Intestinal oxygen and microbiota crosstalk: implications for pathogenesis of gastrointestinal diseases and emerging therapeutic strategies

The gut microbiota and its hypoxic host environment play a critical role in human health. Despite its importance, the mechanisms maintaining homeostasis and the characteristics defining dysbiosis remain largely undefined. In particular, the regulation of intestinal oxygen (IO) levels emerges as a critical factor in maintaining microbial balance. Host-driven factors, including epithelial oxygen consumption, mucosal perfusion, and luminal gas diffusion, establish a hypoxic gradient essential for the stable colonization by obligate anaerobes. Disruptions to this gradient, leading to pathological hyperoxia, are associated with overgrowth of facultative anaerobic bacteria and contribute to gastrointestinal diseases like ulcerative colitis, colorectal cancer, and irritable bowel syndrome. Emerging therapeutic approaches focus on modulating IO homeostasis to address dysbiosis. Compounds like sodium tungstate inhibit microbial respiratory pathways, while PPAR-γ agonists enhance mitochondrial efficiency in colonic epithelial cells, thereby restoring proper hypoxia. Dietary interventions and probiotic therapies also hold promise by promoting local anaerobic conditions and enhancing barrier functions, thus supporting the restoration of a healthy microbial community. This review highlights the role of IO in shaping host-microbe interactions, focusing on how host IO levels influence microbial homeostasis. We evaluate the potential for IO modulation to improve gut microbiota structure and explore its impact on microbial metabolism and disease pathogenesis. Additionally, we discuss the promise of dietary, probiotic, and pharmacological interventions in restoring the host's control over the IO microenvironment and microbiota, aiming to prevent and treat related diseases.