Microbiota‑derived indole‑3‑propionic acid reprograms bone marrow stem cell fate via PPARγ suppression to rescue osteoporosis

Osteoporosis (OP) is increasingly recognised as a disorder driven by impaired lineage allocation of bone marrow stromal cells (BMSCs), characterised by a shift from osteogenesis toward adipogenesis under conditions such as oestrogen deficiency and oxidative stress. Although gut microbiota‑derived metabolites have emerged as critical regulators of skeletal homeostasis, their direct role in BMSC fate determination remains poorly understood. In the present study, indole‑3‑propionic acid (IPA) was identified, a metabolite produced by Clostridium sporogenes, as a key regulator of bone‑fat balance. Integrative analyses combining 16S rRNA Sequencing, metabolomics, transcriptomics and functional assays revealed that IPA levels were significantly reduced in ovariectomised mice and positively correlated with bone mass. Functionally, IPA protected BMSCs from oxidative stress‑induced Apoptosis, restored osteogenic capacity, and suppressed adipogenic differentiation. Mechanistically, RNA Sequencing and molecular docking analyses demonstrated that IPA modulates the peroxisome proliferator‑activated receptor gamma (PPARγ) signalling pathway, thereby reprogramming BMSC lineage commitment. In vivo, oral administration of IPA markedly improved trabecular bone microarchitecture, enhanced bone formation, and corrected marrow adiposity without detectable systemic toxicity. Collectively, the present findings identified IPA as a previously under‑recognised microbiota‑derived metabolite that maintains skeletal homeostasis by restoring the osteogenic‑adipogenic balance through suppression of PPARγ signalling. The present study uncovers a mechanistic link between gut microbial metabolism and BMSC fate regulation and highlights IPA as a promising therapeutic candidate for OP.