Interleukin-22 (IL-22) Enhanced the Mucosal Barrier and Inhibited the Invasion of Salmonella enterica in Human induced Pluripotent Stem Cell-derived Small Intestinal Epithelial Cells.

Human induced pluripotent stem cell-derived small intestinal epithelial cell (hiPSC-SIEC) monolayers are useful in vitro models for evaluating the gut mucosal barrier; however, their reactivity to cytokines, which are closely related to the regulation of mucosal barrier function, remains unclear. Interleukin (IL)-22 is a cytokine that contributes to regulate the mucosal barrier in the intestinal epithelia. Using microarray and Gene Set Enrichment Analysis, we found that hiPSC-SIEC monolayers activate the immune response and enhance the mucosal barrier in response to IL-22. Moreover, hiPSC-SIEC monolayers induced the gene expression of antimicrobials including the regenerating islet-derived protein (REG) 3 family. Furthermore, IL-22 stimulation upregulated Mucin 2 secretion and gene expression of an enzyme that modifies sugar chains, suggesting alteration of the state of the mucus layer of hiPSC-SIEC monolayers. To evaluate its physiological significance, we measured the protective activity agaist Salmonella enterica subsp. enterica infection in hiPSC-SIEC monolayers and found that pre-stimulation with IL-22 reduced the number of viable intracellular bacteria. Collectively, these results suggest that hiPSC-SIEC monolayers enhance the mucosal barrier and inhibit infection by pathogenic bacteria in response to IL-22, as previously reported. These results can contribute to the further application of hiPSC-SIECs in evaluating mucosal barriers.