Dried Ginger Milk Extract Alleviates Inflammatory Bowel Disease-Associated Bone Loss via Gut Microbiota-Metabolite...

Background: Inflammatory bowel disease (IBD) is frequently complicated by secondary bone loss driven by chronic inflammation and gut-bone axis dysregulation. Although dried ginger has pharmacological activities relevant to intestinal inflammation, the effects of dried ginger milk extract (DGME), a lipophilic constituent-enriched preparation, on IBD-associated bone loss (IBD-BL) remain unknown. This study evaluated the preventive and therapeutic effects of DGME on IBD-BL and explored the underlying mechanisms. Methods: Mice with DSS-induced IBD-BL were treated with DGME (250, 125, or 62.5 mg/kg) or sulfasalazine. Colitis severity, bone microarchitecture, osteoclast activity and Th17 cells were assessed by histology, micro-computed tomography, histomorphometry and flow cytometric analysis. UHPLC-Q-TOF MS, network pharmacology, 16S rRNA sequencing, fecal metabolomics, and in vitro assays were used for mechanistic investigation. Results: DGME ameliorated colitis, improved trabecular bone microarchitecture, and reduced osteoclast-related bone destruction. These effects were associated with selective suppression of pathogenic bone marrow TNF-α⁺ Th17 cells and downregulation of Il17a, Rorc, Tnfα, Ccr2, Ccr6, Cxcr4, Csf1, and Tnfsf11. Compared with aqueous extract, DGME was enriched in 19 lipophilic constituents. Multi-omics analyses showed that DGME remodeled gut microbiota and metabolite profiles, characterized by enrichment of Lactobacillus, Anaerotruncus, vanillin, and spermidine. Both vanillin and spermidine suppressed Th17 effector genes and inhibited MEK/ERK signaling in vitro. Conclusions: DGME alleviated IBD-BL by suppressing pathogenic TNF-α⁺ Th17 responses and remodeling the gut microbiota-metabolite axis. This study not only extends the therapeutic application of dried ginger from intestinal inflammation to IBD-BL, but also identifies vanillin and spermidine as candidate functional mediators linked to MEK/ERK inhibition.