Metformin Attenuates Experimental Murine Colitis Via A Protection Of Intestinal Epithelial Cells

Inflammatory bowel diseases(IBD)are a group of chronic inflammatory gastrointestinal disorders.IBD consist of Crohn’s disease and ulcerative colitis that both cause a substantial worsening of life quality.Patients suffering from IBD often require lifelong pharmacologic treatment and sometimes even surgical interventions.Nowadays,conventional medicine is offering a broad range of anti-IBD drugs,including corticosteroids,immunosuppressants,antibiotics,and biologicals.However,none of the drugs presently available for anti-IBD therapy are effective enough to provide complete and life-long relief for the patients.Therefore,more effective and safer drugs are urgently needed.Afer screening of a lot of lead compounds,metform was found to have the ability to significantly ameliorate trinitro-benzene-sulfonic acid(TNBS)-induced experimental colitis in mice.TNBS could induce body weight loss,myeloperoxidase activity increase,shortening of the colon and a robust colonic inflammation in mice.However,these colonic injuries were significantly ameliorated by metformin administration.Both the mRNA and protein levels of proinflammatory cytokines in mice colons,such as IFN-γ,IL-1β,IL-10 and IL-6,were reduced by metformin administration.Moreover,Metformin prevents the TNBS-induced decrease in expression of tight junction proteins,including Occludin and Claudin-1.Then,we investigated the mechanism by which metformin attenuated TNBS-induced colitis in mice.It was shown that metformin did not inhibit the proliferation of T lymphocytes induced by concanavalin A and have no effects on the cytokines secreted by activated T lymphocytes,including IFN-γ,TNF-α,IL-2 and IL-17A.However,metformin demonstrated a notable effect to reverse the down-regulation of tight junction proteins in HCT116 cells treated with IFN-y or LPS.In our further study,we found the LPS-stimulated phosphorylation of IKKα/β,IκBαand p65 in HCT116 cells was suppressed by metformin in a concentration-dependent manner.These data suggest that the inhibition of the NF-κB signaling pathway in HCT116 cells may be one of the most important molecular mechanisms by which metformin attenuates colonic injury and colitis in mice.In summary,we demonstrated that metformin could improve TNBS-induced colitis in mice via a protection of colonic epithelial cells and inhibition of inflammation-related NF-κB signaling.This study not only enriches the theory of basic science,but also offers a new potential drug for clinical treatment of IBD.