Advances in Dietary Modulation of the Intestinal Barrier: Mechanistic, Structural, and Functional Insights

ABSTRACT The intestinal barrier maintains host health through the coordinated integration of mechanical, chemical, immune, and microbial defenses across intestinal segments. Dietary factors are key regulators of barrier integrity, yet the mechanisms by which nutrients act during digestion, absorption, and microbial metabolism from the small intestine to the colon remain incompletely understood, with segment‐specific functions often overlooked. This review summarizes recent advances and elucidates how dietary proteins, carbohydrates, lipids, micronutrients, and bioactive compounds shape intestinal barrier function through “nutrient–gut–host” interactions, providing theoretical support for precision nutrition. Specifically, in the small intestine, preclinical evidence demonstrates that dietary proteins, including milk and soy proteins, upregulate tight junction (TJ) expression and support epithelial repair. Rapidly absorbed carbohydrates modulate small‐intestinal barrier function via glycemic regulation and incretin signaling, whereas lipids—particularly saturated versus polyunsaturated fatty acids—differentially affect mucosal inflammation and epithelial protection through absorption pathways and chylomicron trafficking. In the colon, fermentable carbohydrates, such as inulin, and fructooligosaccharides promote microbial fermentation and short‐chain fatty acid (SCFA) production—especially butyrate—which strengthens epithelial integrity, stimulates mucus secretion, and regulates immune responses. Micronutrients, including zinc, iron, and vitamins, maintain barrier structure, microbial balance, and immune signaling across both intestinal segments, whereas bioactive compounds, such as probiotics, prebiotics, and postbiotics, enhance colonic barrier integrity by upregulating TJs, stimulating mucus secretion, and supporting beneficial microbes. Finally, this review emphasizes the need to assess coordinated dietary effects along the entire small‐to‐large intestine continuum to better guide targeted nutritional strategies for human health.