The Effection Of Dimethyl Fumarate On DSS-induced Colitis In Mice

Background: Ulcerative colitis(UC)is a chronic and specific inflammatory disease of the intestine,manifesting as recurrent mucosal inflammation of the colorectum.And it can affect organs other than the intestine in severe cases.The pathogenesis of UC is still unclear.However,inflammation of the intestinal mucosa and impairment of the intestinal epithelial barrier are found both in UC patients and colitis animal models.Therefore,they play an essential role in UC.Dimethyl fumarate(DMF),a member of the fumaric acid family,has anti-inflammatory and antioxidant properties.In addition,DMF has demonstrated good efficacy in the treatment of multiple sclerosis and psoriasis.In recent years,it is reported that DMF can reduce the clinical manifestations of colitis mice,but the mechanism is unknown.Objective: The study was to investigate the effect of DMF on ulcerative colitis mice and explore the possible mechanisms,which could provide an innovative idea for the treatment of IBD.Methods: Mice were given 2% DSS(Dextran sulfate sodium salt)freely to establish an experimental model of acute ulcerative colitis and gavaged with 50 mg/Kg/Day DMF.Mice were monitored and recorded daily for mental status,weight changes,fecal traits and blood in the stool,etc.Weight changes and DAI(Disease Activity Index)scores were performed to assess the severity of clinical manifestations.To evaluate the inflammatory damage in mice,this study measured the colonic length,weighed the spleen and lymph nodes,and performed HE staining of the colonic tissue.After that,immunohistochemical staining,q PCR,PAS staining,and immunofluorescence staining were employed to detect the expression of tight junction proteins,the number and function of goblet cells and the infiltration of immune cells in colonic tissue;Flow cytometry was used to determine the phenotype of LPL and IEL.Finally,a bioinformatics approach was used to explore the possible important signaling pathways and target genes in the treatment of DMF in mice with colitis.RESULTS: This study found that DMF-treated mice showed lower clinical manifestations and damage to colonic tissues than the model group.The DMF-treated mice exhibited significantly lower body weight changes and DAI scores,longer colon,lighter spleen,and lymph nodes;and significantly less histopathological damage to the colon,with no significant changes to the normal structure of the colon;upregulation of Occluding,E-cadherin and ZO-1 expression,and greater numbers of goblet cells.Meanwhile,it was found that the DMF-treated group has a smaller infiltration of intestinal immune cells(macrophages,neutrophils,and T cells)and a higher number of antiinflammatory subtypes.The bioinformatics analysis suggested that the NF-κB signaling pathway is likely to be a key pathway for the therapeutic effects of DMF in mice with colitis,involving important proteins like ICAM1 and CD40.Conclusion: The results of this study suggest that DMF could suppress intestinal mucosal inflammation and maintain intestinal epithelial barrier function,which is accoutered with ICAM1/CD40 and NF-κB signaling pathway.This study demonstrates the clinical value of DMF for UC.