Abstract
Abstract Background Methylxanthine caffeine and its metabolites are widely consumed bioactive compounds that are known to influence various physiological processes 1. However, their impact on gut health, particularly in modulating inflammation and epithelial permeability, remains underexplored. In this study we aimed to investigate the effects of caffeine and its primary metabolites paraxanthine, theobromine and theophylline on inflammatory responses and barrier integrity in gut epithelial models, providing insights into their potential role in gastrointestinal health in the context of Inflammatory bowel disease (IBD). Methods Primary screening of different concentrations of caffeine and its metabolites paraxanthine, theobromine and theophylline was performed in Caco-2 cells. Selected metabolites were further tested on inflamed 3D intestinal epithelial organoids derived from ulcerative colitis patient (n = 1) and non-IBD individual (n = 1). Inflammation was induced for 24 h using TNF-α and IFN-γ cytokine mix. The effects on inflammation status and epithelial barrier integrity were tested through targeted gene expression analysis using RT-PCR, while the effects on generation of reactive oxygen species were investigated by Flow cytometry and DHE assay. Results Primary screening revealed that both caffeine and its metabolite paraxanthine affected the expression of genes encoding inflammatory cytokines (TNF-α, CXCL9; p < 0.05) and tight junction proteins (OCLN, ZO-1, CLDN1; p < 0.05) and were selected for further analysis in 3D intestinal organoids. Neither caffeine nor paraxanthine reduced the expression of inflammatory cytokine-encoding genes in inflamed intestinal organoids. However, both metabolites significantly restored the expression of tight junction protein-coding genes OCLN, ZO-1 and CLDN1 (p < 0.05). A tendency of reduction in reactive oxygen species production (by 11 %) was also observed after exposure with paraxanthine. Conclusion Methylxanthine caffeine and its primary metabolite paraxanthine might have a positive effect on gut epithelial barrier function through restoration of the expression of tight junction protein-coding genes. Study was funded by the European Union and the State Secretariat for Education, Research and Innovation (SERI) (project: miGut-Health, grant no. 101095470). References Reddy V. S. et al. (2024) Pharmacology of caffeine and its effects on the human body. European Journal of Medicinal Chemistry Reports, 10 (100138). https://doi.org/10.1016/j.ejmcr.2024.100138.
Published Version
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