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Simple Summary: The gut is lined by a single layer of epithelial cells, creating a barrier between the contents of the gut and the underlying tissue. This barrier also controls permeability (to determine if gut contents move to the tissue) and produces proteins that help with immune responses. These epithelial cells are damaged and do not function properly in inflammatory bowel diseases (IBD). IBD is common, and current treatments are not always effective and can have side effects. New treatments are needed. An alternative treatment target is the epithelial gut lining to promote healing. We used an experimental model of human gut tissue epithelial cells (called organoids) and aimed to define the role of the protein interleukin-27 (IL-27) in epithelial barrier function. We show that IL-27 restored permeability associated with changes in several proteins involved in this process, led to changes in genes involved in the immune response and reaction to bugs in the gut and led to enhanced healing and repair of an injury wound in the barrier. In summary, this study demonstrates a new function of IL-27 in the gut to aid epithelial barrier repair. This is a potential new treatment strategy for IBD. A treatment with direct healing effects on the gastrointestinal epithelial barrier is desirable for inflammatory bowel disease (IBD). Interleukin-27 (IL-27) is an immunoregulatory cytokine, and oral delivery is an effective treatment in murine models of IBD. We aimed to define IL-27 effects on the human gastrointestinal epithelial barrier. We characterised gene and protein expression of permeability mediators in a human colon-derived organoid model. Functional permeability was determined in an organoid-derived 2D monolayer by transepithelial electrical resistance. IL-27 effects on epithelial innate immune responses were assessed through expression of cytokines, anti-microbial peptides and MUC genes. IL-27 effects on wound healing and proliferation were determined in human colon epithelial cell lines. IL-27 led to restoration of permeability regulation following inflammatory cytokine insult (p = 0.001), associated with differential expression of tight junction mediators with decrease in claudin 2 (p = 0.024) and increase in claudin 4 (p < 0.001), E-cadherin (p < 0.001) and zona occludens (p = 0.0014). IL-27 evoked differential gene expression of epithelial-derived innate immune responses (reduced IL1B and IL18, and increased IL33, HBD1, MUC1 and MUC2; p < 0.012). IL-27 induced epithelial barrier wound healing through restitution (p < 0.001), and increased proliferation (p < 0.001) following injury. Overall, IL-27 provokes mucosal healing of the human gastrointestinal epithelial barrier. [ABSTRACT FROM AUTHOR]