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This review systematically summarizes the dynamic compositional and functional changes in the gut microbiota in high-altitude natives, immigrant populations, short-term visitors, and relevant animal models. Current evidence indicates that long-term high-altitude adaptation is associated with directional microbial remodeling, including the enrichment of anaerobic and short-chain fatty acid (SCFA)-associated taxa, which may support energy metabolism and immune homeostasis. In contrast, acute high-altitude exposure more readily induces dysbiosis, impairs intestinal barrier integrity, and promotes the translocation of endotoxins and bioactive metabolites. Mechanistically, the gut microbiota and its metabolites participate in high-altitude adaptation and high-altitude-related disease pathogenesis by modulating barrier function, inflammatory responses, oxidative stress, and immune signaling, and by mediating interorgan communication\u2014characterized by metabolite-driven systemic inflammation or tolerance\u2014through the gut\u2013lung, gut\u2013heart, gut\u2013brain, gut\u2013kidney, and gut\u2013testis axes. SCFAs, bile acids, amino acid-derived metabolites, and succinic acid may control immune homeostasis and inflammatory responses through pathways including TLR4\/NF-\u03baB and NLRP3. Although the causal relationships, core microbial effectors, and population-specific heterogeneity remain incompletely defined, microbiota-targeted interventions, including probiotics, prebiotics, and fecal microbiota transplantation, have shown promise for promoting acclimatization and preventing high-altitude-related disorders. Overall, this review provides an integrated framework linking environmental stress, gut microbial ecology, and host immune\u2013metabolic adaptation at high altitude, and highlights future directions for mechanistic and translational research in high-altitude medicine.<\/jats:p>","DOI":"10.3390\/ijms27115096","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T01:23:21Z","timestamp":1780622601000},"page":"5096","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effects of High-Altitude Environments on Gut Microbiota and Their Mechanisms in Immune Regulation and High-Altitude Adaptation"],"prefix":"10.3390","volume":"27","author":[{"given":"Zhipeng","family":"Lu","sequence":"first","affiliation":[{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guojing","family":"Chen","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyang","family":"Chang","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningning","family":"Wang","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiantian","family":"Xia","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaoyuan","family":"Xu","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Zhao","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Shen","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0435-7261","authenticated-orcid":false,"given":"Wei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhexin","family":"Ni","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Gao","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1089\/ham.2024.0107","article-title":"Medical Problems of Chronic Hypoxia in Highlanders Living on the Tibetan Plateau","volume":"26","author":"Ge","year":"2025","journal-title":"High Alt. 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