PGE₂ is a direct and robust mediator of anion/fluid secretion by human intestinal epithelial cells

Intestinal epithelial cells (IECs) play an indispensable role in maintaining body fluid balance partly through their ability to regulate anion/fluid secretion. Yet in various inflammatory gastrointestinal diseases, over-secretion of anions results in symptoms such as severe diarrhoea. Endogenous mediators, such as vasoactive intestinal peptide or prostaglandin E₂ (PGE₂), regulate intestinal anion/fluid secretion, but their direct effect on purified human IECs has never been described in detail. Based on a previously described intestinal organoid swelling model, we established a 3D-scanner-assisted quantification method to evaluate the anion/fluid secretory response of cultured human IECs. Among various endogenous secretagogues, we found that PGE₂ had the lowest EC₅₀ value with regard to the induction of swelling of the jejunal and colonic organoids. This PGE₂-mediated swelling response was dependent on environmental Cl^- concentrations as well as on several channels and transporters as shown by a series of chemical inhibitor studies. The concomitant presence of various inflammatory cytokines with PGE₂ failed to modulate the PGE₂-mediated organoid swelling response. Therefore, the present study features PGE₂ as a direct and robust mediator of anion/fluid secretion by IECs in the human intestine.