Altered Intestinal Permeability and Drug Repositioning in a Post-operative Ileus Guinea Pig Model

BACKGROUND/AIMS: The aim of this study is to identify the alteration in intestinal permeability with regard to the development of post-operative ileus (POI). Moreover, we investigated drug repositioning in the treatment of POI. METHODS: An experimental POI model was developed using guinea pigs. To measure intestinal permeability, harvested intestinal membranes of the ileum and proximal colon was used in an Ussing chamber. To identify the mechanisms associated with altered permeability, we measured leukocyte count and expression of calprotectin, claudin-1, claudin-2, and mast cell tryptase. We compared control, POI, and drug groups (mosapride [0.3 mg/kg and 1 mg/kg, orally], glutamine [500 mg/kg, orally], or ketotifen [1 mg/kg, orally] with regard to these parameters. RESULTS: Increased permeability after surgery significantly decreased after administration of mosapride, glutamine, or ketotifen. Leukocyte counts increased in the POI group and decreased significantly after administration of mosapride (0.3 mg/kg) in the ileum, and mosapride (0.3 mg/kg and 1 mg/kg), glutamine, or ketotifen in the proximal colon. Increased expression of calprotectin after surgery decreased after administration of mosapride (0.3 mg/kg), glutamine, or ketotifen in the ileum and proximal colon, and mosapride (1 mg/kg) in the ileum. The expression of claudin-1 decreased significantly and that of claudin-2 increased after operation. After administration of glutamine, the expression of both proteins was restored. Finally, mast cell tryptase levels increased in the POI group and decreased significantly after administration of ketotifen. CONCLUSIONS: The alteration in intestinal permeability is one of the factors involved in the pathogenesis of POI. We repositioned 3 drugs (mosapride, glutamine, and ketotifen) as novel therapeutic agents for POI.