Gut microbiota metabolites in inflammatory bowel disease: advances in mechanistic insights

Inflammatory bowel disease (IBD), primarily comprising Crohn's disease and ulcerative colitis, represents a group of chronic, relapsing intestinal inflammatory conditions mediated by immune dysregulation. Emerging evidence has established the gut microbiota and its metabolic products as central players in IBD pathogenesis. The human gut microbiota constitutes a vast and dynamic micro-ecosystem whose metabolic activities generate a diverse array of small molecules, including short-chain fatty acids, bile acids, and tryptophan-derived metabolites. These metabolites collectively form a "gut microbiota-metabolite-immune axis" that is deeply involved in maintaining intestinal homeostasis, and their dysregulation is closely linked to IBD initiation and progression. Patients with IBD typically exhibit significant alterations in gut microbial composition and function, with key metabolic perturbations characterized by reduced levels of SCFAs and secondary bile acids, as well as imbalances in specific amino acid-derived metabolites. SCFAs not only serve as essential energy substrates for colonic epithelial cells but also modulate immune responses and enhance barrier integrity through G protein-coupled receptors and inhibition of histone deacetylases. Bile acids contribute to barrier function and immune balance via activation of nuclear receptors such as the farnesoid X receptor and the G protein-coupled bile acid receptor 1. Tryptophan, metabolized by both host enzymes and the gut microbiota into kynurenine, serotonin, and various indole derivatives, participates in immunoregulation through pathways involving the aryl hydrocarbon receptor. These examples underscore the pivotal roles of gut microbial metabolites in both the pathogenesis and treatment of IBD. This review aims to synthesize recent advances in understanding the functions and molecular mechanisms of key gut microbial metabolites in IBD, with a focus on how they orchestrate the initiation and perpetuation of intestinal inflammation through complex immunoregulatory networks and modulate intestinal barrier function. By providing new insights into the mechanisms underlying IBD pathogenesis and intervention, this review seeks to establish a theoretical foundation for the development of novel diagnostic and therapeutic strategies targeting microbial metabolites.