Abstract
Antibiotic use is known to contribute to the development of osteoporosis, although the exact mechanisms remain poorly understood. Metronidazole (MET), a commonly prescribed antibiotic for treating anaerobic infections, has been linked to alterations in the gut microbiota (GM), which in turn are associated with various adverse side effects in the host. Recent studies have shown that the GM plays a key role in regulating bone homeostasis, though the underlying mechanisms remain under investigation. In this study, we demonstrate for the first time that MET promotes inflammatory osteoporosis through gut dysbiosis, with Klebsiella variicola (K. variicola) identified as a major pathogen influencing bone metabolism. The pro-inflammatory extracellular vesicles (EVs) secreted by K. variicola induce enhanced inflammatory responses and osteoclastic differentiation in both bone macrophages and bone tissue. Notably, the use of antibiotics that target K. variicola effectively mitigates MET-induced bone loss in vivo. This study expands our understanding of the mechanisms underlying antibiotic-induced bone loss and underscores the significant role of the pathogenic bacterium K. variicola in the development of osteoporosis, providing new avenues for future research on the microbiota-gut-bone axis in bone-related diseases.