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Gastrin/CCK2R alleviates mucus barrier loss via β-arrestin1/NF-κBp65 signaling in ulcerative colitis
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  • Siwei Tan,
  • Xiuying Peng,
  • Xianzhi Liu,
  • Shuyan Tan,
  • Xiaoli Huang,
  • Xuemei Pan,
  • Jie Jiang,
  • Huiling Liu,
  • Jin Tao,
  • Bin Wu
Siwei Tan
Third Affiliated Hospital of Sun Yat-Sen University
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Xiuying Peng
Third Affiliated Hospital of Sun Yat-Sen University
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Xianzhi Liu
Third Affiliated Hospital of Sun Yat-Sen University
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Shuyan Tan
Third Affiliated Hospital of Sun Yat-Sen University
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Xiaoli Huang
Third Affiliated Hospital of Sun Yat-Sen University
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Xuemei Pan
Third Affiliated Hospital of Sun Yat-Sen University
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Jie Jiang
Third Affiliated Hospital of Sun Yat-Sen University
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Huiling Liu
Third Affiliated Hospital of Sun Yat-Sen University
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Jin Tao
Third Affiliated Hospital of Sun Yat-Sen University
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Bin Wu
Third Affiliated Hospital of Sun Yat-Sen University
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Abstract

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-κBp65IEC-KO) and wild-type (NF-κBp65IEC-WT) 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.

Peer review status:IN REVISION

18 Jan 2021Submitted to British Journal of Pharmacology
18 Jan 2021Assigned to Editor
18 Jan 2021Submission Checks Completed
11 Feb 2021Reviewer(s) Assigned
09 Mar 2021Review(s) Completed, Editorial Evaluation Pending
14 Mar 2021Editorial Decision: Revise Minor
13 Jun 20211st Revision Received