1, both at transcriptional and translational levels. Subsequent luciferase reporter assay confirmed a direct interaction between miR-29a and the 3'-untranslated regions of these genes. In conclusion, this study reveals that IUGR-impaired intestinal barrier function is associated with downregulated ECM and TJ protein expression mediated by the upregulation of miR-29a. Intrauterine growth restricted (IUGR) remains a major problem for both human health and animal production due to its association with high rates of preweaning morbidity and mortality. We have identified the abnormal expression of microRNA-29a (miR-29a) in the small intestine of IUGR neonates, as well as its targets and mechanisms. These results provide new information about biological characteristics of IUGR-affected intestinal dysfunction and can lead to the development of potentially solution for preventing and treating IUGR in the future.
宫内生长受限（IUGR）新生儿的一个重要特征是肠道屏障功能受损。本研究利用猪模型，通过比较IUGR和正常猪新生儿的微小RNA（miRNA）谱，确定导致IUGR新生儿肠道损伤的相关miRNA，并研究其调控机制。与正常猪相比，我们在IUGR猪的空肠中鉴定出83个上调和76个下调的miRNA。值得注意的是，IUGR与空肠中miR-29家族显著增加以及细胞外基质（ECM）和紧密连接（TJ）蛋白表达降低有关。此外，使用猪肠上皮细胞系（IPEC-1）进行的体外研究表明，抑制miR-29a表达可通过增加细胞增殖和跨上皮电阻来改善单层完整性。同样，在IPEC-1细胞中过表达/抑制miR-29a可在转录和翻译水平上抑制/增加整合素-β1、胶原蛋白I、胶原蛋白IV、纤连蛋白和闭合蛋白1的表达。随后的荧光素酶报告基因检测证实了miR-29a与这些基因的3'-非翻译区之间存在直接相互作用。总之，本研究表明，IUGR受损的肠道屏障功能与miR-29a上调介导的ECM和TJ蛋白表达下调有关。由于宫内生长受限（IUGR）与断奶前的高发病率和死亡率相关，它仍然是人类健康和动物生产中的一个主要问题。我们已经确定了IUGR新生儿小肠中微小RNA-29a（miR-29a）的异常表达及其靶点和机制。这些结果为IUGR相关肠道功能障碍的生物学特征提供了新信息，并可能为未来预防和治疗IUGR带来潜在的解决方案。
