Role of intestinal epithelial AMPK in the protective effect of metformin on dextran sodium sulfate‐induced colitis in mice

Abstract

Background Dysfunctions in the intestinal barrier, associated with an altered paracellular pathway, are commonly observed in gastrointestinal disorders, such as inflammatory bowel disease (IBD). The AMP-activated protein kinase (AMPK), principally known as a cellular energy sensor, has also been shown to play a key role in the stabilization and assembly of tight junctions following injury. Here, we aimed to investigate the effect of metformin in strengthening intestinal barrier function by activating intestinal epithelial AMPK. Methods A dextran sodium sulfate (DSS)-induced colitis model was used to assess disease progression in WT and intestinal epithelial cell-specific AMPK KO (IEC AMPK KO) mice in response to metformin treatment. Barrier integrity was analyzed by measuring paracellular permeability following dextran-4kDa gavage and, pro-inflammatory cytokines and tight junctions expression. Results The deletion of intestinal epithelial AMPK delayed intestinal injury repair after DSS-induced colitis and was associated with a slower re-epithelization of the intestinal mucosa coupled to a reduction in tight junctions expression and a higher paracellular permeability, inflammation and histological defects. Metformin administration attenuated the severity of DSS-induced colitis with improvement in intestinal permeability and inflammation in control mice but only partially in IEC AMPK KO mice. Conclusions Taken together these findings suggest that IEC AMPK contributes to intestinal healing and epithelial integrity after injury and may be effective as a therapeutic target to ameliorate dysfunctions of the intestinal barrier.