Gut microbiota preserves bone mass through modulating the hyodeoxycholic acid–TGR5 axis

Background Osteoporosis is an age-related disease. The relationship between gut microbiota (GM) homeostasis and bone health is well established, but the mechanism of GM dysbiosis contributes to senile osteoporosis remains elusive. The objective of this study is to investigate the relationship between GM, bile acids (BAs) and their effects on bone mass.Results 16S rRNA sequencing and untargeted and targeted metabolomics revealed a reduction in microbial diversity, accompanied by the change of BA profile. In particular, the abundance of Parabacteroides goldsteinii and hyodeoxycholic acid (HDCA) in old mice were markedly decreased, compared with young mice. And there was a strong positive correlation between the abundance of P. goldsteinii and HDCA and bone mass. Further, our results demonstrated that old mice cohoused with young mice, with/without coprophagy prevention, were unable to alter the GM composition or reverse age-related bone loss. The transplantation of GM from young mice into old mice, rather than the transplantation of P. goldsteinii alone, reconstructed the GM of old mice and preserved bone mass by inhibiting bone resorption. Mechanistically, HDCA inhibits osteoclast maturation in vitro and exerts the bone protection effect in vivo through the activation of the G protein-coupled bile acid receptor (TGR5). HDCA treatment has been shown to result in the internalization of TGR5, thereby inhibiting the nuclear translocation of P65 in vivo. Knockout of TGR5 attenuated the effects of HDCA on bone microstructure, confirming these findings.Conclusions This study identified the GM–HDCA–TGR5 axis is a key pathway that affects bone mass and targeted intervention of HDCA represents potential therapeutic option for osteoporosis.