Gut-heart axis at high altitude: a dynamic mediator from hypoxic dysbiosis to adaptive cardioprotection

High-altitude hypoxia severely disrupts physiological homeostasis and markedly increases cardiovascular disease (CVD) risk through mechanisms that remain incompletely understood. Emerging evidence regards the gut microbiota as a crucial dynamic regulator within the gut-heart axis, constructing a bridge between the environmental hypoxic stress and the cardiovascular outcomes. This review has summarized the dynamic changes of the gut microbiota in high-altitude environments, from acute dysregulation to adaptive remodeling. We systematically delineate the pathogenic mechanisms whereby acute microbial imbalance drives CVD: at the metabolic level, there is a reduction in the production of short-chain fatty acids (SCFAs), accumulation of trimethylamine N-oxide (TMAO), buildup of hypoxia-induced energy metabolism intermediates (lactic acid and succinic acid), and dysregulation of secondary bile acid metabolism. At the immune inflammatory level, impaired intestinal barrier leads to lipopolysaccharide (LPS) translocation, combined with hypoxia-inducible factor-1α (HIF-1α) overexpression, collectively promoting the development of atherosclerosis, hypertension, and heart failure. The adaptive remodeling reduces vascular injury by enhancing myocardial energy metabolism mediated by SCFA, strengthening the intestinal barrier, regulating anti-inflammatory immunity, stabilizing blood pressure, and also reprogramming uric acid metabolism, thereby playing a role in cardiac protection. Finally, we propose microbiome-targeted intervention strategies, including high-fiber dietary modulation, probiotic/prebiotic/synbiotic supplementation, fecal microbiota transplantation, and metabolite-directed therapies, which provides new theoretical basis and precise therapeutic targets for the prevention of cardiovascular diseases in high-altitude environments.