Immunometabolic and epigenetic reprogramming in inflammatory bowel disease: from mechanistic circuits to therapeutic targeting

Abstract Inflammatory bowel disease (IBD) is a chronic, immune-mediated disorder of the gastrointestinal tract and an escalating global public health challenge, particularly in newly industrializing regions. Its etiology and pathogenesis remain incompletely understood, although disrupted homeostasis between the intestinal microbiota and the mucosal immune system is implicated. Macrophages and T cells contribute to the balance between tissue injury and repair. Increasing evidence suggests that metabolic state and epigenetic programs interact to influence immune cell function. Under hypoxic and inflammatory stress, glucose, lipid, and amino acid metabolism can undergo remodeling, including shifts between glycolysis and oxidative phosphorylation, altered fatty-acid utilization, changes in tryptophan and methionine metabolism, and fluctuations in methyl-donor availability. Metabolic cues may influence chromatin regulation and immune signaling through acetylation, methylation, lactylation, palmitoylation, phosphorylation, and other modifications. These processes can affect effector programs, the T helper 17–regulatory T cell balance, macrophage inflammatory gene expression, inflammasome activation, and interleukin-10–related signaling, with potential implications for mucosal barrier repair and inflammatory amplification. However, the causal roles of these metabolic and epigenetic alterations in IBD remain to be clarified: they may contribute to disease initiation, arise as accompanying features of the disease state, or amplify inflammation once it is established. This review synthesizes current advances in metabolic reprogramming and epigenetic regulation in macrophages and T cells, examining immunometabolic nodes that link environmental stress to chromatin remodeling. We further summarize emerging therapeutic strategies targeting metabolic and epigenetic pathways, assess evidence from preclinical and clinical studies, and discuss interventions directed at immunometabolic checkpoints.