Imbalance of the Brain–Gut–Microbiota Axis in Major Depressive Disorder: From Pathogenesis to Clinical Translation

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Tao Wu,1,* Haoran Xing,2,3,* Tianzhong Wu,1 Xian Xie,1 Long Ji,1 Wei Wang,1 Xiaolina Zhang,2,4 Yingying Zhang,2 Chengrong Jiang,1 Tianhao Bao2 1Department of Child and Adolescent Psychiatry, Zhaotong Mental Health Center, Zhaotong, Yunnan, People’s Republic of China; 2Department of Research and Education, The Affiliated Mental Health Center of Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 3Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 4Department of Pain Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chengrong Jiang, Department of Child and Adolescent Psychiatry, Zhaotong Mental Health Center, Zhaotong, Yunnan, People’s Republic of China, Email 824496472@qq.com Tianhao Bao, Department of Research and Education, The Affiliated Mental Health Center of Kunming Medical University, Kunming, Yunnan, People’s Republic of China, Email doctor@kmmu.edu.cnAbstract: Major depressive disorder (MDD) is one of the most common psychiatric conditions, characterized by complex pathogenesis and marked inter-individual variability in treatment response, leading to persistent impairment of physical and mental health as well as social functioning. In recent years, the brain–gut–microbiota axis (BGMA) has emerged as a key biological pathway linking the gut microbiota with the central nervous system, and its role in MDD has become a major research focus. Although substantial progress has been made in elucidating the association between MDD and the BGMA, the precise mechanisms, critical pathways, and their integrated clinical applications remain to be fully clarified. On the basis of a comprehensive overview of the physiological functions, structural components, and disease associations of the BGMA, this review systematically summarizes the bidirectional interactions between MDD and the BGMA. Integrating the latest findings from preclinical and clinical studies, we further dissect the key regulatory pathways of this axis in MDD and highlight the therapeutic potential of BGMA-based interventions, including pharmacotherapy, fecal microbiota transplantation, dietary modulation, and physical therapies. This work aims to provide a theoretical foundation for developing novel treatment strategies for patients with MDD and for improving their prognosis and quality of life.Keywords: major depressive disorder, brain–gut–microbiota axis, pathogenesis, treatment

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T, W., H, X., T, W., X, X., L, J., W, W., X, Z., Y, Z., C, J., & T, B. (2026). Imbalance of the Brain–Gut–Microbiota Axis in Major Depressive Disorder: From Pathogenesis to Clinical Translation. Neuropsychiatric Disease and Treatment. https://www.dovepress.com/imbalance-of-the-braingutmicrobiota-axis-in-major-depressive-disorder--peer-reviewed-fulltext-article-NDT