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Lithocholic acid is a secondary bile acid drastically reduced during active inflammatory bowel disease but mediates beneficial effects at the mucosal intestinal barrier during intestinal homeostasis. In a dextran sodium sulfate-induced colitis-on-chip model, it was investigated whether the administration of lithocholic acid has a protective impact on inflammation-mediated tissue damage. Physiological responses were successfully recapitulated in the human colitis model, enabling the dissection of individual cell responses. Treatment with lithocholic acid concentrations similar to healthy human intestinal levels efficiently ameliorated the colitis-like phenotype. Lithocholic acid treatment stimulated epithelial cell proliferation, thereby maintaining villus morphology, intestinal barrier integrity, and reducing inflammation. 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