Activating AMPK to Restore Tight Junction Assembly in Intestinal Epithelium and to Attenuate Experimental Colitis by Metformin

Abstract

Adenosine monophosphate-activated protein kinase (AMPK), a crucial molecule in energy metabolism, is reported to play a potential role in gut epithelial differentiation and barrier function recently; however, its performance and mechanisms in the pathological process of inflammatory bowel diseases remain unidentified. In this study, we have found that the phosphorylation of AMPK in colonic tissues is negatively correlated with severity of disease during the initiation and development of experimental colitis induced by dextran sulfate sodium. Activation of AMPK by metformin significantly controls the progression of colitis, which is associated with the maintenance of tight junction in colonic epithelium in mice. Moreover, our in vitro data in colonic epithelial Caco2 cells shows that metformin promotes expression and assembly of tight junctions via an AMPK-dependent way. Overall, our results suggested that activating AMPK by a clinically safe drug metformin could be a beneficial choice for colitis treatment.

l-Arginine alleviates heat stress-induced intestinal epithelial barrier damage by promoting expression of tight junction proteins via the AMPK pathway

“…AMPK is a key factor in the regulation of tight junctions [21,24,42]. These effects have been implicated in some previous studies indicating that AMPK promotes ZO-1 assembly in MDCK cells [44].…”

“…AMPK phosphorylation is reported to be involved in tight junction assembly and cell polarization [21]. Activation of AMPK by metformin maintains TJs in the colonic epithelium of mice and significantly controls the progression of colitis [24]. AMPK activation promotes TJs assembly in Caco-3 cells by enhancing ZO-1 and occludin expression [25].…”

“…Accumulating studies have shown that activation of AMPK by pharmacological or nutraceutical approaches strengthens the epithelial barrier function [21,24,38]. AICAR treatment enhances the barrier function in Caco-2 cells [42].…”

Intestinal enteroids/organoids: A novel platform for drug discovery in inflammatory bowel diseases

“…Celiac disease shares some common immune pathogenesis with IBD, including a dysregulated intestinal epithelial permeability[116], which suggests that AT-1001 might be considered as a novel IBD drug. Moreover, several existing drugs (vitamin D, estradiol, and metformin) also have shown to reduce epithelial permeability and to alleviate mucosal inflammation in IBD mouse models[117-119].…”

Potent Inhibitory Effect of BJ-3105, a 6-Alkoxypyridin-3-ol Derivative, on Murine Colitis Is Mediated by Activating AMPK and Inhibiting NOX

“…AMPK also suppresses NADPH oxidase (NOX) activation [17] and inhibits redox-sensitive nuclear factor kappa B (NF-κB) [18][19][20], and thus inhibits the induction of NF-κB target genes, including TNF-α and IL-6 [21][22][23]. On the other hand, AMPK is inactivated by oxidative stress [24,25], and in line with the inverse relationship between AMPK and NOX, AMPK activation or NOX inhibition ameliorates dextran sulfate sodium (DSS)-induced colitis [26,27]. Thus, it appears a compound that activates AMPK and simultaneously inhibits NOX might be a promising therapeutic candidate for IBD.…”