Helicobacter pylori-secreted outer membrane vesicles induce bone loss and accelerate osteoporosis pathogenesis in mice by regulating gut microbiota and autophagy.

The gut microbiota profoundly influences systemic health, with emerging evidence linking bacterial pathogens to bone metabolism disorders. Helicobacter pylori (H. pylori), a prevalent gastric pathogen, has been epidemiologically associated with osteoporosis, though the mechanisms remain elusive. Bacterial outer membrane vesicles (OMVs) are key mediators of pathogen-host interactions, delivering virulence factors to target cells. This study aimed to explore the potential role of H. pylori OMVs on the bone metabolic disorder and osteoporotic pathology. Results showed that H. pylori OMVs are internalized by osteoblasts, mesenchymal stem cells (MSCs) and osteoclasts, and then suppressed osteogenic differentiation in osteoblasts and MSCs, while promoting osteoclast differentiation. Following intravenous administration in mice, OMVs were able to reach the bone tissue, further inducing significant bone loss in mice and aggravating osteoporosis in ovariectomized (OVX) mice. 16S rRNA gene sequencing revealed that H. pylori OMVs increased the abundance of Bacillota and Campylobacterota in OVX models, resulting in the promotion of inflammation. Meanwhile, the reduction in Lactobacillaceae weakened gut barrier, and both aspects may worsen osteoporosis. In addition, H. pylori OMVs significantly increase reactive oxygen species generation and autophagy protein expression, reduce the type I collagen expression in vitro. These findings reveal a novel pathway by which gut-derived OMVs disrupt bone homeostasis, implicating H. pylori OMVs as potent contributors to osteoporosis pathogenesis through regulating oxidative stress, autophagy and gut microbiota structure. Our study provides critical insights into microbiota-related bone disorders and indicates potential therapeutic targets for mitigating OMVs-driven osteoporotic progression.