Abstract

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-κB 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.

Highlights

  • The involvement of miRNAs in the host mucosal immune response to gut microbes in colitis is still unclear

  • We observed an inverse correlation between PepT1 and miR-193a-3p in inflamed colon tissues with active ulcerative colitis, and we further demonstrated that miR193a-3p reduced PepT1 expression and activity as a target gene and subsequently suppressed the NF-␬B pathway

  • Based on our previous studies [15, 16, 19, 20] and the present understanding of miRNA expression in ulcerative colitis (UC), we investigated whether a suite of inflammation-relevant miRNAs are differentially expressed in UC compared with normal controls by Quantitative RT-PCR (qRT-PCR)

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Summary

Background

The involvement of miRNAs in the host mucosal immune response to gut microbes in colitis is still unclear. In UC, the mucosal inflammation is limited to the colon beginning from the rectum, whereas in CD, inflammation primarily affects the ileum but may occur at random locations in the GI tract, extending through the bowel wall [1] Both diseases are thought to feature alterations in the immune response to environmental and GI microbiota in individuals genetically predisposed to IBD, which is characterized by a disruption in the intestinal epithelial barrier and an influx of immune cells [2]. In this study we identified the differential expression of miRNAs in inflamed colon tissues from active IBD patients Among those miRNAs, miR-193a-3p is down-regulated, leading to the elevated expression and activity of colonic PepT1 and triggering the bacterial peptide-induced inflammatory response. Restoration of miR-193a-3p significantly decreased the intestinal inflammation in vivo using murine models of colitis

Experimental Procedures
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