Reduced Intestinal GLP-1⁺ Cell Numbers Are Associated With an Inflammation-related Epithelial Metabolic Signature

Enteroendocrine cells (EECs) are known for their role in digestion and metabolism, yet their role in intestinal inflammation remains unclear. In inflammatory bowel diseases, a contribution of EECs to pathogenesis is indicated by autoantibodies affecting EEC function and general disease symptoms like insulin resistance and altered intestinal motility. Particularly, the L cell-derived hormone glucagon-like peptide 1 (GLP-1), suggested to orchestrate metabolic-inflammatory responses may influence inflammatory pathways in the intestine.

We quantified numbers of GLP-1⁺ cells in 4 different mouse models of intestinal inflammation and performed transcriptional analyses of colonic epithelial cells from inflamed interleukin-10-deficient mice. Using a publicly available single-cell RNA sequencing dataset including mucosal biopsies from patients with Crohn's disease, we confirmed findings from the murine models. A model of mitochondrial dysfunction (ClpP^ΔIEC mice) as well as murine and human intestinal organoids were used to study molecular mechanisms.

Numbers of GLP-1 expressing cells are consistently reduced at the site of active disease in mouse models and patients with Crohn's disease. Despite this reduction, L cells from inflamed interleukin-10-deficient mice remained functional regarding GLP-1 secretion. Transcriptional analyses of intestinal epithelial cells indicate altered differentiation correlating with an inflammatory metabolic fingerprint. Reduced GLP-1⁺ cells in ClpP^ΔIEC mice and inhibition of respiration in organoid cultures supports a causative role for metabolism in steering differentiation.

Reduction of GLP-1⁺ cells represents a general feature of ileal and colonic inflammation in mice and humans. Given the numerous properties of GLP-1, this reduction likely affects inflammatory processes in the mucosa and disease-related symptoms on multiple levels, and therefore, should be considered a therapeutic target in inflammatory bowel diseases.