Gut microbiota and metabolite remodeling under hypoxia compromises the intestinal barrier

Globally, the incidence of digestive diseases remains persistently high. The intestinal mucosal barrier, a dynamic interface composed of mechanical, chemical, immunological, and microbial components, serves as the primary defense against factors that damage the intestinal mucosa. As a fundamental stressor in both physiological and pathological states of the gastrointestinal tract, hypoxia rapidly activates hypoxia-inducible factor (HIF) in tissue cells, initiating a series of adaptive responses. Notably, the biological effects of HIF are significantly dependent on the environment. Under acute or mild hypoxia, HIF primarily exerts protective functions to maintain the integrity of the intestinal barrier. Conversely, under chronic or severe hypoxia, sustained HIF overactivation induces a "pathological switch" in its function, disrupting intestinal homeostasis by triggering inflammatory responses. This review employs the "microbiota-metabolite-barrier axis" as its core framework to systematically elucidate the molecular mechanisms by which pathological hypoxia remodels the gut microbial community structure, alters microbial metabolite production, and ultimately triggers intestinal mucosal barrier dysfunction via the HIF-1/NF-κB signaling pathway. This review systematically examines the molecular basis of interactions among nodes within this axis and explores recent advances and potential therapeutic value in modulating this axis (e.g., such as supplementation with specific metabolites or regulation of HIF/NF-κB activity) for intervention in intestinal diseases.