What question did this study set out to answer?

This research aims to understand how gut microbiota dysbiosis affects depressive behaviors in adolescents and explore potential treatments targeting lysine.

May 13, 2026Open Access

Gut microbiota dysbiosis drives depression-like behavior in adolescent rats via lysine-regulated mTOR autophagy pathway

Key Points

This research aims to understand how gut microbiota dysbiosis affects depressive behaviors in adolescents and explore potential treatments targeting lysine.
Conducted fecal microbiota transplantation (FMT) from healthy controls and MDD adolescents into antibiotic-treated adolescent rats.
Utilized metagenomic sequencing and various biochemical analyses to evaluate gut microbiota changes and autophagy in the prefrontal cortex.
Assessed the effects of lysine supplementation and its interaction with autophagy activation using rapamycin in a chronic unpredictable mild stress model.
FMT from adolescents with MDD induced depressive-like behaviors in recipient rats, revealing a gut microbiota influence.
Significant autophagy hyperactivation was observed in the prefrontal cortex of FMT-MDD rats, indicated by altered SQSTM1/p62 and LC3 levels.
Lysine supplementation reduced depressive-like behaviors and autophagy hyperactivation, effects negated with co-treatment of rapamycin.

Abstract

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.

Ask AI

Helpful

Bookmark

View Full Paper