Prevotella histicola activates the Wnt/beta-catenin signaling pathway through the gut–bone axis and promotes osteoblastic differentiation of mesenchymal stem cells to alleviate estrogen-deficient osteoporosis

Postmenopausal osteoporosis (PMO) is characterized by dysregulated bone metabolism owing to estrogen insufficiency. Our previous clinical study revealed that postmenopausal women afflicted with osteoporosis exhibited notably diminished levels of Prevotella abundance relative to individuals possessing normal bone density. This study aimed to confirm the anti-osteoporosis-like effects of P. histicola and elucidate its potential mechanism. Mice were treated with P. histicola after ovariectomy (OVX). Changes in bone strength among the mice were detected using micro-computed tomography (CT), and alterations in the microbiome were examined using 16S rRNA sequencing. CT of the distal femurs demonstrated that P. histicola significantly improved bone mineral density (BMD), bone volume fraction (BV/TV), trabecular thickness (Tb.Th), and trabecular separation (Tb.Sp) compared to the OVX + high fat diet (HFD) group. Furthermore, P. histicola ameliorated dysbiosis induced by the HFD and OVX and alleviated intestinal mucosal damage after OVX. Intestinal tight junction proteins ZO-1 and occludin were significantly upregulated in the treatment group, and CD163 angiogenesis-related macrophage marker and Ki-67 proliferation marker increased compared to that in the OVX + HFD group. P. histicola mitigated the levels of circulating and bone TNF-α while enhancing the expression of osteogenic-related transcription factor Runx2. Furthermore, P. histicola upregulated OCN expression in OVX + HFD mice and promoted osteogenesis by facilitating osteogenic differentiation through the Wnt/beta-catenin pathway. In summary, P. histicola potentially ameliorates intestinal permeability, reduces serum and femoral inflammation levels, and promotes osteogenic differentiation of mesenchymal stem cells through the Wnt/beta-catenin pathway to alleviate estrogen deficiency-induced osteoporosis by modulating gut microbiota.