Article

Dipeptidyl peptidase 4 inhibitor sitagliptin protected against dextran sulfate sodium-induced experimental colitis by potentiating the action of GLP-2

Authors: Meng-meng Ning1, Wen-ji Yang1,2, Wen-bo Guan1,2, Yi-pei Gu1, Ying Feng1, Ying Leng1,2
1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
Correspondence to: Ying Leng: yleng@simm.ac.cn,
DOI: 10.1038/s41401-020-0413-7
Received: 2 January 2020
Accepted: 30 March 2020
Advance online: 12 May 2020

Abstract

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-23-33 (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.
Keywords: ulcerative colitis; dextran sulfate sodium; dipeptidyl peptidase 4; sitagliptin; glucagon-like peptide-2; GLP-23-33; apoptosis; proliferation

Article Options

Download Citation

Cited times in Scopus