Reduced intestinal GLP-1 + cell numbers are associated with an inflammation-related epithelial metabolic signature
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Background & Aims
While hormone secretion from enteroendocrine cells (EECs) and their functions in digestion and metabolism are well studied, the role of EECs in intestinal inflammation is virtually unknown. 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) exerts direct effects on intraepithelial lymphocytes and is suggested to orchestrate metabolic- inflammatory responses. However, the role of EECs in intestinal inflammation is poorly understood.
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 Crohńs 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 of intestinal inflammation and CD patients. Colonic L cells from inflamed IL-10 -/- mice remained functional in terms of hormone secretion. Transcriptional analyses of intestinal epithelial cells indicate altered epithelial 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.
