Gut microbiota and short chain fatty acids influence bone health in postmenopausal osteoporosis

Postmenopausal osteoporosis (PMOP) is framed as a systemic bone disease driven by estrogen withdrawal, but emerging evidence positions gut dysbiosis and its fermentation products—short-chain fatty acids (SCFAs)—as equally influential regulators of skeletal fate. Estrogen loss elevates gut permeability, allowing lipopolysaccharide and pro-inflammatory T cells to traffic from intestine to bone marrow, tipping the Th17/Treg balance toward osteoclast-promoting cytokines such as IL-17, TNF-α and RANKL. Germ-free or T-cell-depleted mice do not lose bone after ovariectomy, underscoring the microbiota-immune axis as a mechanistic core.

Cross-sectional profiling reveals PMOP cohorts harbor reduced alpha-diversity, a Firmicutes-enriched/Bacteroidetes-depleted signature, and lower butyrate- and propionate-producing taxa such as Butyricicoccus, Fusicatenibacter and Prevotella histicola. Conversely, pathobionts including Klebsiella, Escherichia and Clostridium are expanded; their endotoxin and AKT2 signaling amplify M1 macrophage polarization and systemic inflammation. These compositional shifts correlate with circulating C-telopeptide, osteocalcin and hip BMD, suggesting GM signatures may serve as biomarkers or therapeutic targets.

Fecal microbiota transplantation from healthy donors into ovariectomized mice restores intestinal barrier integrity, rebalances Th17/Treg ratios in both gut and bone marrow, and prevents trabecular bone loss. Probiotic supplementation with Lactobacillus rhamnosus GG, L. reuteri or Bifidobacterium longum recapitulates these benefits: tight-junction proteins ZO-1 and occludin rise, LPS leakage falls, and Treg-derived IL-10 and TGF-β suppress osteoclastogenesis while enhancing osteoprotegerin expression. Lactic acid, a metabolite of Lactobacillus, further induces histone lactylation in bone-marrow mesenchymal stem cells, steering commitment toward osteoblast differentiation.

SCFAs emerge as central molecular translators of microbial influence. Acetate, propionate and butyrate—generated via fermentation of dietary fiber by Firmicutes and Bacteroidetes—signal through GPCRs (GPR41, GPR43, GPR109A) and act as histone-deacetylase inhibitors. In the gut, they acidify the lumen, increase calcium solubility and transporter expression, and reinforce epithelial barrier integrity.

Systemically, these metabolites skew CD4⁺ T-cell fate toward Foxp3⁺ Tregs while restraining Th17 differentiation, thereby dampening RANKL-mediated osteoclast activation. In bone-marrow cultures, butyrate suppresses NF-κB and p38 MAPK signaling, down-regulates NFATc1, c-Fos and TRAP, and reduces mature osteoclast numbers. Propionate and butyrate shift early osteoclast precursors from oxidative phosphorylation to glycolysis, creating metabolic stress incompatible with differentiation.

Osteoblast lineage cells respond favorably to SCFAs: butyrate dose-dependently increases bone-sialoprotein, osteopontin and osteoprotegerin transcription, enhances mineralized nodule formation, and amplifies Wnt10b expression in a Treg-dependent manner when combined with intermittent parathyroid hormone. Conversely, high-dose butyrate exerts cytostatic effects, illustrating concentration-dependent pleiotropy.

Clinical and pre-clinical evidence converge on dietary or microbial interventions that elevate SCFAs as adjunctive PMOP therapies. High-fiber diets increase acetate and butyrate, prevent ovariectomy-induced bone loss, and synergize with calcium and vitamin D. A 12-month probiotic trial reported modest lumbar-spine BMD gains, while multi-strain formulations reduced bone-turnover markers without changing BMD, highlighting the need for longer follow-up. Outstanding questions include optimal SCFA species ratios, dose thresholds, and interactions with anti-resorptives or anabolic drugs. Multi-omics integration—metagenomics, metabolomics and immune-phenotyping—should guide personalized microbiome-based strategies that safely enhance skeletal health beyond current pharmacologic limits.