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Its alterations have been linked to intestinal and systemic disease. Regulation of intestinal permeability is key in the maintenance of the IBF, in which the intestinal epithelium and tight junctions, the mucus layer, sIgA, and antimicrobial peptides are important factors. This review addresses the concept of IBF, focusing on permeability, and summarizes state\u2010of\u2010the\u2010art information on how starvation and macronutrients regulate it. Novel mechanisms regulate intestinal permeability, like its induction by the normal process of nutrient absorption, the contribution of starvation\u2010induced autophagy, or the stimulation of sIgA production by high\u2010protein diets in a T\u2010cell\u2010independent fashion. In addition, observations evidence that starvation and protein restriction increase intestinal permeability, compromising mucin, antimicrobial peptides, and\/or intestinal sIgA production. Regarding specific macronutrients, substantial evidence indicates that casein (compared to other protein sources), specific protein\u2010derived peptides and glutamine reinforce IBF. Dietary carbohydrates regulate intestinal permeability in a structure\u2010 and composition\u2010dependent fashion; fructose, glucose, and sucrose increase it, while nondigestible oligosaccharides (NDOs) decrease it. Among NDOs, human milk oligosaccharides (HMOs) stand as a promising tool. NODs effects are mediated by intestinal microbiota modulation, production of short\u2010chain fatty acids, and direct interactions with intestinal cells. Finally, evidence supports avoiding high\u2010fat diets for their detrimental effects on IBF. Most studies have been carried out in vitro or in animal models. More information is needed from clinical studies to substantiate beneficial effects and the use of macronutrients in the treatment and prevention of IBF\u2010related diseases.<\/jats:p>","DOI":"10.1111\/1541-4337.70178","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T07:45:17Z","timestamp":1748331917000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Macronutrients as Regulators of Intestinal Epithelial Permeability: Where Do We Stand?"],"prefix":"10.1111","volume":"24","author":[{"given":"Olga","family":"Mart\u00ednez\u2010Augustin","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology II, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd), School of Pharmacy, Insituto de Nutrici\u00f3n y Tecnolog\u00eda de los alimentos Jos\u00e9 Mataix and Instituto de Investigaci\u00f3n 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Nutrici\u00f3n y Tecnolog\u00eda de los alimentos Jos\u00e9 Mataix and Instituto de Investigaci\u00f3n Biosanitaria ibs.GRANADA University of Granada  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1ngela","family":"Jim\u00e9nez\u2010Ortas","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology II, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd), School of Pharmacy, Insituto de Nutrici\u00f3n y Tecnolog\u00eda de los alimentos Jos\u00e9 Mataix and Instituto de Investigaci\u00f3n Biosanitaria ibs.GRANADA University of Granada  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan J.","family":"Enguix\u2010Huete","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd), School of Pharmacy, Instituto 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