Glucocorticoid-induced loss of beneficial gut bacterial extracellular vesicles is associated with the pathogenesis of osteonecrosis

Osteonecrosis of the femoral head (ONFH) commonly occurs after glucocorticoid (GC) therapy. The gut microbiota (GM) participates in regulating host health, and its composition can be altered by GC. Here, this study demonstrates that cohousing with healthy mice or colonization with GM from normal mice attenuates GC-induced ONFH. 16S rRNA gene sequencing shows that cohousing with healthy mice rescues the GC-induced reduction of gut Lactobacillus animalis. Oral supplementation of L. animalis mitigates GC-induced ONFH by increasing angiogenesis, augmenting osteogenesis, and reducing cell apoptosis. Extracellular vesicles from L. animalis (L. animalis-EVs) contain abundant functional proteins and can enter the femoral head to exert proangiogenic, pro-osteogenic, and antiapoptotic effects, while its abundance is reduced after exposure to GC. Our study suggests that the GM is involved in protecting the femoral head by transferring bacterial EVs, and that loss of L. animalis and its EVs is associated with the development of GC-induced ONFH.