Microbial metabolic memory in inflammatory bowel disease: microbiota-derived metabolites, host-microbe reprogramming, and relapse susceptibility.

Inflammatory bowel disease (IBD) is increasingly recognized as a disorder of disrupted host-microbe metabolic communication rather than a consequence of microbial dysbiosis alone. Gut microbiota-derived metabolites, including short-chain fatty acids, tryptophan derivatives, bile acid metabolites, polyamines, lactate, succinate, and trimethylamine N-oxide, act as functional mediators linking microbial ecological changes to epithelial barrier integrity, mucosal immune activation, inflammatory amplification, and tissue repair. However, most existing discussions have focused on individual metabolites or isolated immune pathways, leaving the dynamic and disease-stage-specific nature of microbial metabolic remodeling insufficiently defined. In this review, we reframe IBD pathogenesis from the perspective of microbial metabolic memory, emphasizing how persistent alterations in microbial metabolic output may imprint epithelial and immune cell responses even after clinical remission. We summarize how protective metabolite depletion and proinflammatory metabolite accumulation contribute to immune tolerance breakdown, barrier dysfunction, inflammatory propagation, extraintestinal immune manifestations, and relapse susceptibility. We further discuss how mucosal inflammation reciprocally reshapes microbial niches, oxygen tension, nutrient availability, and metabolic pathway activity, thereby establishing self-reinforcing host-microbe feedback loops. Finally, we evaluate emerging therapeutic strategies, including metabolite supplementation, blockade of proinflammatory metabolic signaling, microbiota-based metabolic remodeling, engineered probiotics, and metabolomics-guided precision interventions. This metabolic-memory framework may provide a more integrated basis for understanding IBD recurrence and for developing microbiota-targeted strategies aimed at restoring durable intestinal homeostasis.