{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T21:48:39Z","timestamp":1787694519299,"version":"build-2784847793"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>The emergence and development of bone tumors stem from a combination of intrinsic genetic alterations in tumor cells, remodeling of the bone marrow microenvironment, and shifts in the host\u2019s systemic immune-metabolic state. In recent years, gut microorganisms have been shown not only to influence bone mass regulation and conditions involving disrupted bone homeostasis, such as osteoporosis, but also to substantially affect the formation of primary bone tumors and metastatic lesions by modulating immune cell differentiation, inflammatory activity, and the coupling of bone remodeling. Focusing on the \u201cMicrobiota\u2013Immune\u2013Bone axis\u201d (MIB), a growing body of fundamental and translational research indicates that alterations in gut microbial composition and function can reshape metabolite profiles\u2014including short-chain fatty acids, bile acids, indole derivatives\u2014and pathogen-associated molecular patterns (PAMPs). These signals act on the intestinal barrier and bone marrow immunity through G-protein\u2013coupled receptors, nuclear receptors, and pattern-recognition receptors, thereby shifting the balance between bone resorption and formation and modifying the immune characteristics of the bone microenvironment, ultimately facilitating bone tumor cell colonization, proliferation, and immune escape. This review takes the MIB axis as its central framework to integrate the major pathways through which gut microbes and their metabolites regulate intestinal and myeloid immunity, bone remodeling, and bone tumor biology, to construct a systems-level model of tumor initiation and progression, to identify druggable signaling nodes, and to assess the potential and challenges of microbiota-modulating approaches\u2014including antibiotics, probiotics, dietary strategies, and fecal microbiota transplantation\u2014in preventing and treating bone tumors, thereby offering a theoretical foundation for developing integrated interventions targeting the gut microbiota and the MIB axis.<\/jats:p>","DOI":"10.3389\/fcimb.2026.1762046","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T06:45:48Z","timestamp":1770187548000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["The role of the microbial-immune-bone axis in bone tumor development: mechanistic integration, systems modeling, and intervention prospects"],"prefix":"10.3389","volume":"16","author":[{"given":"Yan","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Oncology, Mianyang Fulin Hospital, Mianyang Fulin Hospital Co., Ltd","place":["Mianyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Mianyang Fulin Hospital, Mianyang Fulin Hospital Co., Ltd","place":["Mianyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaokun","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mianyang Fulin Hospital, Mianyang Fulin Hospital Co., Ltd","place":["Mianyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongzhong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology, Luxian People\u2019s Hospital","place":["Luzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueyan","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Oncology, Luxian People\u2019s Hospital","place":["Luzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1038\/nrgastro.2017.20","article-title":"Gut microbiota modulation of chemotherapy efficacy and toxicity","volume":"14","author":"Alexander","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"641","DOI":"10.3390\/microorganisms3040641","article-title":"The gut microbiota as a therapeutic target in ibd and metabolic disease: A role for the bile acid receptors fxr and tgr5","volume":"3","author":"Baars","year":"2015","journal-title":"Microorganisms"},{"key":"B3","doi-asserted-by":"publisher","first-page":"4229","DOI":"10.3390\/cancers13164229","article-title":"Recent advances in the treatment of bone metastases and primary bone tumors: an up-to-date review","volume":"13","author":"B\u0103dil\u0103","year":"2021","journal-title":"Cancers"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1978","DOI":"10.3390\/cells10081978","article-title":"The roadmap of rankl\/rank pathway in cancer","volume":"10","author":"Casimiro","year":"2021","journal-title":"Cells"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.877776","article-title":"Gut microbiota and bone diseases: A growing partnership","volume":"13","author":"Chen","year":"2022","journal-title":"Front. Microbiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1097\/MIB.0000000000000955","article-title":"An overview of the innate and adaptive immune system in inflammatory bowel disease","volume":"23","author":"Choy","year":"2017","journal-title":"Inflamm. Bowel. Dis."},{"key":"B7","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1053\/j.gastro.2022.10.018","article-title":"Gut microbiota modulation of efficacy and toxicity of cancer chemotherapy and immunotherapy","volume":"164","author":"Chrysostomou","year":"2023","journal-title":"Gastroenterology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1152\/physrev.00012.2019","article-title":"Bone metastasis: mechanisms, therapies, and biomarkers","volume":"101","author":"Cl\u00e9zardin","year":"2021","journal-title":"Physiol. Rev."},{"key":"B9","doi-asserted-by":"publisher","first-page":"6243s","DOI":"10.1158\/1078-0432.CCR-06-0931","article-title":"Clinical features of metastatic bone disease and risk of skeletal morbidity","volume":"12","author":"Coleman","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2021.617485","article-title":"Dysbiosis from a microbial and host perspective relative to oral health and disease","volume":"12","author":"Cugini","year":"2021","journal-title":"Front. Microbiol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1007\/s00223-017-0331-y","article-title":"Gut microbiota, immune system, and bone","volume":"102","author":"D\u2019Amelio","year":"2018","journal-title":"Calcified. Tissue Int."},{"key":"B12","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1080\/02648725.2021.1989847","article-title":"Gut-microbiota derived bioactive metabolites and their functions in host physiology","volume":"37","author":"Debnath","year":"2021","journal-title":"Biotechnol. Genet. Eng. Rev."},{"key":"B13","doi-asserted-by":"publisher","first-page":"743","DOI":"10.3390\/cells11040743","article-title":"Role of dietary supplements and probiotics in modulating microbiota and bone health: the gut-bone axis","volume":"11","author":"de Sire","year":"2022","journal-title":"Cells"},{"key":"B14","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1038\/s41568-022-00513-x","article-title":"Targeting the gut microbiota for cancer therapy","volume":"22","author":"Fernandes","year":"2022","journal-title":"Nat. Rev. Cancer"},{"key":"B15","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1016\/j.tips.2009.08.001","article-title":"Bile-acid-activated receptors: targeting tgr5 and farnesoid-X-receptor in lipid and glucose disorders","volume":"30","author":"Fiorucci","year":"2009","journal-title":"Trends Pharmacol. Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.critrevonc.2019.09.003","article-title":"Gut microbiota and cancer: how gut microbiota modulates activity, efficacy and toxicity of antitumoral therapy","volume":"143","author":"Gori","year":"2019","journal-title":"Crit. Rev. Oncology\/Hematol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"210","DOI":"10.3390\/cancers13020210","article-title":"The functional crosstalk between myeloid-derived suppressor cells and regulatory T cells within the immunosuppressive tumor microenvironment","volume":"13","author":"Haist","year":"2021","journal-title":"Cancers"},{"key":"B18","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/B978-0-12-416721-6.00001-7","article-title":"Epidemiology of primary bone tumors and economical aspects of bone metastases","author":"Hauben","year":"2015","journal-title":"Bone Cancer"},{"key":"B19","doi-asserted-by":"publisher","first-page":"2495","DOI":"10.1007\/s00198-022-06557-x","article-title":"The potential mechanism of the microbiota-gut-bone axis in osteoporosis: A review","volume":"33","author":"He","year":"2022","journal-title":"Osteoporosis. Int."},{"key":"B20","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1038\/s41571-021-00499-9","article-title":"Novel approaches to target the microenvironment of bone metastasis","volume":"18","author":"Hofbauer","year":"2021","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"482","DOI":"10.21037\/atm.2020.03.55","article-title":"Incidence of patients with bone metastases at diagnosis of solid tumors in adults: A large population-based study","volume":"8","author":"Huang","year":"2020","journal-title":"Ann. Trans. Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1038\/s41579-024-01107-0","article-title":"Examining the healthy human microbiome concept","volume":"23","author":"Joos","year":"2025","journal-title":"Nat. Rev. Microbiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1038\/s41571-019-0272-7","article-title":"Oncolysis without viruses\u2014Inducing systemic anticancer immune responses with local therapies","volume":"17","author":"Kepp","year":"2020","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.748254","article-title":"Crosstalk between intestinal serotonergic system and pattern recognition receptors on the microbiota-gut-brain axis","volume":"12","author":"Layunta","year":"2021","journal-title":"Front. Endocrinol. (Lausanne)."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.824117","article-title":"Roles of the rankl\u2013rank axis in immunity\u2014Implications for pathogenesis and treatment of bone metastasis","volume":"13","author":"Li","year":"2022","journal-title":"Front. Immunol."},{"key":"B26","first-page":"321","article-title":"Bone metastases: an overview","volume":"11","author":"Macedo","year":"2017","journal-title":"Oncol. Rev."},{"key":"B27","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1002\/ajpa.10398","article-title":"Life history theory and the immune system: steps toward a human ecological immunology","volume":"122","author":"McDade","year":"2003","journal-title":"Am. J. Phys. Anthropol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1146\/annurev.anthro.34.081804.120348","article-title":"The ecologies of human immune function","volume":"34","author":"McDade","year":"2005","journal-title":"Annu. Rev. Anthropol."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.01283","article-title":"Targeting the rankl\/rank\/opg axis for cancer therapy","volume":"10","author":"Ming","year":"2020","journal-title":"Front. Oncol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1242\/dmm.017400","article-title":"How informative is the mouse for human gut microbiota research","volume":"8","author":"Nguyen","year":"2015","journal-title":"Dis. Models Mech."},{"key":"B31","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1097\/00003081-198712000-00004","article-title":"Bone remodeling and bone loss: understanding the pathophysiology of osteoporosis","volume":"30","author":"Parfitt","year":"1987","journal-title":"Clin. Obstet. Gynecol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1016\/j.molmed.2023.07.002","article-title":"The global human gut microbiome: genes, lifestyles, and diet","volume":"29","author":"Parizadeh","year":"2023","journal-title":"Trends Mol. Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1016\/j.ccell.2023.02.018","article-title":"Immune determinants of the pre-metastatic niche","volume":"41","author":"Patras","year":"2023","journal-title":"Cancer Cell"},{"key":"B34","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1152\/physrev.00049.2019","article-title":"Molecular physiology of bile acid signaling in health, disease, and aging","volume":"101","author":"Perino","year":"2021","journal-title":"Physiol. Rev."},{"key":"B35","first-page":"1353","article-title":"Physiology and pathophysiology of bone remodeling","volume":"45","author":"Raisz","year":"1999","journal-title":"Clin. Chem."},{"key":"B36","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1038\/nature25973","article-title":"Environment dominates over host genetics in shaping human gut microbiota","volume":"555","author":"Rothschild","year":"2018","journal-title":"Nature"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1709","DOI":"10.1136\/gutjnl-2017-313872","article-title":"Feeding the microbiota: transducer of nutrient signals for the host","volume":"66","author":"Shanahan","year":"2017","journal-title":"Gut"},{"key":"B38","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1016\/j.clnesp.2024.08.005","article-title":"Targeting the microbiome to improve human health with the approach of personalized medicine: latest aspects and current updates","volume":"63","author":"Shukla","year":"2024","journal-title":"Clin. Nutr. ESPEN."},{"key":"B39","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1038\/s41571-023-00803-9","article-title":"Towards modulating the gut microbiota to enhance the efficacy of immune-checkpoint inhibitors","volume":"20","author":"Simpson","year":"2023","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1546","DOI":"10.3390\/medicina59091546","article-title":"From cells to environment: exploring the interplay between factors shaping bone health and disease","volume":"59","author":"Singh","year":"2023","journal-title":"Medicina"},{"key":"B41","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1038\/s41577-019-0178-8","article-title":"Osteoimmunology: evolving concepts in bone\u2013immune interactions in health and disease","volume":"19","author":"Tsukasaki","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1002\/JLB.3MR0321-755R","article-title":"The microbiota-gut-bone axis and bone health","volume":"110","author":"Tu","year":"2021","journal-title":"J. Leukocyte. Biol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"3365","DOI":"10.1172\/JCI80006","article-title":"Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages","volume":"125","author":"Ugel","year":"2015","journal-title":"J. Clin. Invest."},{"key":"B44","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1038\/s41577-020-00490-y","article-title":"Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity","volume":"21","author":"Veglia","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"3688","DOI":"10.3390\/ijms21103688","article-title":"Gut microbiota metabolism and interaction with food components","volume":"21","author":"Vernocchi","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1111\/j.0105-2896.2005.00336.x","article-title":"Osteoclast precursors, rankl\/rank, and immunology","volume":"208","author":"Xing","year":"2005","journal-title":"Immunol. Rev."},{"key":"B47","doi-asserted-by":"publisher","first-page":"3697","DOI":"10.7150\/ijms.61080","article-title":"The role of the immune microenvironment in bone regeneration","volume":"18","author":"Yang","year":"2021","journal-title":"Int. J. Med. Sci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"7510","DOI":"10.1080\/10408398.2022.2047005","article-title":"The regulative effect and repercussion of probiotics and prebiotics on osteoporosis: involvement of brain-gut-bone axis","volume":"63","author":"Zhang","year":"2023","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"B49","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/s13073-016-0296-x","article-title":"Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions","volume":"8","author":"Zhang","year":"2016","journal-title":"Genome Med."},{"key":"B50","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/s12979-020-00202-z","article-title":"The correlation between the th17\/treg cell balance and bone health","volume":"17","author":"Zhu","year":"2020","journal-title":"Immun. Ageing"}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2026.1762046\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T06:45:49Z","timestamp":1770187549000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2026.1762046\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,4]]},"references-count":50,"alternative-id":["10.3389\/fcimb.2026.1762046"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2026.1762046","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,4]]},"article-number":"1762046"}}