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.
Loss of interleukin 33 expression in colonic crypts - a potential marker for disease remission in ulcerative colitis
