The Microbiota‐Gut‐Brain Axis in the Pathophysiology of Major Depressive Disorder: A Mechanistic Review

Major Depressive Disorder (MDD) is a globally prevalent and debilitating psychiatric condition whose pathophysiology remains incompletely understood. Emerging evidence compels a paradigm shift from a purely neurocentric model to one that incorporates the microbiota-gut-brain (MGB) axis, a complex bidirectional communication network. This review synthesizes current research to build a comprehensive mechanistic model of how disruptions within this axis contribute to the development and maintenance of MDD. We deconstruct the core communication pathways, beginning with the foundational state of gut dysbiosis and compromised intestinal barrier integrity observed in MDD patients. We then delve into the downstream consequences, examining how microbial metabolites, particularly short-chain fatty acids and products of tryptophan metabolism, act as critical signaling molecules. The review details how these signals are conveyed to the central nervous system (CNS) via direct neural pathways, including the enteric nervous system and the vagus nerve, and through systemic humoral and neuroimmune cascades. Specifically, we explore the roles of gut-derived inflammation, microglial activation, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. By integrating these pathways, we present a cohesive model wherein gut-derived pathology drives central neuroinflammation, neurotransmitter disruption, and impaired neuroplasticity, culminating in the clinical manifestation of MDD. This MGB axis framework not only provides a more holistic understanding of MDD as a systemic illness but also illuminates novel targets for diagnostic biomarkers and therapeutic interventions.