<p>With the increasing number of individuals travelling to or residing in high-altitude regions, understanding the physiological and pathological consequences of such environments has become increasingly important. High-altitude exposure poses significant challenges to human health, primarily due to hypobaric hypoxia, which triggers a cascade of responses, including energy deficiency, oxidative stress, and inflammation. One of the critical consequences is the disruption of the gut barrier, which facilitates the translocation of the gut microbiota and further exacerbates local and systemic inflammation. Notably, the gut microbiota, a dynamic environmental sensor, undergoes significant remodelling in high-altitude environments. The modified production of microbial metabolites such as bile acids influences gut homeostasis as well as glucose and lipid metabolism, and ultimately contributes to individual variability in high-altitude acclimatization. These changes have been implicated in the pathogenesis of altitude-related illnesses such as acute and chronic mountain sickness, as well as in metabolic and gastrointestinal disorders such as diabetes, obesity, irritable bowel syndrome, colorectal cancer, cholelithiasis, and osteoporosis. Preliminary explorations have demonstrated the therapeutic potential of microbiome-based interventions such as faecal microbiota transplantation in acute and chronic mountain sickness. Further research into gut microbiota modulation may provide applicable options for promoting high-altitude acclimatization and preventing high-altitude illness.</p>