From signals to systems: the epigenetic-microbiome-mitochondrial axis in IBD pathogenesis.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is increasingly recognized not merely as an immune-mediated disorder, but as a systems-level condition arising from dynamic interactions among host genetics, environmental exposures, the gut microbiome, and epigenetic regulation. While genetic susceptibility confers risk, accumulating evidence indicates that epigenetic mechanisms act as molecular integrators that translate environmental and microbial signals into sustained transcriptional programs governing immune tolerance, epithelial integrity and tissue repair. Concurrently, intestinal dysbiosis, characterized by loss of short-chain fatty acid-producing commensals and expansion of pro-inflammatory taxa, reshapes host metabolism and chromatin states through microbial-derived metabolites including short-chain fatty acids, secondary bile acids, and tryptophan catabolites. These metabolites affect epigenetic enzymes and modulate the epigenetic chromatin landscape as well as mitochondrial bioenergetics, linking microbial ecology to inflammatory gene regulation. In turn, epigenetic alterations in epithelial and immune compartments influence antimicrobial defense, barrier function, and cytokine networks, thereby sculpting microbial community organization. This bidirectional microbiome-epigenome dialogue creates self-reinforcing circuits that can either sustain mucosal homeostasis or drive chronic inflammation and colitis-associated tumorigenesis. In this review, we synthesize emerging insights into the microbiome-epigenome-mitochondrial axis in IBD and propose a conceptual framework in which metabolic, microbial, and genome-mediated signals converge to determine disease trajectory. We discuss how this integrative perspective may assist biomarker discovery and therapeutic innovation, including epigenetic modulators and microbiota-targeted interventions. Understanding IBD as a dynamically regulated host-microbe ecosystem may accelerate the development of precision strategies aimed at restoring resilient mucosal equilibrium.