Background and Aims:
Despite years on a gluten-free diet, individuals with celiac disease may exhibit reduced expression of several key intestinal brush-border enzymes involved in the digestion of proline-rich dietary peptides (e.g., gliadin). While potentially clinically significant, the contribution of brush border enzyme insufficiencies to persistent symptoms in celiac disease remains unknown.
This study aimed to establish a human induced pluripotent stem cell (hiPSC)-derived intestinal epithelial model of celiac disease to investigate the effects of gluten-induced inflammatory reaction on brush border enzyme digestive activity.
Materials and Methods:
The hiPSC-derived intestinal epithelial cells were differentiated and cultured under conditions promoting intestinal maturation. To model intestinal inflammation associated with celiac disease, cultures were stimulated with interferon-γ (IFN-γ), and changes in enzyme expression were evaluated. Enzyme activity assays were performed to determine the functional capacity of peptidases.
Results:
Celiac disease and healthy control patient-derived hiPSC intestinal epithelial cells expressed both leucine aminopeptidase (ANPEP) and dipeptidyl peptidase 4 (DPP4) and demonstrated functional enzymatic activity, confirming the suitability of the model for studying dietary peptide digestion at the intestinal epithelium. IFN-γ stimulation altered the expression of both ANPEP and DPP4 in celiac patient-derived cells, indicating that inflammatory signaling can modulate brush border digestive enzyme function.
Conclusions:
Our hiPSC-based intestinal model recapitulates the expression and activity of key brush border enzymes involved in the digestion of proline-rich dietary peptides. The observed effects of IFN-γ on ANPEP and DPP4 expression suggest that inflammation may contribute to digestive enzyme insufficiencies reported in celiac disease, potentially impairing digestion and nutrient absorption by the small intestine. These findings indicate that hiPSC-derived intestinal epithelial cells provide a physiologically relevant platform for studying brush border digestive enzyme dysfunction associated with enteropathy and celiac disease.