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Here, we demonstrate that prenatal prednisone therapy (PPT) in humans and prenatal prednisone exposure (PPE) in rats result in sex\u2010specific long bone dysplasia in offspring, including reduced peak bone mass (PBM) and heightened osteoporosis risk in female offspring. Multi\u2010omics profiling and fecal microbiota transplantation show that PPE alters maternal gut microbiota composition and depletes the microbial metabolite daidzein (DAI). DAI deficiency suppresses\n                    <jats:italic>Hoxd12<\/jats:italic>\n                    expression, impairs osteogenesis, and leads to PBM decline in female offspring. In bone marrow\u2010derived mesenchymal stem cells from PPE female offspring, DAI promoted\n                    <jats:italic>Hoxd12<\/jats:italic>\n                    expression and osteogenic differentiation. Notably, DAI supplementation restored H3K9ac levels, enhanced\n                    <jats:italic>Hoxd12<\/jats:italic>\n                    expression, and promoted osteogenic differentiation through the ER\u03b2\/KAT6A pathway. Furthermore, maternal DAI supplementation during pregnancy prevented osteoporosis susceptibility in PPE female offspring and alleviated functional abnormalities in multiple organs, including the liver, hippocampus, ovary, and adrenal gland. In conclusion, PPE induces multiorgan dysplasia and increases disease predisposition (e.g., osteoporosis) in female offspring by disrupting maternal gut microbiota and depleting DAI. Maternal DAI supplementation provides a promising preventive strategy to counteract these adverse outcomes.\n                  <\/jats:p>","DOI":"10.1002\/imt2.70037","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T00:07:56Z","timestamp":1745885276000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Maternal gut microbiota\u2010derived daidzein prevents osteoporosis in female offspring following prenatal prednisone exposure"],"prefix":"10.1002","volume":"4","author":[{"given":"Chi","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery Division of Joint Surgery and Sports Medicine, Zhongnan Hospital of Wuhan University Wuhan China"},{"name":"Department of Pharmacology Basic Medical School of Wuhan University Wuhan 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