Combined metabolomics and microbiota analysis reveals the therapeutic effect of indole-3-propionic acid on ovariectomy-induced osteoporosis

Background Osteoporosis is a process of bone tissue destruction jointly caused by chronic inflammation and oxidative stress. Indole-3-propionic acid (IPA), as a metabolic molecule of the gut microbiota, exerts anti-inflammatory and antioxidant properties. However, the role of IPA in ovariectomy-induced osteoporosis in rats remains unclear. Methods We utilized ELISA and qRT-PCR to measure cytokine levels in serum and the mRNA expression of bone metabolism-related genes, respectively. Meanwhile, bone microstructure was analyzed using CT scanning technology. Additionally, we conducted non-targeted metabolomics and 16S rDNA gene sequencing studies on mouse fecal samples, employing multivariate statistical analysis for data visualization. Results IPA administration significantly attenuated the elevation of inflammatory mediators (TNF-α, IL-1β, IL-6) in OVX rats, while enhancing anti-inflammatory IL-10 levels. It could alter biochemical markers (Ca, P, ALP, CTX-1 and PINP) and suppress the expression of critical osteoclast differentiation genes (NFATc1, CTSK, ACP5, OSCAR), preventing OVX-induced bone loss. Additionally, the bone microstructure improved. Metabolomic profiling revealed IPA's regulatory role in fatty acid and amino acid metabolic pathways. Phloretin may serve as biomarker for the bone-protective effects of IPA. Additionally, IPA restored the balance of the Bacteroidota/Firmicutes gut microbiota. Conclusion These findings underscore IPA's therapeutic potential, providing a scientific rationale for developing IPA-based interventions for osteoporosis management.