Background: Aberrant expression of miRNAs was a critical element in the pathogenesis of inflammatory bowel disease (IBD). This study aimed to explore the involvement and mechanism of miR-126 in IBD. Methods: In this study, the endogenous expressions of miR-126, S1PR2 and SIP in the pathological tissues of patients with IBD were detected using qRT-PCR and western blot assay, respectively. The luciferase reporter gene assay was performed to confirm the targeting regulatory relation between mi-126 and S1PR2. The transendothelial electrical resistance assay was used to measured the value of TEER. Results: The expressions of miR-126, S1PR2 and S1P in the pathological tissues of IBD patients were significantly higher than that of the control group. Moreover, miR-126 overexpression contributed to intestinal mucosal barrier dysfunction in vitro. S1PR2 was a direct target of miR-126, and S1PR2 expression was negatively regulated by miR-126 in Caco-2 cells. However, S1PR2 activated by SIP had the protection effect for the integrity and permeability of intestinal mucosal barrier via a PI3K/Akt dependent mechanism. MiR-126 silencing possessed obvious protective effects on the intestinal barrier function, but these effects could be reversed by JTE-013 or LY294002. Conclusion: MiR-126 down-regulated S1PR2 and then prevented the activation of PI3K/AKT signaling pathway, which ultimately could damage intestinal mucosal barrier function. (c) 2017 Published by Elsevier Inc.