Linagliptin, a dipeptidylpeptidase 4 inhibitor, ameliorates indomethacin‐induced enteropathy via GLP‐2 pathway

Glucagon‐like peptide‐2 (GLP‐2) is an intestinotrophic hormone secreted from enteroendocrine L cells. We have reported that dipeptidylpeptidase 4 (DPP4) inhibition prevents formation and promotes healing of indomethacin (IND)‐induced small intestinal ulcers in rats via GLP‐2 release and GLP‐2 receptor activation. We thus further examined the effect of the clinical DPP4 inhibitor linagliptin (LNG) on IND‐induced enteropathy. Small intestinal ulcers were induced by IND treatment (10 mg/kg, sc) in rats. LNG (0.1 – 5 mg/kg) was given once before IND for prevention, and for healing, once daily for 2 days starting 1 day after IND treatment. LNG treatment dose‐dependently reduced ulcer scores, accompanied by an increase of portal venous GLP‐2 concentrations. LNG promoted ulcer healing of IND‐induced intestinal ulcers. LNG‐induced healing was reversed by a GLP‐2 receptor antagonist. Ulcer healing was further accelerated by co‐treatment with L‐alanine plus inosinate, an umami taste receptor agonist. Compared to LNG, the DPP4 inhibitor NVP‐728, metabolized in the kidney, had a little effect on the enteropathy, suggesting that a long‐acting, entero‐hepatically circulated DPP4 inhibitor may be more efficacious in the prevention of intestinal mucosal damage. These results confirm our previous study that DPP4 inhibition prevents ulceration and promotes ulcer healing of NSAID‐induced enteropathy, enhanced by the luminal umami taste receptor activation, suggesting that GLP‐2 release enhanced by DPP4 inhibition and nutrient receptor activation is useful for the treatment of NSAID‐induced enteropathy. Supported by Boehringer Ingelheim, VA Merit Review, NIH R01 DK54221