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


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

Author information




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.

Corresponding author

Correspondence to Ying Leng.

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The authors declare no competing interests.

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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).

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

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