MicroRNA-193a-3p Reduces Intestinal Inflammation in Response to Microbiota via Down-regulation of Colonic PepT1
MicroRNA-193a-3p Reduces Intestinal Inflammation in Response to Microbiota via Down-regulation of Colonic PepT1
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DOI：
10.1074/jbc.m115.659318
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发表时间：
2015-06-26
影响因子：
4.8
通讯作者：
Xia, Lu
中科院分区：
文献类型：
--
作者：
Dai, Xin;Chen, Xi;Xia, Lu
背景：在结肠炎中，miRNAs参与宿主对肠道微生物的粘膜免疫应答仍不清楚。结果：miR-193 a-3 p下调PepT 1，并且结肠内递送miR-193 a-3 p改善结肠炎的严重程度。结论：miRNA-193 a-3 p可靶向结肠PepT 1，减轻肠道炎症反应。重要性：我们的研究阐明了miRNAs在结肠炎期间调节宿主对微生物的免疫应答中的新作用。肠道炎症的特征是上皮破坏，导致屏障功能丧失，免疫细胞募集和宿主对肠道微生物群的免疫应答。PepT 1是一种摄取细菌产物的二/三肽转运蛋白，在发炎的结肠组织中上调，这意味着它在细菌相关的肠道炎症中的作用。虽然microRNA（miRNA）介导的基因调控已被发现参与炎症性肠病（IBD）的多种过程，但miRNAs在IBD发病机制中的生物学功能仍有待进一步研究。在本研究中，我们检测了结肠炎时结肠组织中miRNA的表达模式，并研究了miRNA对结肠PepT 1的调控机制。我们观察到PepT 1和miR-193 a-3 p在活动性溃疡性结肠炎的炎症结肠组织中呈负相关，我们进一步证明miR-193 a-3 p降低了PepT 1作为靶基因的表达和活性，随后抑制了NF-B通路。结肠内递送miR-193 a-3 p显著改善葡聚糖硫酸钠诱导的结肠炎，而通过PepT 1 3-非翻译区突变慢病毒载体过表达结肠PepT 1则消除了miR-193 a-3 p的抗炎作用。此外，抗生素治疗消除了存在和不存在miR-193 a-3 p之间葡聚糖硫酸钠诱导的炎症的差异。这些发现表明，miR-193 a-3 p调节PepT 1介导细菌产物的摄取，并且是结肠炎症过程中的有效机制。总之，我们认为miR-193 a-3 p可能是结肠PepT 1维持肠道稳态的有效调节剂。
Background: The involvement of miRNAs in the host mucosal immune response to gut microbes in colitis is still unclear. Results: miR-193a-3p down-regulates PepT1, and intracolonic-delivery of miR-193a-3p ameliorated the severity of colitis. Conclusion: miRNA-193a-3p can target colonic PepT1 and reduce intestinal inflammation. Significance: Our study illustrates the new role of miRNAs in regulating the host immune response to microbes during colitis.Intestinal inflammation is characterized by epithelial disruption, leading to the loss of barrier function, recruitment of immune cells, and host immune responses to gut microbiota. PepT1, a di/tripeptide transporter that uptakes bacterial products, is up-regulated in inflamed colon tissue, which implies its role in bacterium-associated intestinal inflammation. Although microRNA (miRNA)-mediated gene regulation has been found to be involved in various processes of inflammatory bowel disease (IBD), the biological function of miRNAs in the pathogenesis of IBD remains to be explored. In this study we detected miRNA expression patterns in colon tissues during colitis and investigated the mechanism underlying the regulation of colonic PepT1 by miRNAs. We observed an inverse correlation between PepT1 and miR-193a-3p in inflamed colon tissues with active ulcerative colitis, and we further demonstrated that miR-193a-3p reduced PepT1 expression and activity as a target gene and subsequently suppressed the NF-B pathway. Intracolonic delivery of miR-193a-3p significantly ameliorated dextran sodium sulfate-induced colitis, whereas the overexpression of colonic PepT1 via PepT1 3-untranslated region mutant lentivirus vector abolished the anti-inflammatory effect of miR-193a-3p. Furthermore, antibiotic treatment eliminated the difference in the dextran sodium sulfate-induced inflammation between the presence and absence of miR-193a-3p. These findings suggest that miR-193a-3p regulation of PepT1 mediates the uptake of bacterial products and is a potent mechanism during the colonic inflammation process. Overall, we believe miR-193a-3p may be a potent regulator of colonic PepT1 for maintaining intestinal homeostasis.