Reduced intestinal GLP-1+ cell numbers are associated with an inflammation-related epithelial metabolic signature

Background & Aims Enteroendocrine cells (EECs) are known for their role in digestion and metabolism, yet their role in intestinal inflammation remains unclear. In inflammatory bowel diseases (IBD), 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. Methods 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 (IL)10-deficient mice. Using a publicly available single-cell RNA sequencing dataset including mucosal biopsies from Crohn’s disease (CD) patients, 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. Results Numbers of GLP-1 expressing cells are consistently reduced at the site of active disease in mouse models and CD patients. Despite this reduction, L cells from inflamed IL-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. Conclusion Reduction of GLP-1 + cells represents a general feature of ileal and colonic inflammation in mice and human. 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 IBD. Data Transparency All data generated or analyzed during this study are included in this published article. Additional datasets, including raw data, are available from the corresponding author upon reasonable request. Synopsis This study examines GLP-1 + cells in intestinal inflammation, showing consistent reductions in inflamed areas. Findings from mouse models and human data reveal an inflammatory metabolic profile linked to altered epithelial differentiation. GLP-1, involved in endocrine-immune crosstalk, may impact mucosal inflammation and symptoms, making it a therapeutic target. Graphical Abstract