Reactivation Of Adenosine 5’-monophosphate-activated Protein Kinase Suppresses Inflammatory Bowel Disease And Maintains Epithelial Tight Junction In The Mice Colons

Inflammatory bowel diseases(IBD),which consist of Crohn’s disease and ulcerative colitis,are characterized with weight loss,diarrhea accompanied by blood,and abdominal pain.IBD not only causes a substantial worsening of patients’ life quality,but also greatly increases the risk of colorectal cancer.Therefore,clarification of the molecular targets in the development of IBD is of great significance for the safe and effective therapy of IBD.In the present study,it was found that the phosphorylation of Adenosine 5’-monophosphate-activated protein kinase(AMPK)gradually decreased in colonic tissues after mice dextransulfatesodium(DSS)and suffered ulcerative colitis.The decrease in phosphorylated AMPK was positively correlated with the damage degree of colonic tissue.Alternatively,administration of metformin,a clinically used AMPK agonist,remarkably increased phosphorylated AMPK in colonic tissue and ameliorated colitis in mice.Metformin reversed the mice weight loss,diarrhea,bloody stool,colon pathological score,and notably restrained the mRNA level of inflammatory factors,including interleukin(IL)-18,IL-1β,IL-6,Cyclooxygenase-2 and inducible nitric oxide synthase in colons.Furthermore,the therapeutic effect of metformin in colitis was closely related to its efficacy to maintain the epithelial tight junction in mice colons.After inflammatory injury,the permeability of colonic epithelium increased with decreased expression of epithelial tight junction proteins Claudin-1,Occludin and Zonula Occludens-1(ZO-1).Metformin could significantly reverse these pathological changes.In the in vitro Caco-2 cell model,metformin promoted the phosphorylation of AMPK,which caused the phosphorylation of Connexin43(Cx43)at serine 368 and reduced the binding of Cx43 to ZO-1.Cx43 entered cytoplasm and leave ZO-1 to format more stable tight junctions.In conclusion,these findings suggest that colonic injury-induced downregulation of AMPK may interrupt the epithelial tight junctional function and contribute to IBD,thus the AMPK agonist can reduce colonic inflammation probably partly via regulating the epithelial tight junctions.This study may provide a new strategy for treating IBD using AMPK agonists in the clinic.