Mechanisms and Intervention Strategies of the Gut-Brain Axis in the Development and Progression of Depression

Abstract

Major depressive disorder is a heterogeneous psychiatric syndrome in which affective, cognitive, somatic, endocrine, and immune phenotypes arise from interacting biological networks rather than from a single neurotransmitter deficit. The gut-brain axis provides a biological model for explaining how intestinal microorganisms, epithelial barrier integrity, mucosal immunity, microbial metabolites, vagal afferents, and hypothalamic-pituitary-adrenal signaling shape brain function under conditions of stress and disease. Clinical studies have reported altered fecal microbial composition, reduced microbial richness in selected patient groups, changes in tryptophan and short-chain fatty acid metabolism, and associations between neuroactive microbial potential and depressive symptoms. Experimental transfer studies further indicate that depression-associated microbiota can reproduce behavioral, metabolic, and inflammatory features in recipient animals, supporting a causal contribution in susceptible contexts. This review summarizes the structural basis and research evidence for gut-brain axis involvement in depression, analyzes mechanisms involving microbial metabolites, neuroactive substances, intestinal barrier disruption, immune inflammation, neuroendocrine imbalance, and impaired neuroplasticity, and discusses intervention strategies based on dietary modulation, probiotics, prebiotics, fecal microbiota transplantation, live biotherapeutic products, and pathway-oriented precision approaches. Current data support the gut-brain axis as a biologically plausible and clinically tractable target, while indicating that patient stratification, mechanistic biomarkers, and rigorous longitudinal trials are required before microbiome-centered interventions can be integrated into standardized depression care.