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.
Subscribe to Journal
Get full journal access for 1 year
only $33.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Loddo I, Romano C. Inflammatory bowel disease: genetics, epigenetics, and pathogenesis. Front Immunol. 2015;6:551.
Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2018;390:2769–78.
Mak WY, Zhao M, Ng SC, Burisch J. The epidemiology of inflammatory bowel disease: east meets west. J Gastroenterol Hepatol. 2020;35:380–9.
Lucafò M, Franca R, Selvestrel D, Curci D, Pugnetti L, Decorti G, et al. Pharmacogenetics of treatments for inflammatory bowel disease. Expert Opin Drug Metab Toxicol. 2018;14:1209–23.
Matteucci E, Giampietro O. Dipeptidyl peptidase-4 (CD26): knowing the function before inhibiting the enzyme. Curr Med Chem. 2009;16:2943–51.
Klemann C, Wagner L, Stephan M, von Hörsten S. Cut to the chase: a review of CD26/dipeptidyl peptidase-4’s (DPP4) entanglement in the immune system. Clin Exp Immunol. 2016;185:1–21.
Mulvihill EE, Drucker DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev. 2014;35:992–1019.
Birnbaum Y, Bajaj M, Qian J, Ye Y. Dipeptidyl peptidase-4 inhibition by Saxagliptin prevents inflammation and renal injury by targeting the Nlrp3/ASC inflammasome. BMJ Open Diabetes Res Care. 2016;4:e000227.
Benjamin MA, McKay DM, Yang PC, Cameron H, Perdue MH. Glucagon-like peptide-2 enhances intestinal epithelial barrier function of both transcellular and paracellular pathways in the mouse. Gut. 2000;47:112–9.
Bremholm L, Hornum M, Henriksen BM, Larsen S, Holst JJ. Glucagon-like peptide-2 increases mesenteric blood flow in humans. Scand J Gastroenterol. 2009;44:314–9.
Janssen P, Rotondo A, Mulé F, Tack J. Review article: a comparison of glucagon-like peptides 1 and 2. Aliment Pharmacol Ther. 2013;37:18–36.
Kato Y, Yu D, Schwartz MZ. Glucagonlike peptide-2 enhances small intestinal absorptive function and mucosal mass in vivo. J Pediatr Surg. 1999;34:18–20.
Boushey RP, Yusta B, Drucker DJ. Glucagon-like peptide 2 decreases mortality and reduces the severity of indomethacin-induced murine enteritis. Am J Physiol. 1999;277:E937–47.
Boushey RP, Yusta B, Drucker DJ. Glucagon-like peptide (GLP)-2 reduces chemotherapy-associated mortality and enhances cell survival in cells expressing a transfected GLP-2 receptor. Cancer Res. 2001;61:687–93.
Nakame K, Kaji T, Mukai M, Shinyama S, Matsufuji H. The protective and anti-inflammatory effects of glucagon-like peptide-2 in an experimental rat model of necrotizing enterocolitis. Peptides. 2016;75:1–7.
Ban H, Bamba S, Imaeda H, Inatomi O, Kobori A, Sasaki M, et al. The DPP-IV inhibitor ER-319711 has a proliferative effect on the colonic epithelium and a minimal effect in the amelioration of colitis. Oncol Rep. 2011;25:1699–703.
Mimura S, Ando T, Ishiguro K, Maeda O, Watanabe O, Ujihara M, et al. Dipeptidyl peptidase-4 inhibitor anagliptin facilitates restoration of dextran sulfate sodium-induced colitis. Scand J Gastroenterol. 2013;48:1152–9.
Salaga M, Binienda A, Draczkowski P, Kosson P, Kordek R, Jozwiak K, et al. Novel peptide inhibitor of dipeptidyl peptidase IV (Tyr-Pro-D-Ala-NH2) with anti-inflammatory activity in the mouse models of colitis. Peptides. 2018;108:34–45.
Salaga M, Mokrowiecka A, Zielinska M, Malecka-Panas E, Kordek R, Kamysz E, et al. New peptide inhibitor of dipeptidyl peptidase IV, EMDB-1 extends the half-life of GLP-2 and attenuates colitis in mice after topical administration. J Pharmacol Exp Ther. 2017;363:92–103.
Yazbeck R, Sulda ML, Howarth GS, Bleich A, Raber K, von Hörsten S, et al. Dipeptidyl peptidase expression during experimental colitis in mice. Inflamm Bowel Dis. 2010;16:1340–51.
Lee M, Rhee MK. Sitagliptin for Type 2 diabetes: a 2015 update. Expert Rev Cardiovasc Ther. 2015;13:597–610.
Ceriello A, Sportiello L, Rafaniello C, Rossi F. DPP-4 inhibitors: pharmacological differences and their clinical implications. Expert Opin Drug Saf. 2014; 13(Suppl 1):S57–68.
Zou Y, Lin J, Li W, Wu Z, He Z, Huang G, et al. Huangqin-tang ameliorates dextran sodium sulphate-induced colitis by regulating intestinal epithelial cell homeostasis, inflammation and immune response. Sci Rep. 2016;6:39299.
Matsunaga T, Hashimoto S, Yamamoto N, Kawasato R, Shirasawa T, Goto A, et al. Protective effect of daikenchuto on dextran sulfate sodium-induced colitis in mice. Gastroenterol Res Pract. 2017;2017:1298263.
Yazbeck R, Howarth GS, Butler RN, Geier MS, Abbott CA. Biochemical and histological changes in the small intestine of mice with dextran sulfate sodium colitis. J Cell Physiol. 2011;226:3219–24.
Durinx C, Lambeir AM, Bosmans E, Falmagne JB, Berghmans R, Haemers A, et al. Molecular characterization of dipeptidyl peptidase activity in serum: soluble CD26/dipeptidyl peptidase IV is responsible for the release of X-Pro dipeptides. Eur J Biochem. 2000;267:5608–13.
Friedrich D, Hoffmann T, Bär J, Wermann M, Manhart S, Heiser U, et al. Does human attractin have DP4 activity? Biol Chem. 2007;388:155–62.
Zhang H, Chen Y, Keane FM, Gorrell MD. Advances in understanding the expression and function of dipeptidyl peptidase 8 and 9. Mol Cancer Res. 2013;11:1487–96.
Araki Y, Mukaisyo K, Sugihara H, Fujiyama Y, Hattori T. Increased apoptosis and decreased proliferation of colonic epithelium in dextran sulfate sodium-induced colitis in mice. Oncol Rep. 2010;24:869–74.
Korom S, De Meester I, Stadlbauer TH, Chandraker A, Schaub M, Sayegh MH, et al. Inhibition of CD26/dipeptidyl peptidase IV activity in vivo prolongs cardiac allograft survival in rat recipients. Transplantation. 1997;63:1495–500.
Hildebrandt M, Rose M, Ruter J, Salama A, Mönnikes H, Klapp BF. Dipeptidyl peptidase IV (DP IV, CD26) in patients with inflammatory bowel disease. Scand J Gastroenterol. 2001;36:1067–72.
Lee TM, Chen WT, Chang NC. Dipeptidyl peptidase-4 inhibition attenuates arrhythmias via a protein kinase A-dependent pathway in infarcted hearts. Circ J. 2015;79:2461–70.
Mulvihill EE, Varin EM, Gladanac B, Campbell JE, Ussher JR, Baggio LL, et al. Cellular sites and mechanisms linking reduction of dipeptidyl peptidase-4 activity to control of incretin hormone action and glucose homeostasis. Cell Metab. 2017;25:152–65.
Reichetzeder C, von Websky K, Tsuprykov O, Mohagheghi Samarin A, Falke LG, Dwi Putra SE, et al. Head-to-head comparison of structurally unrelated dipeptidyl peptidase 4 inhibitors in the setting of renal ischemia reperfusion injury. Br J Pharmacol. 2017;174:2273–86.
Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999;20:876–913.
This study was financially supported by a grant from the National Natural Science Foundation of China (no. 81872922).
The authors declare no competing interests.
About this article
Cite this article
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
- ulcerative colitis
- dextran sulfate sodium
- dipeptidyl peptidase 4
- glucagon-like peptide-2