Signaling pathways in control of gastric acid secretion and food‐stomach‐bone axis revealed by gene expression profiling in the stomach of genetically targeted mice deficient in CCK1 receptor and gastrin/CCK2 receptor

Abstract

Stomach plays important roles in the regulations of digestion, food intake, and mineral homeostasis, which involve CCK1 and gastrin/CCK2 receptors. The aim of this study was to reveal signaling pathways for drug development. Genome‐wide gene expression profiling was performed in the stomachs of wild‐type (WT) and CCK1 and/or CCK2 receptor knockout (KO) mice in response to food intake. The results showed that the KEGG “gastric acid secretion pathway” was neither altered in CCK1 receptor KO, CCK2 receptor KO nor in CCK1+2 receptor double KO mice, which was in line with normal ultrastructural appearance of the parietal cells in all the three mutant strains. A novel “ECL cell pathway” was found and it was inhibited in CCK2 receptor KO mice, but not in CCK1 receptor KO nor CCK1+2 receptor double KO mice. The typical WT ECL cells remained in CCK1 receptor KO mice, disappeared in CCK2 receptor KO mice, and re‐appeared in CCK1+2 receptor KO mice. The ECL cells contain pthlh gene‐related peptide gastrocalcin, a PTH‐like hormone, which was up‐regulated by food intake in WT mice but downregulated in both CCK2 receptor KO and CCK1+2 receptor double KO mice compared with WT mice. In addition, immune signaling pathways, TFF2, BMP, vitamin D synthesis and A‐like cell ghrelin were found to be altered. Perturbation of these signaling pathways might lead to the development of osteoporosis, which is a phenotype of CCK2 receptor KO mice. In conclusion, the revealed signaling pathways represent new targets for the control of acid secretion and for the bone metabolism and mineral homeostasis.