Curcumin Ameliorates Osteoporosis via Gut Microbiota-Dependent Modulation of TMAO in Ovariectomized Rats

Despite its poor oral bioavailability, curcumin demonstrates efficacy against postmenopausal osteoporosis, presenting a paradox between its pharmacokinetics and pharmacological effects. This study elucidates a gut microbiota-dependent mechanism underlying this phenomenon. In ovariectomized rats, curcumin improved bone mass and microstructure, effects that were abolished upon gut microbiota depletion but partially transferable via fecal microbiota transplantation. Mechanistically, curcumin reversed estrogen deficiency-induced gut dysbiosis, enhanced microbial diversity, and significantly reduced levels of the gut-derived metabolite trimethylamine-N-oxide (TMAO) and the pro-inflammatory cytokine IL-1. Our findings establish that curcumin exerts its osteoprotective effects indirectly by remodeling the gut microbiome and its metabolic output, thereby proposing a new paradigm for its therapeutic action—not as a systemically available drug, but as a targeted gut microbiota modulator.