6-Shogaol alleviates high-fat diet-induced intestinal tight junction impairment in mice via miR-215-3p_R+1/occludin axis

Accumulating evidence has shown that high-fat diet (HFD) can lead to intestinal epithelial barrier dysfunction. We previously found that 6-shogaol was able to attenuate palmitic acid (PA)-induced intestinal barrier damages in human intestinal epithelial Caco-2 cells through regulation of tight junctions (TJs). However, the in vivo protective effects and action mechanism of 6-shogaol against HFD-induced intestinal barrier dysfunction remains unexplored. In this study, HFD-fed C57BL/6J mice were used as the intestinal barrier dysfunction model to investigate the protective effects of 6-shogaol. The results showed that the 6-shogaol significantly (P < 0.05) suppressed HFD-stimulated increase of serum fluorescein isothiocyanate (FITC)-dextran level and proinflammatory cytokines (interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha (TNF-α)) in the ileum, whilst significantly (P < 0.05) increased the expression of TJ-associated proteins (e.g., Zona occludens 1, occludin, and claudin-1). Furthermore, miR-sequencing and qRT-PCR analysis revealed that miR-215-3p_R+1 was one of the highest expressed miRNAs in the ileum in response to the 6-shogaol treatment. MiR-215-3p_R+1 overexpression significantly (P < 0.01) downregulated occludin expression in PA-treated Caco-2 cells compared with the mimics NC+PA+6-shogaol group, partially compromising the protective effects 6-shogoal against intestinal epithelial barrier dysfunction. Taken together, these findings provide the evidence for the first time that 6-shogaol has the potential to treat HFD-induced TJs impairment via the miR-215-3p_R+1/occludin axis.