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

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.

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Fig. 1: DPP enzyme activity in serum and intestinal tissues of normal control mice and DSS-induced colitis mice.
Fig. 2: Inhibitory effects of sitagliptin on DPP enzyme activity in serum and intestine.
Fig. 3: Sitagliptin improved the symptoms and pathological changes in DSS-induced colitis.
Fig. 4: Effect of sitagliptin on the mRNA expression of proinflammatory mediators and junction-associated components in colons.
Fig. 5: Influence of sitagliptin on incretin hormones and correlated genes in DSS-induced colitis mice.
Fig. 6: GLP-23-33 repressed the protective effect of sitagliptin on the DAI, colon length, colon weight/length ratio, and colon histological injury in DSS-induced colitis mice.
Fig. 7: The modulatory effects of sitagliptin on the apoptosis and proliferation of colonic epithelial cells were repressed by GLP-23-33 in DSS-induced colitis mice.

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Acknowledgements

This study was financially supported by a grant from the National Natural Science Foundation of China (no. 81872922).

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MMN and YL designed the study. MMN, WJY, WBG, YPG, and YF conducted the experiments. MMN and WBG analyzed the data. MMN and YL wrote the manuscript.

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Correspondence to Ying Leng.

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Ning, Mm., Yang, Wj., Guan, Wb. et al. Dipeptidyl peptidase 4 inhibitor sitagliptin protected against dextran sulfate sodium-induced experimental colitis by potentiating the action of GLP-2. Acta Pharmacol Sin 41, 1446–1456 (2020). https://doi.org/10.1038/s41401-020-0413-7

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Keywords

  • ulcerative colitis
  • dextran sulfate sodium
  • dipeptidyl peptidase 4
  • sitagliptin
  • glucagon-like peptide-2
  • GLP-23-33
  • apoptosis
  • proliferation

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