Liraglutide upregulates the Cftr gene and regulates the mucus transcriptome profile in Brunner's glands in mice

Abstract

Background: The metabolic syndrome encompasses a state of inflammation and metabolic dysfunction, possibly mediated via a disturbed intestinal barrier. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as liraglutide, have shown promising anti-inflammatory effects beyond glucose lowering and weight loss, but the underlying mechanism remains to be elucidated. We hypothesised that GLP-1RAs improve the intestinal barrier function and overall inflammatory status by direct gene activation in mucus-secreting Brunner's glands in the mouse duodenum, known for their high density of glucagon-like peptide-1 receptors (GLP-1Rs).

Methods: Using bulk RNA sequencing, in situ hybridisation, and immunohistochemistry, we analysed the change in the genetic phenotype of mouse Brunner's gland cells following GLP-1R activation by liraglutide.

Results: We show that liraglutide induces a novel and robust upregulation of the gene for the Cystic fibrosis transmembrane conductance regulator, Cftr, in Brunner's glands as a part of an overall genetic phenotype involved in ion channel activity, mucus secretion, and hydration via GLP-1R activation. Additionally, we found a robust upregulation of the genes Muc5b, Il33, Ren1, and Vldlr in Brunner's glands.

Conclusion: Collectively, our results imply an enhanced mucus response from Brunner's glands following GLP-1R activation, which might play a role in the effect of GLP-1.

Keywords

Brunner's glands / Cftr / GLP-1 / gut / incretin / intestinal barrier / mucus

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