Analysis of gut microbiota and intestinal mucosal neurotransmitter changes and their correlation in adolescent depression mice

BACKGROUND: Adolescent depression is a major mental health disorder with increasing prevalence and substantial long-term consequences. Although growing evidence suggests that the gut-brain axis is involved in depression, the relationships among gut microbiota, intestinal mucosal neurotransmitters, and adolescent depression remain insufficiently understood. This knowledge gap limits a better understanding of the pathophysiological mechanisms underlying adolescent depression and the identification of potential microbiota-related targets. Therefore, this study aimed to investigate alterations in gut microbiota and intestinal mucosal neurotransmitters, as well as their correlations, in an adolescent mouse model of depression. METHODS: We established an adolescent depression mouse model using chronic unpredictable mild stress (CUMS), and collected data with the Smart video tracking system. We collected intestinal contents and mucosal tissues from mice. We analyzed gut microbial composition using metagenomic sequencing and quantified mucosal neurotransmitters with liquid chromatography-tandem mass spectrometry (LC-MS/MS). We analyzed correlations among gut microbiota, intestinal mucosal neurotransmitters, and behavioral indicators. RESULTS: Mice in the CUMS group exhibited a significantly reduced sucrose preference rate in the sucrose preference test (P < 0.001); a significantly prolonged immobility time in the forced swim test (P < 0.01); and a significantly decreased total movement distance in the open field test (P < 0.01). No significant intergroup difference was observed in the tail suspension test. Regarding the gut microbiome, the CUMS group showed significantly lower Simpson index (P = 0.018) and Pielou's evenness index (P = 0.022). Beta diversity analysis indicated a statistically significant but modest between-group difference in community structure (ANOSIM R = 0.145, P = 0.03); this finding was supported by PERMANOVA (Bray-Curtis; pseudo-F = 1.675, R² = 0.0897, P = 0.033). LEfSe (Linear discriminant analysis Effect Size) analysis suggested 27 candidate taxa with discriminatory signals between groups (nominal P < 0.05; exploratory). Neurotransmitter analysis demonstrated that levels of 5-HIAA (5-hydroxyindoleacetic acid), 5-HT (serotonin), 5-HTP (5-hydroxytryptophan), and Kyn (kynurenine) in the colon were significantly decreased in the CUMS group, whereas levels of PA (phenylethylamine) and NE (norepinephrine) were significantly elevated (P < 0.05). Spearman correlation analysis found that Lactobacillus and Lactobacillus acidophilus correlated positively with sucrose preference and negatively with immobility in the forced swim test. Lactobacillus acidophilus also showed a positive correlation with 5-HT pathway metabolites: 5-HIAA, 5-HT, 5-HTP, and Kyn. CONCLUSION: Adolescent mice exposed to CUMS showed depression-relevant behavioral alterations, shifts in gut microbiota composition, and changes in 5-HT pathway metabolites. Gut microbiota dysbiosis was significantly associated with alterations in 5-HT pathway metabolites. Because this study is correlational, causal relationships require validation in future interventional studies.