Gastrin Increases Murine Intestinal Crypt Regeneration Following Injury

Background & Aims: A number of growth factors affect the regeneration of intestinal epithelia following injury, but the effects of amidated gastrin have not previously been assessed. We therefore investigated the effects of gastrin on intestinal regeneration following a range of stimuli. Methods: Intestinal crypt regeneration was assessed in transgenic mice overexpressing amidated gastrin (INS-GAS) and mice in which hypergastrinemia was induced using omeprazole, following γ-radiation, 5-fluorouracil, and dextran sulphate sodium (DSS). Abundance of the CCK-2 receptor was assessed in intestinal epithelia and IEC-6 intestinal epithelial cells following γ-radiation. Results: Four days following 14 Gy γ-radiation, or 2 injections of 400 mg/kg 5-fluorouracil, INS-GAS mice exhibited significantly increased small intestinal and colonic crypt survival compared with their wild-type counterparts (FVB/N). INS-GAS mice treated with 3% DSS for 5 days showed less weight loss and increased colonic crypt regeneration at 8 days compared with FVB/N. Increased small intestinal and colonic crypt survival was also demonstrated following γ-radiation in FVB/N mice rendered hypergastrinemic using omeprazole. The increased crypt survival in INS-GAS mice following 14 Gy γ-radiation was inhibited by administration of a CCK-2 receptor antagonist (YF476). Increased abundance of the CCK-2 receptor was demonstrated in intestinal epithelia following 14 Gy γ-radiation by Western blotting and immunohistochemistry. Similarly, increased CCK-2 receptor mRNA abundance and increased 125I-gastrin binding was demonstrated in IEC-6 cells following 4 Gy γ-radiation. Conclusions: Hypergastrinemia increases regeneration of intestinal epithelia following diverse forms of injury. Induction of the CCK-2 receptor in damaged epithelium confers potential for protection against injury by administration of gastrin.