Integrative mechanisms and intervention targets of the microbiota–gut–brain axis in depressive disorders: advances across immune, endocrine, and central nervous system pathways

Depressive disorders are highly heterogeneous syndromes characterized not only by depressed mood but also by cognitive impairment, sleep-circadian rhythm disturbances, altered appetite, somatic discomfort, and metabolic or gastrointestinal comorbidities. In recent years, the microbiota-gut-brain axis (MGBA) has been increasingly recognized as an integrative biological framework linking abnormalities in mood regulation, immune responses, endocrine function, metabolism, and neuroplasticity. This review provides a systematic synthesis of gut microbial ecology and host phenotypic features associated with depressive disorders, with particular emphasis on the depletion of short-chain fatty acid-producing commensals, the enrichment of potentially pro-inflammatory taxa, and the functional remodeling of key metabolic pathways, including the tryptophan-kynurenine pathway, short-chain fatty acids, bile acids, and trimethylamine N-oxide. We further discuss how bidirectional gut-to-brain and brain-to-gut communication may contribute to the onset and progression of depressive disorders through intestinal barrier disruption, low-grade systemic inflammation, hypothalamic-pituitary-adrenal axis activation, vagal signaling, and dysregulation of neurotransmitter and neurotrophic pathways. Current interventional evidence suggests that dietary and lifestyle modification, psychobiotics, and fecal microbiota transplantation may exert antidepressant potential in selected populations; however, the overall effect sizes remain limited and between-study heterogeneity is substantial. Patients with prominent gastrointestinal symptoms, metabolic abnormalities, or low-grade inflammatory states may represent priority candidates for MGBA-targeted interventions; nevertheless, a putative microbiota-responsive phenotype should not be simply equated with high stress exposure alone, and its definition requires prospective validation integrating stress burden, host responses, and microbial/metabolic readouts. Overall, MGBA research is gradually moving beyond descriptive profiling of microbial composition toward functional integration and clinical translation; however, causal inference, multi-omics standardization, and the identification of stratification biomarkers remain major challenges. Future studies should incorporate phenotype-based stratification, strengthened functional readouts, and precision intervention designs to determine which patients are most likely to benefit from microbiota-targeted therapies.