Supplementum 291: Abstracts of the Annual meeting of the Swiss Society of Gastroenterology, the Swiss Society of Visceral Surgery, the Swiss Association for the Study of the Liver and the Swiss Society of Endoscopy Nurses and Associates (Interlaken,

Background: Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder driven by dysregulated cytokine activity and compromised epithelial barrier function.While G protein-coupled receptor 35 (GPR35) modulates these processes, its role in EoE remains unknown.Methods: By combining computational docking and organoid barrier assays with an SDS-induced EoE model, we defined GPR35's role in driving IL-18-mediated epithelial dysfunction.Results: Our study demonstrates that GPR35 is markedly upregulated in esophageal biopsies from patients with active EoE.In a murine EoE model, Gpr35 expression was localized to esophageal macrophages.Strikingly, Gpr35 Cx3cr1 mice exhibited attenuated EoE pathology, which correlated with reduced IL-18 levels.Using computational docking, we identified 8methoxykynurenate (8-MK), a tryptophan derivative, as a putative endogenous ligand for GPR35.Functional validation revealed that 8-MK stimulation in macrophages upregulated IL-18 production.Mechanistically, we found that GPR35 drives IL-18 expression by dysregulating intracellular calcium flux, leading to inflammasome activation.Critically, IL-18 directly impaired epithelial barrier function in human esophageal organoids, reduced transepithelial electrical resistance, and increased macromolecule flux in air-liquid interface cultures. Conclusion:Our study identifies GPR35 as a key driver of EoE pathogenesis via IL-18-mediated barrier dysfunction, revealing a macrophage-epithelial axis that could be targeted therapeutically.