Microbiota-derived extracellular vesicles mediate gut-brain axis dysfunction in long COVID

Post COVID-19 condition (Long COVID, LC) is a heterogenous post-infectious condition frequently accompanied by persistent neurological symptoms, but its mechanisms remain unclear1-4. Here we identify gut microbiota-derived extracellular vesicles (GMEVs) as effectors linking LC-associated intestinal dysbiosis to systemic and neuroinflammation. In a longitudinal, deeply phenotyped cohort, individuals with LC and neurological symptoms (LC-Neuro) show a distinct intestinal microbiome profile that persists over time. Transplantation of LC-Neuro microbiota into germ-free mice disrupts intestinal barrier integrity and induces neurobehavioral alterations and neuroinflammation. GMEVs isolated from individuals with LC activate intestinal epithelial cells, macrophages and induced pluripotent stem cell-derived microglia in vitro, engaging inflammasome signalling, impairing epithelial barrier function and promoting inflammatory cytokine production. These effects are strongest for LC-Neuro-derived GMEVs in gut epithelium and macrophage models, whereas microglial activation is observed across LC-derived GMEVs. Oral administration of LC-Neuro GMEVs to conventional mice is sufficient to induce intestinal inflammation and systemic immune activation, accompanied by neurobehavioral changes and neuroinflammation. Together, these findings implicate GMEVs as mediators of gut-brain axis dysfunction and provide a mechanistic framework linking intestinal dysbiosis to neurological sequelae in LC.