Trained immunity: An unexplored component of IBD pathogenesis

Abstract Trained immunity (TI) describes the capability of the innate immune system and its tissue-resident cells to acquire long-lasting functional adaptations following an initial inflammatory or microbial insult. These changes are maintained through coordinated immunometabolic rewiring and epigenetic remodeling, resulting in amplified or altered responses upon subsequent challenges. Inflammatory bowel disease (IBD) is a chronic, relapsing disorder of the gastrointestinal tract, and TI offers a useful framework for understanding disease persistence, relapse proneness, and incomplete resolution despite effective targeting of adaptive immune pathways. While TI has been extensively studies in various chronic inflammatory disorders, its role in IBD remains rather underexplored and largely confined to early preclinical evidence. Within this narrative review, we aim to address this gap by providing current insights into the potential pathogenetic mechanisms underpinning TI in IBD. We examine how the shaping of the behavior of monocytes, macrophages, and their bone marrow progenitors and how steady exposure to microbial ligands, dysbiotic metabolites, and metabolic stressors within the intestinal lumen may establish a sustained proinflammatory “memory” in the context of IBD. From a translational perspective, we consider how TI may favor relapse even during clinical remission and discuss its potential relevance for patient stratification, biomarker identification, and the development of novel therapeutic strategies. Ultimately, integration of TI into IBD pathophysiology may corroborate more lasting, mechanism-based approaches to remission.