Gut Microbiota-Targeted Therapies for Major Depressive Disorder: Mechanisms, Clinical Evidence, and Future Directions

Major Depressive Disorder (MDD) severely impairs individuals' physical and mental health, imposing substantial burdens on families and society. The pathogenesis of MDD remains elusive, but it is hypothesized to involve genetics, central neurotransmitter imbalance, hypothalamic- pituitary-adrenal (HPA) axis hyperactivity, and gut microbiota dysbiosis, among other factors. Antidepressants, which primarily address central neurotransmitter imbalances, are the first-line treatment; however, approximately half of patients exhibit suboptimal responses to conventional therapies. In recent years, attention has been drawn to specific alterations in gut microbiota composition observed in patients with severe depression. Animal studies have demonstrated that fecal transplantation from MDD patients to rodents can induce depressive-like behaviors, whereas fecal transplantation from healthy individuals may reverse such changes. Based on these findings, gut microbiota-targeted interventions have been progressively investigated in subclinical and clinical settings, including probiotic supplementation, fecal microbiota transplantation, and dietary modifications (such as the Mediterranean diet and ketogenic diet). These interventions may offer significant therapeutic effects with minimal side effects and high acceptability, providing new hope for patients with treatment-resistant depression. However, critical parameters such as optimal treatment regimens, dosages, and intervention durations remain unstandardized, and their underlying mechanisms and specific efficacy are still unclear. This review comprehensively evaluates existing clinical studies, focusing on the design of intervention protocols, therapeutic outcomes, adverse effects, and potential mechanisms of action, with the aim of providing guidance for future research.