Gut microbial metabolic disorder in depression: insights from computational modeling and mediation analysis

Depression is increasingly recognized as a disorder not only of the brain but also of systemic metabolic dysfunction, particularly involving the gut microbiota. Integrating multi-cohort gut microbiome data with constraint-based metabolic modeling, this study investigates how microbial metabolic fluxes mediate depressive symptoms. Significant alterations in microbial pathways, notably those related to amino acid metabolism and neurotransmitter precursors, were identified. Causal mediation analysis showed that gut microbial composition influenced depressive symptoms, significantly mediated by specific metabolites including butyrate, Cu2+, and tryptophan-derived compounds. This study, employing systems biology and mediation analysis, suggests that microbial metabolic activity mediates the gut-brain axis’s role in depression development and severity. These results enhance our understanding of microbiota-related mechanisms in mental health and highlight potential metabolic targets for depression treatment. • Gut Microbiome Diversity and Depression: This study demonstrates that individuals with depression exhibit significantly reduced gut microbial diversity compared to healthy controls. The decline is most pronounced in measures of species richness and evenness, as indicated by lower Observed, Shannon, and Chao1 indices. Notably, taxa such as the Micrococcaceae family are enriched in the depression group, while Firmicutes are more prevalent in healthy individuals. These shifts suggest that a less diverse gut microbiome may be associated with depression, potentially influencing host metabolic functions and mental health. • Metabolic Pathway Alterations in Depression: The study identified significant alterations in several key metabolic pathways between individuals with depression and healthy controls. These include disruptions in fatty acid synthesis, pentose and glucuronate interconversions, thiamine metabolism, and primary amine metabolism. Such metabolic dysfunctions in the gut microbiota may interfere with nutrient processing, neurotransmitter production, and redox balance, potentially contributing to the development and progression of depressive symptoms. These pathway-level differences emphasize the functional role of the gut microbiome in mental health beyond taxonomic shifts alone. • Potential Biomarkers and Therapeutic Targets: The study identified 21 metabolites with significantly different fluxes between depression patients and healthy individuals, highlighting key disruptions in L-Dopa metabolism and copper (Cu$$\:{\text{}}^{\text{2+}}$$) metabolism. These findings suggest that gut microbial modulation of neurotransmitter precursors and metal ion homeostasis may play a pivotal role in depression pathophysiology. Specifically, altered L-Dopa metabolism may reduce dopamine availability in the brain, while reduced Cu$$\:{\text{}}^{\text{2+}}$$ consumption by gut microbes could elevate systemic copper levels, enhancing oxidative stress. These metabolite-level differences offer promising biomarkers for depression diagnosis and open up novel therapeutic avenues, such as targeting microbial metabolism to restore neurochemical balance.