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Review
. 2025 May;24(3):e70178.
doi: 10.1111/1541-4337.70178.

Macronutrients as Regulators of Intestinal Epithelial Permeability: Where Do We Stand?

Olga Martínez-Augustin  1 , Mireia Tena-Garitaonaindia  1 , Diego Ceacero-Heras  1 , Ángela Jiménez-Ortas  1 , Juan J Enguix-Huete  2 , Ana I Álvarez-Mercado  2 , Guillermo Ruiz-Henares  2 , Carlos J Aranda  3 , Reyes Gámez-Belmonte  2   4 , Fermín Sánchez de Medina  2
Affiliations
Review

Macronutrients as Regulators of Intestinal Epithelial Permeability: Where Do We Stand?

Olga Martínez-Augustin et al. Compr Rev Food Sci Food Saf. 2025 May.

Abstract

The intestinal barrier function (IBF) is essential for intestinal homeostasis. 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-of-the-art 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-induced autophagy, or the stimulation of sIgA production by high-protein diets in a T-cell-independent 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-derived peptides and glutamine reinforce IBF. Dietary carbohydrates regulate intestinal permeability in a structure- and composition-dependent 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-chain fatty acids, and direct interactions with intestinal cells. Finally, evidence supports avoiding high-fat 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-related diseases.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Intestinal barrier function elements. IEL: intraepithelial lymphocyte; sIgA: secretory immunoglobulin A.
FIGURE 2
FIGURE 2
Tight junction structure and proteins involved. JAM: junction adhesion molecules.
FIGURE 3
FIGURE 3
Zonulae occludens 1 (ZO‐1) domains and TJ protein interaction. ABR: actin‐binding region; Guk: guanylate kinase homology domain; JAM: junction adhesion molecules; U5: unique 5.
FIGURE 4
FIGURE 4
Pore and leak pathways. CLDN: claudin, JAM: junction adhesion molecules; MLC: myosin light chain; MLCK: myosin light chain kinase; OCLN: occludin; ZO: zonulae occludens.
FIGURE 5
FIGURE 5
Regulation of pore and leaky pathways by Na+ and nutrients.
FIGURE 6
FIGURE 6
Summary of the effects of starvation and macronutrients on intestinal permeability.
See this image and copyright information in PMC

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