Dipeptidyl peptidase 4 (DPP4),a ubiquitously expressed protease that cleaves off the N-terminal dipeptide from proline and alanine on the penultimate position,has important roles in many physiological processes.In the present study,experimental colitis was induced in mice receiving 3％ dextran sulfate sodium (DSS) in drinking water.We found that mice with DSS-induced colitis had significantly increased intestinal DPP activity and decreased serum DPP activity,suggesting a probable correlation of DPP4 with experimental colitis.Then,we investigated whether sitagliptin,a specific DPP4 inhibitor could protect against DSS-induced colitis.We showed that oral administration of single dose of sitagliptin (30 mg/kg) on D7 remarkably inhibited DPP enzyme activity in both serum and intestine of DSS-induced colitic mice.Repeated administration of sitagliptin (10,30 mg/kg,bid,from D0 to D8) significantly ameliorated DSS-induced colitis,including reduction of disease activity index (DAI) and body weight loss,improvement of histological score and colon length.Sitagliptin administration dose-dependently increased plasma concentrations of active form of GLP-1 and colonic expression of GLP-2R.Co-administration of GLP-2R antagonist GLP-2333 (500 μg/kg,bid,sc) abolished the protective effects of sitagliptin in DSS-induced colitic mice.Moreover,sitagliptin administration significantly decreased the ratio of apoptotic cells and increased the ratio of proliferative cells in colon epithelium of DSS-induced colitic mice,and this effect was also blocked by GLP-23-33.Taken together,our results demonstrate that sitagliptin could attenuate DSS-induced experimental colitis and the effects can be attributed to the enhancement of GLP-2 action and the subsequent protective effects on intestinal barrier by inhibiting epithelial cells apoptosis and promoting their proliferation.These findings suggest sitagliptin as a novel therapeutic approach for the treatment of ulcerative colitis.