MicroRNA‑microbiome cross‑kingdom networks drive inflammatory bowel disease through dynamic regulatory ecosystems...

Inflammatory bowel disease (IBD) pathogenesis reflects complex interactions between host immunity and gut microbiome dynamics, with microRNAs (miRNAs) functioning as key mediators of cross‑kingdom communication. Host‑derived miRNAs modulate bacterial gene expression and reshape microbial communities, while gut microbiota influences host miRNA expression through microbial metabolites and multiple immune signaling. In IBD, dysregulated miRNAs disrupt immune homeostasis by affecting inflammatory responses, lymphocyte differentiation and epithelial barrier integrity. Yet many miRNAs exhibit context‑dependent dual functions, complicating therapeutic targeting. Despite their biomarker potential for distinguishing IBD subtypes and tracking disease activity, clinical validation faces substantial obstacles including methodological inconsistencies, patient heterogeneity and temporal expression variability. Single-target miRNA therapeutics have yielded modest clinical outcomes, exposing the resilience of regulatory networks and compensatory mechanisms that limit intervention efficacy. The bidirectional architecture of miRNA‑microbiome communication argues against reductionist approaches. Effective IBD management requires integrated strategies that address multiple regulatory nodes rather than isolated pathways. Advancing this field demands deeper investigation of temporal dynamics, spatial organization and network‑level interactions. Such understanding will inform precision medicine strategies that restore regulatory equilibrium without compromising the adaptive capacity of host‑microbiome systems. Progress depends on recognizing the integrated nature of these regulatory networks rather than treating components in isolation.