Fecal microbiota transplants from depressed adolescents into healthy rats successfully induced depression-like behaviors, establishing a causal relationship between gut dysbiosis and mood disorders. The mechanism involves depleted plasma lysine levels and hyperactivated autophagy in the prefrontal cortex, characterized by elevated LC3-II/LC3-I ratios and increased autolysosomes. Lysine supplementation reversed both the depressive behaviors and excessive brain autophagy, but this protective effect was eliminated when autophagy activator rapamycin was co-administered. This discovery illuminates a previously unknown gut-brain pathway where microbiome disruption creates lysine deficiency, triggering neuronal autophagy dysfunction that manifests as depression. The finding carries significant implications for adolescent mental health, as it suggests lysine supplementation could serve as a targeted intervention for depression linked to gut dysbiosis. However, the research remains limited to animal models, and the translation to human therapeutics requires validation in clinical trials. The work represents a meaningful advance in mechanistic understanding of the gut-brain axis, moving beyond correlational observations to demonstrate specific biochemical pathways linking microbiome health to psychiatric outcomes.