ABSTRACT Emerging evidence suggests that gut microbiota‐derived signals can influence distant organs including the skeleton, yet the key microbial effectors remain elusive. Here, we identify Amuc₁473, a previously uncharacterized protein enriched in extracellular vesicles (EVs) from the commensal bacterium Akkermansia muciniphila (Akk), as a critical mediator of gut–bone communication. Amuc₁473 directly promotes osteogenesis and suppresses osteoclastogenesis by binding to negative elongation factor E (NELF‐E) and ribosomal protein L26 (RPL26), regulators of transcriptional pausing and mRNA translation, respectively. Notably, Amuc₁473 levels decline in bone and circulation under diverse pro‐osteoporotic conditions—including aging, estrogen deficiency, mechanical unloading, high‐fat diet, smoking, alcohol, and chronic stress—paralleling reductions in Akk and its EVs. Intermittent fasting robustly restores Akk abundance, Amuc₁473 levels, and bone quality in these models, via enhanced mucin production. Our findings establish Amuc₁473 as a microbial effector that systemically regulates bone homeostasis, offering a translatable strategy to prevent or treat multifactorial osteoporosis.
Rao et al. (Sat,) studied this question.