The endocannabinoid-derived prostaglandin glycerol esters and prostaglandin ethanolamides modulate intestinal epithelial hallmarks of colitis.

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract with a high impact on patients' quality of life. The endocannabinoids 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA) are important modulators of inflammation. Their metabolism by cyclooxygenase (COX)-2 produces prostaglandin glycerol esters (PG-Gs) and prostaglandin ethanolamides (PG-EAs) that are endogenous analogues of the arachidonic acid-derived prostaglandins. Several PG-G and PG-EA possess interesting biological properties, notably in the context of colitis as we reported for PGD2-G. However, while the properties of prostaglandins (such as PGE2) on epithelial cells in the context of colon inflammation are well described, the biological effects of PG-Gs and PG-EAs are unknown. Here we used Caco-2 spheroids and mouse colon organoids to evaluate how PG-Gs and PG-EAs modulate three epithelial hallmarks of colitis, namely the epithelial barrier integrity, the production of cytokines, and the wound healing process. Importantly, we tested the corresponding prostaglandins in parallel. When analyzing the effects of these prostanoids on the production of pro-inflammatory cytokines, we found that PGD2-G did decrease the production of TNFα and MCP-1 in activated Caco-2 spheroids. On colon organoids, PGE2-G modulated the levels of TNFα, MIP2α, and KC and improved the survival of colon organoids in a DSS-plating efficiency assay without affecting stem cell dynamics. Our results put forth differential effects for PG-Gs, PG-EAs and the corresponding prostaglandins, and suggest that PGE2-G could be an interesting lipid mediator in the context of colon epithelium inflammation.