Metformin restores marrow mesenchymal lineage homeostasis in glucocorticoid-induced osteoporosis through a gut microbiota–butyrate–ERK1/2 axis
Abstract
Abstract Objective Glucocorticoid (GC)-induced osteoporosis during skeletal development is accompanied by increased marrow adiposity. This study investigated whether metformin (MET) alleviates GC-induced bone–fat imbalance through gut microbiota remodeling and identified the microbial metabolite and downstream signaling mechanism involved. Methods Late-adolescent C57BL/6J mice were exposed to GC with or without oral MET. Skeletal phenotypes and bone marrow mesenchymal stromal cells (BMSCs) differentiation were assessed by micro-CT, dual-energy X-ray absorptiometry, three-point bending, histological analyses, and ex vivo differentiation, complemented by reanalysis of a publicly available scRNA-seq dataset. Gut microbiota, intestinal barrier integrity, and cecal short-chain fatty acids (SCFAs) were characterized by 16S rRNA sequencing and targeted metabolomics. Fecal microbiota transplantation (FMT) in antibiotic-pretreated mice evaluated microbiota-mediated effects, while Sodium butyrate (NaB) and U0126 were used to examine ERK1/2-dependent regulation of BMSC osteogenic–adipogenic balance. Results Marrow adiposity emerged after 2 weeks of GC exposure, preceding overt trabecular and cortical deterioration at 4 weeks. MET preserved bone microarchitecture and mechanical competence, reduced marrow lipid accumulation, and restored BMSC osteogenic–adipogenic balance. MET also remodeled the gut microbiota and SCFA profile while preserving intestinal barrier integrity. FMT from GC +…
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