Gut‑bone metabolites: SCFAs, polyamines and microbial metabolomics in osteoporosis risk and therapy (Review)

Osteoporosis (OP), a major global skeletal disorder characterized by reduced bone mass and increased fracture risk, is increasingly understood through the lens of the gut‑bone axis. The present review critically synthesizes mechanistic and translational evidence for two classes of gut microbial metabolites short‑chain fatty acids (SCFAs) and polyamines, as active regulators of bone remodeling. SCFAs (acetate, propionate and butyrate) suppress osteoclastogenesis via the TRAF6/NFATc1 pathway, promote osteoblast differentiation through GPR43/GPR109A signaling and histone deacetylase inhibition, and expand immuno‑protective regulatory T cells in the bone marrow. Microbial polyamines (spermidine, spermine and putrescine) promote osteogenesis by upregulating Runx2 and alkaline phosphatase and inhibit osteoclastogenesis through suppression of the Ca²⁺‑PYK2‑Src‑NFATc1 axis. Integrative multi‑omics analyses and Mendelian randomization studies provide causal evidence linking specific gut taxa, their metabolic outputs and OP risk. Distinct from prior reviews of the gut‑bone axis, the present review uniquely integrates microbial metabolomics platforms, eIF5A hypusination as a novel polyamine‑dependent translational mechanism, and a hierarchical framework of translational interventions from prebiotics and probiotics to postbiotics and next‑generation receptor agonists. Collectively, these insights support a hierarchical translational framework from dietary prebiotics and probiotics to standardized postbiotics and next‑generation G‑protein‑coupled receptors agonists as a complement to existing anti‑OP pharmacotherapy. Key knowledge gaps include metabolite identification challenges ('metabolic dark matter') and the need for adequately powered clinical trials with bone‑specific endpoints.