Gut‐derived bacterial vesicles carrying lipopolysaccharide promote microglia‐mediated synaptic pruning

Abstract INTRODUCTION Growing evidence links gut microbiota (GM) to Alzheimer's disease (AD). Elevated lipopolysaccharide (LPS) levels, a Gram‐negative bacteria component, are found in AD brains, but how LPS breaches the blood–brain barrier (BBB) remains unclear. Hypotheses suggest that bacteria‐derived extracellular vesicles (bEVs) may transport LPS across the BBB. METHODS bEVs were extracted from human and mouse feces and blood, and LPS levels were measured. In vivo imaging and immunofluorescence confirmed the transport of blood LPS‐carrying bEVs across the BBB. The role of these bEVs in microglia was investigated both in vivo and in vitro. RESULTS Elevated LPS‐containing bEVs were detected in the plasma of AD patients compared to healthy individuals. These bEVs activated microglial Piezo1, consequently precipitating an excessive synaptic pruning process mediated by the C1q‐C3 complement pathway. DISCUSSION These findings illuminate the complex interplay between the gut microbiota, bEVs, neuroinflammation, and synaptic plasticity – a key early event in AD – offering insights for potential therapeutic interventions. Highlights GM‐derived bEVs can traverse the BBB. LPS was necessary for bEVs’ penetration into the brain, and bEVs might be closely related to AD progression. bEVs mediated microglial activation and synaptic pruning via C1q‐C3 complement pathway. Microglia Piezo1 was involved in bEV‐induced excessive synaptic pruning.