Gut microbiota-derived indole-3-propionic acid suppresses osteoclast formation by promoting IL-10+ Breg differentiation via AhR signaling.

Gut microbiota-derived metabolites play pivotal roles in immune and bone homeostasis; however, the specific metabolites involved in postmenopausal osteoporosis (PMOP) remain poorly understood. In this study, we investigated the role of indole-3-propionic acid (IPA), a microbial metabolite of tryptophan, in estrogen deficiency-induced bone loss through integrated microbiome, metabolomic, and immunological analyses. Using 16S rRNA gene sequencing combined with targeted metabolomics, we identified significant alterations in gut microbial composition and dysregulation of tryptophan metabolism in ovariectomized (OVX) mice. Serum IPA levels were markedly reduced in both PMOP patients and OVX mice. IPA supplementation inhibited osteoclast differentiation, promoted osteoblast differentiation, improved trabecular microarchitecture, and increased bone mineral density (BMD), thereby alleviating OVX-induced osteoporosis. Mechanistically, IPA activated aryl hydrocarbon receptor (AhR) signaling in B cells, promoting the differentiation of IL-10-producing regulatory B cells (Bregs) and enhancing IL-10 secretion, which in turn suppresses osteoclastogenesis. These effects were further confirmed by adoptive transfer experiments and pharmacological AhR inhibition. Collectively, our findings demonstrate that the gut microbiota-derived metabolite IPA mitigates estrogen deficiency-associated osteoporosis by modulating immune-bone crosstalk, providing new mechanistic insights and a potential therapeutic strategy for PMOP.