Berberine reshapes gut microbiota and attenuates bone loss in estrogen-deficient osteoporosis via the gut-bone axis

Postmenopausal osteoporosis (PMO) is a metabolic bone disorder characterized by estrogen deficiency-induced bone loss, deterioration of bone microstructure, and increased fracture risk. Current therapeutic agents are limited in efficacy and may have adverse effects. Berberine, a traditional Chinese medicinal compound, exhibits multitarget regulatory potential. However, its mechanism of action in alleviating PMO through modulation of the gut microbiota remains unclear. The objectives of this study are to assess the potential of berberine in mitigating estrogen deficiency-induced osteoporosis through modulation of the gut microbiota and to elucidate its underlying mechanisms. An ovariectomy (OVX)-induced PMO mouse model was established and divided into control, model, and berberine-treated (100 mg/kg/day) groups. Bone microstructure was examined using micro-CT, gut microbiota composition was analyzed through 16S rRNA sequencing; inflammatory factors and bone metabolism markers were evaluated using immunofluorescence; western blotting, qRT-PCR, and serum cytokine levels were quantified using ELISA. Berberine effectively reversed the OVX-induced gut dysbiosis by restoring the diminished levels of norank_f_Muribaculaceae and mitigating the elevated abundance of Lachnospiraceae_NK4A136_group, norank_f_Lachnospiraceae, and Roseburia. This modulation led to the suppression of intestinal inflammation, evidenced by decreased expression of IL-1β, IL-6, IL-8, and TNF-α, and an enhancement in gut barrier integrity, as indicated by increased levels of occludin and ZO-1. These changes collectively reduced the translocation of LPS into circulation. Consequently, berberine attenuated systemic and local release of pro-inflammatory cytokines and the activation of osteoclasts, resulting in the amelioration of PMO. Berberine mitigates PMO by reshaping the gut microbiota, improving intestinal barrier function, and suppressing systemic inflammation, thereby inhibiting bone resorption and restoring bone metabolic balance. This study offers a novel microbiome-targeted therapeutic approach for PMO.