Background The aging small intestine has a great impact on body health. One of the obvious characteristics is the degeneration of epithelium turnover. The acknowledged Lgr5+ intestinal stem cell is the key factor. Methods We used Lgr5-EGFP transgenic mice in three different ages (young group:3-6 months, middle group:12-14 months and old group:22-24 months) to mark the Lgr5+ISCs. We collected the jejunum for histology, immunofluorescence, western-blotting and PCR, we isolated the crypts for organoid culture and sorted out the Lgr5hi cells for bulk RNA sequence. Results In tissue, the crypts depth, proliferating cells and Lgr5+ISCs number increased in middle group (12-14 months) and then decreased in old group (22-24 months). The number of proliferating Lgr5+ISCs gradually decreased from young to old. In organoids, the buddings number and projected area, Lgr5+ISCs ratio also decreased from young to old. Both gene expression of Parp3 and protein level of Parp3 increased in middle and old group. Parp3 inhibitors slowed down organoids’ growth of the middle age. Conclusion Parp3 might participate in regulating the proliferation capacity of Lgr5+ISCs during aging.

Background and Purpose: The defective colonic mucus barrier is a feature of ulcerative colitis (UC) that enables increased bacterial contact with the epithelium, which triggers mucosal damage, and gastrin has been reported to be able to promote healing through the cholecystokinin 2 receptor (CCK2R) signaling to increase epithelial regeneration and protect against colonic injury. However, the role of gastrin in UC remains unclear. Experimental Approach: Colonic samples from human sections and mouse models using β-arrestin1 wild-type (β-arr1-WT) and β-arrestin1 knockout (β-arr1-KO) littermates, intestinal epithelial cells specific NF-κBp65 deletion (NF-κBp65) and wild-type (NF-κBp65) mice were analyzed. The mucosal injury, goblet cells status, MUC2 expression and bacteria penetration/colonisation were examined, and the effect of gastrin in colitis was also investigated. Key Results: We demonstrate that mucus barrier loss and bacterial colonisation of the crypts were observed in colitis, and exogenous gastrin could restore the mucus barrier, reduce bacterial colonisation of the colonic crypts and alleviate colitis via CCK2R. Furthermore, targeting CCK2R by YF476, β-arrestin1 (β-arr1) deletion or intestinal epithelial NF-κBp65 deficiency breached gastrin-mediated mucus barrier restoration and mucosal protection in colitis. Conclusion and Implications: These data demonstrate that gastrin alleviates mucus barrier loss and bacterial colonisation of the colonic crypts via CCK2R/β-arr1/NF-κBp65 signaling in colitis, and this network may be a potential therapeutic target for UC.