Gut microbiota metabolites and microbiota-targeted interventions in bone metabolism: from SCFAs and TMAO to probiotics and FMT.

Abstract

Accumulating evidence supports a microbiota-gut-bone axis in which intestinal microbes influence skeletal remodeling through barrier integrity, immune signaling, and metabolite production. This review emphasizes specific metabolites, strain-level intervention data, and translational limitations. Preclinical studies consistently show that dysbiosis, barrier disruption, and altered microbial metabolites promote osteoclastogenesis and suppress osteoblast function. Among short-chain fatty acids, propionate and butyrate have the strongest direct anti-osteoclast evidence, whereas acetate a bone-relevant systemic substrate/signaling molecule with context-dependent skeletal effects. Trimethylamine N-oxide has been linked mechanistically to impaired osteogenic commitment of bone marrow stromal cells and inflammatory signaling, although human epidemiologic findings are not uniform. These mechanisms appear particularly relevant in postmenopausal osteoporosis and glucocorticoid-induced osteoporosis, where estrogen deficiency or glucocorticoid exposure amplifies intestinal permeability, inflammatory tone, and microbial dysbiosis. In humans, the clinical signal is promising but heterogeneous. Fecal microbiota transplantation remains largely preclinical in bone disease and faces major challenges in donor selection, protocol standardization, timing, and long-term safety. Overall, the field is moving from associative observations toward causal and precision-oriented models, but large, well-phenotyped human studies integrating metagenomics, metabolomics, proteomics, and host clinical data are still needed before microbiota-targeted therapies can be routinely incorporated into osteoporosis care.