Do immune system and microbiome–gut–brain axis interactions associate with major depressive disorder?

Major depressive disorder (MDD) is a leading psychiatric disorder with increasing global prevalence, yet its underlying pathogenesis remains inadequately elucidated. Increasing evidence highlights the complex interplay between the immune system, gut microbiota, and their bidirectional crosstalk with the central nervous system. Gut microbiota dysbiosis affects neuroimmune and intestinal immune homeostasis, driving bidirectional peripheral-central immune responses through immune-to-brain and gut-to-brain communication. This process involves impaired intestinal barrier integrity (bacterial translocation), systemic low-grade inflammation, activation of innate immune signaling pathways (e.g., TLR4 and NLRP3 inflammasomes), glial cell activation, neuroinflammation, and blood-brain barrier (BBB) dysfunction, ultimately leading to neuronal injury and disturbances in mood, cognition, and behavior. Conversely, gut microbiota and their metabolites exert neuroprotective effects through facilitating neurotransmitter synthesis, regulating the hypothalamic-pituitary-adrenal axis activity, and modulating immune response. Collectively, these actions enhance synaptic plasticity, suppress hippocampal neuronal apoptosis, and maintain BBB integrity. Understanding these immune-mediated multidimensional mechanisms not only deepens our understanding of the pathophysiology of MDD but also provides new perspectives for identifying potential biomarkers and developing therapeutic targets.