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This bioprocessing weakens the matrix and promotes the release of the phenolic compounds, which then exert beneficial effects on intestinal function. Although this notion is widely accepted, supporting evidence remains scarce. In this study, we subjected grape pomace skin to in vitro digestion to obtain an indigestible fraction suitable for SHIME bioreactors. Throughout these stages, we observed a sequential increase in the release of phenolic compounds, with colonic fermentation playing an important role. Although we did not observe an increase in short-chain fatty acid (SCFA) production by the gut microbiota, we performed a repeated-challenge design on differentiated Caco-2 monolayers. With this approach, we found that the phenolic-rich ferment prevented the transepithelial electrical resistance (TEER) drop on the second challenge and modulated the transcriptomic profile assessed by RNA-seq. Our findings indicate that the Caco-2 cellular responses mentioned above were SCFA-independent and likely due to the differential impact of phenolic compound load after colonic fermentation of grape pomace skin.<\/jats:p>","DOI":"10.3390\/ijms27094123","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T10:01:30Z","timestamp":1777975290000},"page":"4123","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Phenolic Compounds of Grape Pomace Skin Released During SHIME Colonic Fermentation Shape the Transcriptomic Profile of Tight Junctions, Improving the Barrier Properties in Caco-2 Cells"],"prefix":"10.3390","volume":"27","author":[{"given":"Miltha","family":"Hidalgo","sequence":"first","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en Nutrici\u00f3n Funcional, Instituto de Nutrici\u00f3n y Tecnolog\u00eda de los Alimentos (INTA), Universidad de Chile, El L\u00edbano 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