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

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.