Ghrelin mitigates partial body irradiation-induced gastrointestinal acute radiation syndrome by promoting intestinal stem cell regeneration.

BACKGROUND: Gastrointestinal acute radiation syndrome (GI-ARS) is characterized by disruption of the intestinal barrier function, leading to bacterial translocation and sepsis. Intestinal stem cells are highly radiosensitive and dramatically reduced after radiation injury. Clusterin (Clu)-positive revival stem cells contribute to the restoration of intestinal stem cells. Ghrelin, a gastric peptide hormone, has been shown to improve intestinal integrity in models of inflammatory enteropathy. In this study, we investigated the effects of ghrelin on intestinal stem cell recovery and its potential to mitigate radiation-induced intestinal injury. METHODS: Mice were subjected to 12 Gy partial body irradiation (PBI). Ghrelin at the doses of 2 to 6 nmol per mouse was administered daily for 4 consecutive days, starting at 24 h post-PBI, and survival was monitored for 30 days. To assess intestinal histology, cell proliferation, and intestinal stem cell markers, mice were treated with 6 nmol of ghrelin on days 1, 2, and 3 post-PBI, and on day 4 jejunal samples were collected for qPCR, immunofluorescence, and microcolony assays. Intestinal permeability was assessed in vivo by the leakage of gavage-fed 4-kDa FITC-dextran into the circulation. RESULTS: Ghrelin administration significantly improved 30-day survival rate following 12-Gy PBI in a dose-dependent manner. Treatment with ghrelin restored villus length and enhanced intestinal barrier integrity. Ghrelin also significantly increased the expression of proliferation markers in the jejunum. Microcolony assays revealed that ghrelin reversed the decrease in BrdU-positive cells following PBI. The mRNA and protein expression of intestinal stem cell markers was decreased after PBI but was restored by ghrelin treatment. Finally, ghrelin significantly increased the population of Clu+ population following irradiation. CONCLUSIONS: These findings indicate that ghrelin mitigates radiation-induced intestinal injury by promoting the expansion of Clu+ revival stem cells and the recovery of intestinal stem cells. This study highlights the therapeutic potential and identifies the mechanism of action of ghrelin as a medical countermeasure against GI-ARS.