Microbiota–Gut–Brain Axis as a Therapeutic Nexus: Multimodal Probiotic, Antidepressant, and Nutritional Strategies

Major depressive disorder (MDD) is a highly prevalent psychiatric illness worldwide, yet current therapeutic approaches still face challenges, including limited treatment efficacy, high interindividual variability, and high rates of treatment resistance. In recent years, the mechanisms by which the gut microbiota participates in emotional regulation and neuropsychiatric disorders through the “microbiota–gut–brain axis” have drawn increasing attention. Accumulating evidence indicates that influencing factors of depression, such as stress and diet, can alter gut microbial richness. Experimental studies have shown that gut microbes can modulate chemical signaling in the brain, induce neuroinflammation, and thereby affect the development and progression of depression. In humans, probiotic supplementation has shown promising antidepressant-like effects in preclinical models and some clinical trials, but its efficacy remains heterogeneous, appears to be strain-specific, and has not been consistently reproduced in placebo-controlled trials; it should therefore be considered an adjunctive or investigational approach requiring further validation before it can be recommended as a standalone or preventive intervention. This review will integrate findings from animal experiments demonstrating the preventive and therapeutic roles of probiotics and provide a critical overview of current research. To enable more effective translation of microbiota–gut–brain axis research into clinical trials and the use of probiotics as novel therapies, future studies should pay greater attention to the complex bidirectional communication between the gut and the brain. The brain influences gut microbes through neuroendocrine pathways, whereas gut microbes act back on the brain via vagal and immune modulation. Future research should also focus on the parallel effects of microbes on depression through neural, immunological, and metabolic routes. Clinical evidence remains heterogeneous, and probiotic or microbiota-targeted approaches should currently be interpreted as adjunctive or investigational rather than established standalone therapies.