Traditional Chinese Medicine Ameliorates Depression via the Gut-Brain Axis: A Review Focus on NLRP3/TLR4-Mediated Inflammatory Pathways and Gut Microbiota Modulation

Longfei Che,1 Jiaming Xie,2 Chunlei Xia,1 Qinming Yu3 1Graduate School, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, 150040, People’s Republic of China; 2Yangsheng College of Traditional Chinese Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, 550025, People’s Republic of China; 3School of Humanities and Management, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, 150040, People’s Republic of ChinaCorrespondence: Qinming Yu, School of Humanities and Management, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, 150040, People’s Republic of China, Tel +86151-4642-3222, Email 4773615@qq.comObjective: Depression, a global mental disorder, is linked to gut-brain axis (GBA) dysfunction. This review explores how traditional Chinese medicine (TCM)—including single herbs (eg, Astragalus membranaceus, Lycium barbarum), herbal formulas (eg, Xiaoyaosan, Xiaochaihu Decoction), and acupuncture—alleviates depression via the GBA, focusing on neuroscience-relevant mechanisms (inflammation, neurotrophy).Methods: A systematic literature search was conducted on PubMed, China National Knowledge Infrastructure (CNKI), and Embase from database inception to July 2025. Keywords included [“Traditional Chinese Medicine” or “TCM” or “herb” or “herbal extracts” or “Chinese herbal formulas”], [“depression” or “Depressive like behavior”], [“immune regulation”], [“inflammatory reaction”], [“neuroregeneration” or “nerve” or “neurotransmitter”]. Including peer-reviewed studies on human/animal models, articles that do not meet the requirements are excluded. A total of 307 eligible studies were included.Results: TCM regulates gut microbiota composition—eg, increasing Lactobacillus and Bifidobacterium while reducing pathogenic taxa. Mechanistically, TCM inhibits pro-inflammatory pathways: herbs (eg, Astragalus membranaceus) and formulas (eg, Xiaoyaosan) downregulate IL-6, TNF-α, and IL-1β via suppressing NLRP3 inflammasome and TLR4/NF-κB signaling. They also enhance anti-inflammatory IL-10, elevate neurotransmitters (5-HT, DA), and upregulate BDNF. Acupuncture mirrors these effects, reducing plasma IL-6/TNF-α and restoring microbial balance to improve depressive behaviors.Conclusion: TCM alleviates depression by integrating gut microbiota modulation, inflammatory suppression, and neuroprotection through the GBA. This review highlights TCM’s potential as a safe, alternative therapy for depression and identifies directions for standardized, large-scale clinical validation.Keywords: traditional chinese medicine, Depression, gut microbiota, gut-brain axis, inflammatory reaction, immune regulation, neuroregeneration