Acupuncture Modulation of the Microbiota-Gut-Brain Axis in Major Depressive Disorder: Integrative Mechanisms, Emerging Evidence, and Future Therapeutic Perspectives.

Major depressive disorder (MDD) is a prevalent and disabling psychiatric condition. Its pathophysiology extends beyond monoamine deficiency to encompass systemic dysregulation of the gut-brain axis-a bidirectional network integrating neural, immune, endocrine, and microbial signals. Accumulating evidence indicates that MDD patients frequently exhibit gut microbiota dysbiosis, impaired intestinal mucosal barrier integrity, and systemic low-grade inflammation. These gut-derived pathological alterations may collectively contribute to the onset and progression of depression through complex interactions involving microbial metabolites, immune signaling, and neuroendocrine pathways. Although several recent reviews have addressed gut-brain axis dysfunction in depression or the therapeutic effects of acupuncture individually, a systematic synthesis integrating neuroimmune, neuroendocrine, and microbiome mechanisms within a unified framework remains lacking. This review integrates three key regulatory dimensions-neuroimmune regulation, hypothalamic-pituitary-adrenal (HPA) axis homeostasis, and gut microbiota remodeling-through which acupuncture is proposed to modulate the gut-brain axis in MDD. Acupuncture, a core modality of Traditional Chinese Medicine (TCM), offers unique advantages in intervening in this complex system due to its multi-target regulatory properties. Modern studies have linked classical TCM principles to the vagus-adrenal axis, the endocannabinoid system, the HPA axis, and the TLR4/NF-κB pathways. Specifically, preclinical evidence suggests that acupuncture may induce systemic anti-inflammatory responses, suppress NLRP3 inflammasome activation, restore HPA axis negative feedback, and repair the intestinal barrier, while also reshaping gut microbiota composition, promoting short-chain fatty acid synthesis, and regulating tryptophan metabolism. These coordinated actions may generate synergistic multi-system antidepressant effects. Clinical evidence further suggests that acupuncture combined with pharmacotherapy may outperform medication alone, although high-quality clinical trials remain limited. This review critically appraises current evidence and methodological limitations, and proposes future directions including rigorous randomized controlled trials, multi-omics integrative approaches, and microbiome-guided precision acupuncture strategies, aiming to advance individualized acupuncture treatment for MDD.