Metabolic regulation of gut barrier integrity in IBD: protein, lipid, and carbohydrate pathways
Dietary macronutrients—proteins, lipids, and carbohydrates—influence the pathogenesis of inflammatory bowel disease (IBD) through distinct but interconnected metabolic pathways that extend beyond their roles as energy substrates. This narrative review synthesizes current evidence on how each macronutrient class modulates gut microbiota composition, intestinal barrier integrity, and mucosal immune responses. In the protein domain, the study examines how amino acid metabolism, particularly the tryptophan–kynurenine–indole axis and the arginine–inducible nitric oxide synthase–arginase balance, serves as a regulatory interface between microbial signals and immune cell function, and evaluates the clinical potential of targeted amino acid supplementation. In the lipid domain, a multi-level cascade is traced from phospholipid-dependent barrier structure through the pro-inflammatory/pro-resolving lipid mediator network to immune cell lipid reprogramming, and the study discusses how systemic lipoprotein abnormalities both reflect and amplify intestinal inflammation. In the carbohydrate domain, the study distinguishes between fermentable fiber and high-glycemic carbohydrates, and presents a dual-pathway model in which excess sugar drives IBD through two parallel routes: a microbiota-dependent pathway involving mucus depletion, barrier breach, and short-chain fatty acid deprivation; and a microbiota-independent pathway that directly impairs the metabolism of colonic epithelial stem cells. Throughout the study the emphasis is on the bidirectional nature of diet–inflammation interactions and identifies convergent mechanisms across macronutrient classes. The study concludes by outlining the translational challenges that must be addressed—cross-nutrient interactions, causal inference, and disease-stage-specific interventions—to move from generic dietary guidance toward mechanism-informed, personalized nutritional strategies for IBD, and highlights the need for well-designed intervention studies that test these strategies in defined patient subsets.