Soy-whey dual-protein alleviates osteoporosis of ovariectomized rats via regulating bone fat metabolism through gut-liver-bone axis

Osteoporosis is increasingly prevalent, especially among postmenopausal women, both in China and worldwide. In previous work, soy-whey dual-protein (DP) intervention improved muscle status via regulation of gut microbiota. However, little information is available about the relationship between DP supplementation and osteoporosis. In this study, the ovariectomized rat model was used to detect the effect of DP on improving osteoporosis. Significant improvement was observed in bone mineral density, bone microstructure, and bone biomechanics with both DP and zoledronic acid (positive control) intervention. DP supplementation dramatically reduced the levels of serum osteocalcin and parathyroid hormone in ovariectomized rats. Ingestion of DP also resulted in a significant decrease in the number of bone marrow adipocytes and a marked increase in the number of osteoblasts, accompanied by elevated expression of the key regulator osteoprotegerin at both mRNA and protein levels. In the analysis of fecal metabolites and intestinal microbiota, the fat metabolism–related molecules chenodeoxycholate, 21-hydroxypregnenolone, and tetrahydrocorticosterone were markedly upregulated with DP treatment, whereas the content of fatty acids such as oleic acid were significantly downregulated. The abundance of three bacterial taxa (upregulated: Ruminococcaceae UCG_002; downregulated: anaerobic digester metagenome and Enterorhabdus) dramatically changed with DP intervention and was closely associated with fat metabolism–related metabolite content These results suggest that DP intervention could improve osteoporosis via regulation of bone marrow adipose tissue content and mesenchymal stem cell lineage differentiation. Furthermore, this effect might be mediated by the interaction between intestinal microbiota and metabolites.