Endoplasmic reticulum stress as a mechanistic link between nutrition and inflammatory bowel disease.

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders that arise from the complex interplay among genetic predisposition, immune dysregulation, environmental factors, and disruption of intestinal epithelial barrier integrity. Increasing evidence suggests that endoplasmic reticulum (ER) stress may represent an important mechanistic pathway in this multifactorial pathogenesis. Experimental evidence indicates that dietary patterns and nutrient-derived factors may modulate ER stress responses. In this review, the role of ER stress in IBD is discussed from a mechanistic perspective, with particular emphasis on the effects of nutrition on ER stress pathways and the relationship between these interactions and IBD pathogenesis. The available findings are evaluated according to whether they derive from direct human IBD studies, experimental colitis models, intestinal cellular systems, or indirect non-intestinal models. Evidence derived predominantly from experimental and non-intestinal metabolic models indicates that high-fat and high-fructose exposures can activate PERK- and IRE1-associated signaling and CHOP-related terminal responses; however, their direct effects on intestinal UPR signaling and epithelial barrier integrity in human IBD have not been established. In contrast, polyunsaturated fatty acids, flavonoids, polyphenols, and certain micronutrients have been reported to modulate selected UPR markers and support cellular adaptation in experimental systems, although differences in dose, bioavailability, and study model limit clinical extrapolation. Collectively, current evidence suggests that ER stress may represent an important mechanistic pathway linking nutrition and intestinal inflammation, although direct causal evidence linking nutritional exposures to mucosal ER stress and clinical outcomes in humans remains limited. Controlled dietary studies incorporating standardized, pathway-specific mucosal biomarkers are required before this mechanistic framework can inform personalized nutritional strategies or ER-stress-targeted interventions.