The Mechanism of <i>Dendrobium officinale</i> Polysaccharides in Alleviating Osteoporosis via Regulation of Wnt/β-Catenin Signaling Pathways and Modulation of Gut Microbiota

Osteoporosis (OP) poses a significant global health burden, with emerging therapies targeting the gut microbiota (GM). This study investigated the effects of Dendrobium officinale polysaccharides (DOP), characterized as an acetylated glucomannan with a linear β-(1 → 4)-mannose backbone, on ovariectomy (OVX)-induced OP through the gut–bone axis. DOP administration significantly attenuated bone loss in OVX mice by modulating bone turnover and inflammation markers, activating Wnt/β-catenin signaling, and preserving intestinal barrier function. Furthermore, DOP dose-dependently reshaped the GM composition, increasing the Firmicutes/Bacteroidetes ratio, especially enriching short chain fatty acids (SCFA)-producing genera Allobaculum and Clostridia_UCG-014, which consequently restored butyric and isovaleric acid levels. Crucially, fecal microbiota transplantation from DOP-treated donors reproduced the osteoprotective phenotype in recipient mice, establishing a causal role for DOP-modulated GM. These findings demonstrate that DOP alleviates OP via GM-driven SCFA production, barrier integrity, anti-inflammation, and Wnt/β-catenin signaling activation, underscoring its prebiotic potential for OP management.