From microbes to mind and actions: Uncovering the gut-brain connection in major depressive disorder and its implications for human health and lifestyle

The gut microbiome, shaped by dietary choices, medication use, and host genetics, is emerging as a key determinant of physical and mental health. In this study, we explored the intricate links between the gut microbiome and major depressive disorder (MDD). Using a comprehensive dataset included 16S rRNA gene sequences from 7,472 individuals across Eastern and Western Europe, we employed a discovery-replication design followed by meta-analysis. Data processing and bioinformatics analyses were conducted using the QIIME2 platform.In the discovery set, 544 individuals (12%) reported a clinical diagnosis of MDD, compared to 3,912 without. Similarly, in the replication set, 285 (12%) reported MDD, while 2,167 did not. We applied linear regression models and meta-analysis across the two datasets using MaAsLin2 and ANCOM-BC2, adjusting for geographic region, age, gender, and batch effects using bacterial relative abundance was the primary outcome. Meta-analysis across the datasets identified 22 taxa significantly associated with MDD (q<0.05) using MaAsLin2, with nine taxa: Romboutsia, Clostridium sensu stricto, Agathobacter, Bacteroides pectinophilus group, Flavonifractor, Coprococcus, Victivallis, Tyzzerella, and Bacteroides, - confirmed by ANCOM-BC2.MR analysis using MiBioGen and depression GWAS data revealed no consistent causal relationships between bacterial taxa and MDD. However, mediation analyses showed that Bacteroides mediated 3–8% of single lifestyle effects and up to 61% of total effects on MDD, with notable contributions for healthy weight, physical activity, and diet. Specific taxa such as Bacteroides pectinophilus group, Victivallis, and Tyzzerella mediated 14–16%, 3–6%, and 4% of certain lifestyle effects, respectively. Additionally, a history of supplementation with Lactobacillus and Bifidobacteria probiotics was positively associated with MDD, indicating potential microbial alterations in individuals with depressive disorders. The integration of multiple bacterial taxa into a microbiome risk score outperformed single-taxon associations, achieving an AUC of 0.6 and demonstrating its potential to capture broader microbial patterns.Our findings reveal consistent microbial signatures linked to MDD. Individuals with a history of MDD exhibited notably reduced microbiome alpha diversity but higher relative abundance of SCFA-producing bacteria. These results suggest that the gut microbiota may play a significant role in the pathophysiology of MDD and highlight the importance of microbial composition in understanding and potentially managing MDD.