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The brain\u2013bone\u2013gut axis, proposed in recent years, provides an integrative physiological framework describing a bidirectional regulatory network linking the central nervous system, bone metabolism, and the GM via neural, endocrine, and immune pathways, thereby offering a unified perspective on multi-organ comorbidities. This article systematically examines the interconnections and synergistic effects across three core pathways within this framework: the brain\u2013bone axis, the gut\u2013bone axis, and the gut\u2013brain axis. It further emphasizes immune-inflammatory processes as a central hub that connects gut dysbiosis with bone metabolic disturbances and alterations in brain function. On this basis, we propose an integrated approach that combines microecological interventions with nutritional and exercise management to improve gut homeostasis, preserve skeletal health, and support brain function, with the overarching aim of generating coordinated benefits across organ systems.<\/jats:p>","DOI":"10.3389\/fendo.2026.1755305","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T05:28:55Z","timestamp":1772083735000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["The brain\u2013bone\u2013gut axis: a microbial bridge underlying multisystem comorbidities"],"prefix":"10.3389","volume":"17","author":[{"given":"Xingli","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Coloproctology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine","place":["Shanghai, 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