The prevalence of major depressive disorder (MDD) is increasing globally, particularly among adolescents. Although gut-brain axis dysfunction has been implicated in adolescent depression, the mechanisms by which gut microbiota dysbiosis drives depressive behaviors and potential antidepressant targets remain unclear. In this study, fecal microbiota transplantation (FMT) was performed from either healthy controls (HCs) or adolescents with MDD into antibiotic-treated adolescent rats. FMT from MDD adolescents induced depressive-like behaviors in recipient rats. Metagenomic sequencing revealed that FMT from MDD adolescents led to alterations in gut microbiota in recipient rats. While qPCR, Western blotting, immunofluorescence, and transmission electron microscopy (TEM) confirmed that these rats exhibited prefrontal cortex (PFC) autophagy hyperactivation, evidenced by a reduction in SQSTM1/p62 levels, an elevation in the LC3-II/LC3-I ratio, upregulated Beclin1, and increased numbers of autolysosomes. Similar autophagy-related transcriptional changes were observed in peripheral blood from MDD adolescents. Furthermore, ELISA showed reduced plasma lysine levels in MDD adolescents and decreased lysine concentrations in the PFC of FMT-MDD rats. The antidepressant effect of lysine and its interaction with autophagy were explored in a chronic unpredictable mild stress (CUMS) rat model with or without rapamycin (the autophagy activator, RAPA). Lysine supplementation alleviated depressive-like behaviors and suppressed PFC autophagy hyperactivation, while these effects were abolished by RAPA co-treatment. These findings reveal lysine deficiency as a metabolic bridge between gut microbiota imbalance and neuronal autophagy dysregulation, suggesting a gut microbiota-lysine-autophagy axis as an innovative mechanism and therapeutic focus for adolescent depression.
