Hesperetin mitigates IBD-associated bone loss via Akkermansia muciniphila enrichment and IDA-driven gut-bone axis crosstalk.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder frequently accompanied by extraintestinal complications such as bone loss, yet effective treatment options remain elusive. In this study, we investigated whether hesperetin mitigates colitis-associated bone loss by modulating the "gut-bone axis." Using a DSS-induced mouse model of chronic colitis, we found that hesperetin significantly reduced intestinal inflammation, restored mucosal barrier integrity, and suppressed serum inflammatory cytokines. Furthermore, hesperetin effectively alleviated DSS-induced bone microstructure damage, promoted the expression of ALP, Runx2, OCN, and inhibited NFATc1 and CTSK. Fecal microbiota transplantation experiments further confirmed that the intestinal microbiota from hesperetin-treated group attenuated intestinal inflammation and bone loss. 16S rRNA sequencing and metabolomics revealed that hesperetin enriched Akkermansia muciniphila (A. muciniphila) and increased the tryptophan metabolite 3-indoleacrylic acid (IDA). Supplementation with A. muciniphila or IDA alone simulated the therapeutic benefits of hesperetin. Furthermore, RNA-seq revealed that hesperetin regulated bone metabolism-related gene expression by ECM-receptor interaction and PI3K-AKT signaling, while inhibiting the NOD-like receptor pathway. In conclusion, hesperetin mitigates intestinal inflammation and bone homeostasis imbalance by reshaping the gut microbiota, enriching A. muciniphila, and promoting IDA production, thus providing new insights into potential therapies for IBD-related bone loss.