Systems Biology of Gut Microbiome Dysbiosis in Major Depressive Disorder: Functional Microbial Networks Linked to Inflammation, Illness Severity, Recurrence, and Suicidal Behavior

Background Major depressive disorder (MDD) is characterized by disruptions in neuroimmune, metabolic, and oxidative stress (NIMETOX) pathways, which are influenced by leaky gut. Most microbiome studies in MDD focused on taxonomic differences rather than systems biology analyses of functional microbial pathways. Methods This cross-sectional study included 102 MDD inpatients and 38 healthy controls. Gut microbiome composition was assessed using 16S rRNA amplicon sequencing. Taxonomic differences across hierarchical levels were examined using ANCOM-BC and machine learning approaches. Functional metabolic pathways were inferred using Tax4Fun and PICRUSt. Microbial genera were grouped into functionally coherent modules. Results Beta diversity revealed significant differences in microbial community composition. Taxonomic analyses showed selective shifts at the genus and species levels. Feature selection identified 9 functional modules that discriminated MDD from controls. Functional module analysis demonstrated increased pro-inflammatory dysbiosis, lipopolysaccharide-related taxa, oral pathobionts, and Actinobacteria host–metabolite transformation, alongside reduced lactobacilli, and lactate cross-feeding modules. Specific and combined genera accounted for a substantial part of the variance in overall severity of depressive (75.7%) and physiosomatic symptoms (64.8%), suicidal ideation (27.2%), and recurrence of illness (36.7%). The acute phase inflammatory response was associated with dysbiotic genera promoting endotoxin exposure and mucosal immune activation. MDD microbiomes exhibit enhanced microbial stress responses, host–microbe interactions, and biofilm formation pathways, supporting a systems biology model linking gut dysbiosis with the clinical phenome and NIMETOX pathways. Conclusions MDD is associated with functional restructuring of the gut microbiome, characterized by inflammatory and barrier-disrupting microbial networks that define systems biology-informed personalized dysbiotic profiles.