Dietary goat milk extracellular vesicles remodel the microbiota–gut–brain axis to alleviate adolescent anxiety

Safe and effective strategies for managing adolescent anxiety disorders are urgently needed. This study demonstrates that goat milk-derived extracellular vesicles (gEVs), a natural nanostructure from dairy origin, effectively alleviate chronic restraint stress (CRS)-induced anxiety-like behaviors in adolescent mice through modulation of the gut–brain axis. The purified gEVs were characterized by transmission electron microscopy, nanoparticle tracking analysis, and western blotting, confirming their nanoscale morphology and vesicular protein markers. Behavioral tests revealed that oral gEVs significantly reversed CRS-induced anxiety-like behaviors. Mechanistically, gEVs suppressed neuroinflammation in the hippocampus and prefrontal cortex, restored brain-derived neurotrophic factor expression, and alleviated neuronal injury. Concurrently, gEVs enhanced intestinal tight junction protein expression, improved colonic barrier function, and modulated the gut microbiota composition by reducing the Firmicutes/Bacteroidetes ratio and increasing beneficial bacteria. These changes elevated short-chain fatty acid (SCFAs) levels, particularly acetate and propionate, which were negatively correlated with neuroinflammation and anxiety-like behaviors. Fecal microbiota transplantation confirmed the essential role of gut microbiota in mediating gEVs' anxiolytic effects. Moreover, early-life gEVs intervention significantly reduced anxiety susceptibility in adulthood. Collectively, these findings identify gEVs as a safe and effective dietary-derived nanomaterial capable of modulating the gut microbiota–SCFA–brain axis, offering promising potential for functional food development targeting adolescent anxiety management.