Deregulation of small intestine permeability by miRNA-21 in liver disease

Abstract

The gut-liver axis influences a wide variety of liver diseases. High fat, choline-deficient (HFCD) diet and common bile duct ligation (BDL) are experimental models of liver disease associated with early increased small intestinal permeability (SIP), disturbed bile acid homeostasis and gut microbiota (GM) dysbiosis. Here we investigate the impact of whole body genetic deletion or therapeutic modulation of miR-21 in SIP as well as in the GM, which may influence miR-21 effects in the liver. We have previously demonstrated that miR -21 contributes to BDL-induced liver injury and fibrosis. Here we reveal that occludin and claudin-1 mRNA levels were decreased in small intestine of WT mice after BDL, suggesting increased SIP. Moreover, zonula occludens (ZO-1) and occludin mRNA levels were also decreased in HFCD-fed mice. Strikingly, both genetic deletion of miR-21 and Anti-miR-21 treatment reverted mRNA levels of tight junction proteins to control. Moreover, the GM of WT mice became dysbiotic, with decreased Bacteroidetes and increased Proteobacteria and Firmicutes. In miR-21 KO mice, the GM was not affected by BDL surgery. Our results suggest miR-21 involvement in liver injury by impacting on liver and intestinal targets.