What question did this study set out to answer?

To explore gut microbial changes in major depressive disorder (MDD) and their relationship with metabolic pathways and clinical symptoms.

January 25, 2026Open Access

Functional Shotgun Metagenomic Insights into Gut Microbial Pathway and Enzyme Disruptions Linking Metabolism, Affect, Cognition, and Suicidal Ideation in Major Depressive Disorder

Key Points

To explore gut microbial changes in major depressive disorder (MDD) and their relationship with metabolic pathways and clinical symptoms.
Conducted shotgun metagenomics to profile gut microbiome in MDD compared to controls.
Used MetaPhlAn for taxonomic profiling and HUMAnN for functional profiling.
Aligned microbial reads to pangenomes and protein databases for analysis.
Gut microbiome diversity showed no significant difference between MDD and controls.
Identified dysbiosis in MDD linked to leaky gut and metabolic pathways.
Protective taxa in controls indicated anti-inflammatory properties and resilience.
Pathway analysis revealed loss of antioxidant functions and activated metabolic pathways related to MDD.

Abstract

Abstract Background: Major depression (MDD) is linked to neuro-immune, metabolic, and oxidative stress (NIMETOX) pathways. The gut microbiome may contribute to these pathways via leaky gut and immune-metabolic processes. Aims: To identify gut microbial alterations in MDD and to quantify functional pathways and enzyme gene families and integrate these with the clinical phenome and immune–metabolic biomarkers of MDD. Methods: Shotgun metagenomics with t axonomic profiling was performed in MDD versus controls using MetaPhlAn v4.0.6, and functional profiling was conducted using HUMAnN v3.9, aligning microbial reads to species-specific pangenomes (Bowtie2 v2.5.4) followed by alignment to the UniRef90 v201901 protein database (DIAMOND v2.1.9). Results: Gut microbiome diversity, both species richness and evenness, is quite similar between MDD and controls. The top enriched taxa in the multivariate discriminant profile of MDD reflect gut dysbiosis associated with leaky gut and NIMETOX mechanisms, i.e., Ruminococcus gnavus, Veillonella rogosaem and Anaerobutyricum hallii . The top four protective taxa enriched in controls indicate an anti-inflammatory ecosystem and microbiome resilience, i.e., Vescimonas coprocola , C oprococcus , Faecalibacterium prausnitzii , and Faecalibacterium parasitized . Pathway analysis indicates loss of barrier protection, antioxidants and short-chain fatty acids, and activation of NIMETOX pathways. The differential abundance of gene families suggests that there are metabolic distinctions between both groups, indicating aberrations in purine, sugar, and protein metabolism. The gene and pathway scores explain a larger part of the variance in suicidal ideation, recurrence of illness, neurocognitive impairments, immune functions, and atherogenicity. Conclusion: The gut microbiome changes might contribute to activated peripheral NIMETOX pathways in MDD.

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