Farrerol alleviates microbiota dysbiosis-associated osteoporosis in IBD by inhibiting PI3K-AKT/MAPK signaling pathways.

BACKGROUND

IBD, a global health concern, elevates osteoporosis risk primarily due to gut dysbiosis and chronic inflammation. While knowledge of the gut-bone axis advances, its exact mechanisms remain unclear, and effective treatments are still lacking.

METHODS

In vivo, we assessed FA's effects on femoral bone mass in UC mice and analyzed gut microbiota changes via 16S rRNA sequencing. Metabolomics measured short-chain fatty acids to evaluate their role in bone loss. We performed RNA sequencing on femoral BMMs to identify FA-regulated genes and pathways. In vitro studies examined FA's mechanisms in inflammation and osteoclastogenesis using immunofluorescence, bone resorption assays, and molecular analyses.

RESULTS

FA demonstrated significant protective effects against DSS-induced colitis. Specifically, it increased beneficial gut bacteria and short-chain fatty acid levels while reducing intestinal inflammation. Importantly, FA treatment reduced osteoclast-specific markers and inhibited nuclear translocation of key transcription factors. Moreover, FA suppressed bone resorption and osteoclastogenesis, thereby mitigating inflammatory bone remodeling. At the molecular level, FA exerted its protective effects by blocking PI3K-AKT and MAPK pathway activation, which subsequently inhibited osteoclast differentiation and function, ultimately preventing bone loss.

CONCLUSIONS

This study demonstrated FA's protective effect against osteoporosis in UC mice through bone microstructure analysis and functional assays. FA reduced colonic inflammation and mucosal damage by modulating gut microbiota composition and fatty acid levels. These findings suggest FA mitigates bone loss by decreasing intestinal inflammation, improving gut flora, and suppressing osteoclast formation.