Yigu Decoction polysaccharides mediate gut microbiota and metabolites to promote bone formation-related protein expression and improve osteoporosis.

Osteoporosis (OP) is a metabolic bone disorder characterized by a progressive decrease in bone mass. Yigu Decoction polysaccharides (YGDP) is a traditional Chinese herbal formula, preliminary clinical and basic research has demonstrated its therapeutic advantages in treating osteoporosis (OP). However, the specific mechanism by which it mediates bone formation through the gut microbiota (GM) and metabolites remains incompletely understood. The aim of this study is to elucidate the mode of action of YGDP in OP treatment through an integrated approach involving multi-omics analysis and in/ex-vivo experiments. Our findings suggest that YGDP may treat OP by improving GM and metabolite levels, primarily through its ability to alter the OP mice GM structure restoring to a level comparable to that of controls. Cluster and difference analyses revealed significant changes at the genus level, particularly in Alistipes. Metabolomics identified key metabolic pathways associated with significant differential metabolites, including the citrate cycle (TCA cycle), amino acid biosynthesis, and ABC transporters et al. Furthermore, integrated analysis indicated that Alistipes and metabolite oxaloacetic acid (OAA) might be key mediators of the effect of YGDP on OP. Molecular docking confirmed the strong binding capacity of OAA to Osteocalcin (OCN)/ Osterix (OSX)/ Runt-related transcription factor 2 (RUNX2)/ Alkaline Phosphatase (ALP)/ Collagen Type I (COL1). Experimental evidence has shown that YGDP and OAA enhance bone microarchitecture in OP mice and upregulate the expression of OCN/OSX/RUNX2/ALP/COL1, thereby improving OP. In conclusion, this study provided evidence that YGDP improves osteoporosis by enhancing bone microarchitecture in osteoporotic mice through improving GM and mediating metabolite OAA, while upregulating the expression of OCN/OSX/RUNX2/ALP/COL1.