Unraveling the drug resistance web in IBD: The gut microbiota-immunity-epigenetics axis

Drug resistance in inflammatory bowel disease (IBD) precision therapy remains a critical barrier to clinical outcomes, with traditional studies focusing on single molecules or isolated pathways but failing to systematically dissect the bidirectional, context-dependent dynamic crosstalk among gut microbiota, immunity, and epigenetic modifications. This review dissects resistance mechanisms of key biologics (e.g., antitumor necrosis factor-α agents, vedolizumab) and small-molecule drugs (e.g., janus kinase inhibitors), proposing and validating the "triple-loop hierarchical regulation model"-gut microbiota dysbiosis as the initiator, immune dysregulation as the amplifier, and epigenetic maintenance as the stabilizer, with a bidirectional feedback loop sustaining resistance. It identifies the interaction network as the central regulatory axis, outlining a cascade where altered microbiota composition, signature metabolites (e.g., short-chain fatty acids), epigenetic modification (e.g., acetylation), and Th17/Treg imbalance may collectively contribute to the emergence of drug-resistant phenotypes. Four distinct subtypes (immunogenic, metabolic, epigenetic, barrier-deficient) are defined, with targeted strategies: precise microbiota regulation (e.g., fecal microbiota transplantation), immunity-epigenetics intervention (e.g., histone deacetylase inhibitors), and synergistic schemes that could partially rescue resistant clinical presentations. It also discusses multi-omics biomarkers for early prediction and formulation translation challenges, emphasizing cutting-edge technologies (single-cell multi-omics, organoid-microbiota co-cultures) and interdisciplinary collaboration. This review provides a comprehensive framework for overcoming IBD drug resistance and advancing personalized therapies.