Fecal microbiota transplantation ameliorates postmenopausal osteoporosis by restoring intestinal barrier function and suppressing inflammation in ovariectomized rats

Estrogen-deficient bone loss in postmenopausal osteoporosis (PMOP) represents a major global health challenge. Current therapies are limited by side effects and inconsistent efficacy, and the ways in which the gut microbiota influences bone metabolism and intestinal barrier integrity in PMOP remain unclear. Growing evidence links gut dysbiosis to impaired bone remodeling, making the gut–bone axis an attractive but still mechanistically undefined therapeutic target. This study aimed to investigate the effects of fecal microbiota transplantation (FMT) on bone loss, osteoclast activity, intestinal barrier function, and inflammatory responses in an ovariectomized (OVX) rat model of PMOP. In vivo animal experimental study. Three-month-old female Sprague–Dawley rats were divided into sham control, OVX, and OVX + FMT groups. OVX rats underwent bilateral ovarian resection to induce PMOP, followed by daily FMT (1 mL, 108 CFU/mL) for 8 weeks. Bone density and microstructure were assessed by micro-CT and histomorphometry (H&E, TRAP staining). Intestinal barrier function was evaluated using immunohistochemistry and Western blotting for tight-junction proteins (ZO-1 and occludin). Serum inflammatory cytokines (TNF-α and IL-1β) and bone turnover markers (TRACP5B and OPG) were measured by ELISA. Compared to OVX group, FMT significantly reduced weight gain in OVX + FMT group (24.1% vs. OVX group’s 35.5%, P < 0.01) and improved bone density (BMD + 11.1%, BV/TV + 51.4%, P < 0.01) by suppressing osteoclastogenesis (reduced TRACP5B levels) and enhancing osteoblast activity (increased RUNX2 and β-catenin expression). FMT is associated with the restoration of intestinal barrier integrity, as evidenced by upregulated ZO-1 and occludin (P < 0.01), and reduced systemic inflammation, reflected in lower TNF-α and IL-1β (P < 0.01). Collectively, these findings position FMT as a pivotal intervention that dampens systemic inflammation and restores healthy gut–bone axis communication. Overall, our results position FMT as a promising strategy for postmenopausal osteoporosis, capable of restoring gut microbiota balance, repairing the intestinal barrier, quelling systemic inflammation, and ultimately re-activating protective gut–bone axis signaling.