{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T22:37:03Z","timestamp":1792708623615,"version":"4.5.0"},"reference-count":42,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T00:00:00Z","timestamp":1749081600000},"content-version":"vor","delay-in-days":155,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82074471"],"award-info":[{"award-number":["82074471"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012246","name":"Priority Academic Program Development of Jiangsu Higher Education Institutions","doi-asserted-by":"publisher","award":["035062005001"],"award-info":[{"award-number":["035062005001"]}],"id":[{"id":"10.13039\/501100012246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Mediators of Inflammation"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p>\n                    <jats:bold>Background:<\/jats:bold>\n                    The role of gut microbiota and its metabolites in regulating bone metabolism has been well established, with inflammatory immune responses potentially playing a critical role. Glucocorticoid\u2010associated osteonecrosis of the femoral head (GA\u2010ONFH), caused by high\u2010dose glucocorticoid use for inflammatory or immune\u2010related diseases, is a prevalent condition of bone metabolic imbalance. However, the regulatory role and mechanisms of gut microbiota and its metabolites in the development and progression of GA\u2010ONFH remain unclear. This study aims to investigate the intervention effects of gut microbiota and its metabolite butyric acid on GA\u2010ONFH through a series of multi\u2010omics\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    experiments.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Methods:<\/jats:bold>\n                    Sprague Dawley rats were randomly divided into four groups. The gut microbial composition of the groups was analyzed through 16S rDNA sequencing. Targeted metabolomics was employed to assess differences in short\u2010chain fatty acids (SCFAs) among the groups. Butyric acid, identified as a key differential metabolite, was then selected for further exploration of its effects on bone marrow mesenchymal stem cells (BMSCs) and GA\u2010ONFH rat models through\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    experiments.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Results:<\/jats:bold>\n                    16S rDNA sequencing revealed alterations in gut microbiota structure in GA\u2010ONFH rats. Micro\u2010CT and HE staining demonstrated that depletion of gut microbiota with broad\u2010spectrum antibiotics prior to GA\u2010ONFH modeling exacerbated the disease\u2019s development. In contrast, fecal microbiota transplantation (FMT) was shown to alleviate GA\u2010ONFH progression. Targeted metabolomics indicated that FMT mitigated the reduction in butyric acid levels induced by dexamethasone (DXM). Subsequent\n                    <jats:italic>in vitro<\/jats:italic>\n                    cell experiments confirmed that butyric acid promotes BMSC proliferation, migration, and osteogenic differentiation. RNA sequencing revealed that butyric acid regulates T cell\u2010mediated inflammatory cytokine genes in BMSCs, while Western blot and immunofluorescence assays confirmed that butyric acid modulates the expression of TNF\u2010\u03b1 and IL\u20102\/IL\u20104 in BMSCs. Finally,\n                    <jats:italic>in vivo<\/jats:italic>\n                    experiments demonstrated that butyric acid supplementation attenuated the progression of GA\u2010ONFH and improved the expression of inflammation\u2010related cytokines in femoral head tissue.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Conclusions:<\/jats:bold>\n                    Our study demonstrates that gut microbiota depletion exacerbates GA\u2010ONFH, while FMT restores butyric acid levels and alleviates disease severity. Butyric acid reduced the expression of TNF\u2010\u03b1 and IL\u20102 while increasing the level of IL\u20104\n                    <jats:italic>in vivo<\/jats:italic>\n                    and\n                    <jats:italic>in vitro<\/jats:italic>\n                    , thereby improving the local inflammatory environment of the femoral head and alleviating the progression of GA\u2010ONFH. These findings highlight that reduction in butyric acid levels due to gut microbiota dysbiosis is a crucial factor in the progression of GA\u2010ONFH.\n                  <\/jats:p>","DOI":"10.1155\/mi\/8742817","type":"journal-article","created":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T07:34:04Z","timestamp":1749108844000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Gut Microbiota\u2010Derived Butyric Acid Alleviates Glucocorticoid\u2010Associated Osteonecrosis of the Femoral Head via Modulating Inflammatory Cytokines in Bone Marrow Mesenchymal Stem 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