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

Introduction

The Gut-Brain Axis (GBA) refers to a bidirectional communication network between the gut microbiota and the central nervous system, which has gradually gained attention in the research of psychological disorders such as depression.¹ Depression is a global mental health crisis: the World Health Organization (WHO) estimates it affects 280 million people worldwide (3.8% of the global population), with 5% of adults suffering from major depressive disorder (MDD).^2,3 It is the leading cause of disability globally, imposing substantial economic burdens (exceeding $2 trillion annually) and increasing the risk of suicide—accounting for over 700,000 deaths each year.^4,5 Its pathological mechanism is complex, involving genetics, environment, neuroinflammation, and neurotransmitter imbalance, with GBA dysfunction emerging as a key contributor.⁶

Conventional treatments for depression primarily rely on pharmacotherapy (eg, selective serotonin reuptake inhibitors, SSRIs) and psychotherapy (eg, cognitive-behavioral therapy, CBT). However, these approaches have notable limitations: SSRIs often cause side effects (gastrointestinal distress, sexual dysfunction, weight gain) that lead to 30–50% of patients discontinuing treatment;⁷ approximately 30% of MDD patients are refractory to first-line drugs.⁸ Psychotherapy, while effective, is limited by high costs, poor accessibility in low- and middle-income countries, and reliance on trained professionals. Thus, there is an urgent need to explore safe, accessible alternative therapies.

In traditional Chinese medicine (TCM) theory, intestinal health is regarded as an important component of overall health.⁹ TCM aims to improve the intestinal environment by regulating visceral functions and balancing yin and yang (A core TCM theory describing two opposing yet complementary forces that maintain bodily homeostasis; TCM treats depression by balancing yin-yang)., thereby influencing mental health.¹⁰ In recent years, a growing number of studies have begun to explore the role of TCM in regulating the gut microbiota, especially in the treatment of depression.^11–13 Zhi-Zi-Chi decoction, a TCM formula consisting of Gardenia jasminoides and fermented soybean, with effects of clearing heat and relieving restlessness. Studies have shown that Zhi-Zi-Chi decoction can increase the production of short-chain fatty acids, which have been proven to exert positive effects on depression.¹⁴ TCM can regulate the gut microbiota through multiple mechanisms, such as improving diet, enhancing the functions of the spleen and stomach, and using specific herbal formulas, thereby affecting the symptoms of depression.^15,16 TCM can regulate the gut microbiota through multiple mechanisms, such as improving diet, enhancing the functions of the spleen and stomach, and using specific herbal formulas, thereby affecting the symptoms of depression.

This review aims to explore the basic concept of the GBA and its significance in depression research, elaborate on the traditional applications and modern research progress of TCM in regulating gut microbiota, and introduce the research objectives and structure of this article. By reviewing relevant literature, it is expected to provide new perspectives and ideas for the application of TCM in the treatment of depression, with a view to offering guidance and references for clinical practice.

Methods

Search Strategy

We searched PubMed, China National Knowledge Infrastructure, and Embase. The search is limited to English or non English articles with published English abstracts since the establishment of the database. Key words include [“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”]. Preliminary screening is conducted using search engines provided by various databases. Preliminary screening is conducted using search engines provided by various databases. After deleting 256 duplicate records, we identified 712 related articles. Before reading the full text of the selected paper, we use Endnote software to identify references related to the topic. Among them, 87 articles lack full-text abstracts, and 318 articles are unrelated to traditional Chinese medicine and depression. Finally, 307 full-text original research papers related to the topic were included.

Data Extraction and Synthesis

Prior to reading the full text of the given papers, we manually selected topic-related references using Excel software. Eventually, all included articles are peer-reviewed ones relevant to this subject. During the process of writing the paper, one author was responsible for data extraction. Subsequently, other authors cross-checked the extracted data to ensure its completeness and reliability.

Basic Concepts of Gut-Brain Axis

The GBA refers to a bidirectional communication network between the gut and the brain, which transmits information through multiple pathways including the neural, endocrine, and immune systems.¹⁷ The gut microbiota plays a pivotal role in this process, influencing brain function and emotional regulation.¹⁸ Studies have demonstrated that alterations in the composition and function of the gut microbiota are closely associated with the pathogenesis of various neuropsychiatric disorders, such as depression and anxiety.^19,20 The functions of the GBA are not limited to the regulation of the digestive system but also include impacts on mental health.²¹ By secreting metabolites like short-chain fatty acids and neurotransmitters, the gut microbiota can directly affect neural activity and emotional states in the brain.^22,23 The interaction mechanism of the GBA is illustrated in Figure 1.

Figure 1 Schematic diagram of gut-brain axis.

The GBA plays a significant role in the regulation of emotions and behaviors. Studies have found that gut microbial dysbiosis (ie, an imbalance of the gut microbiota) may exacerbate mental health issues such as depression and anxiety.^24,25 Specifically, the gut microbiota influences the brain’s emotional regulation mechanisms by modulating the synthesis and metabolism of neurotransmitters (eg, serotonin and dopamine).²⁶ For instance, the gut microbiota can affect the levels of serotonin, a key neurotransmitter closely linked to emotional regulation.^27,28 Agmatine is a substance primarily derived from beneficial gut microbes. Rahangdale et al found that oral administration of agmatine alone or in combination with probiotics significantly reversed antibiotic-induced dysbiosis, restored the gut microbiota, and alleviated depression-like behaviors.²⁹ Research indicates that dysfunction of the GBA may further exacerbate depressive symptoms by affecting the activity of the hypothalamic-pituitary-adrenal (HPA) axis.³⁰ Additionally, the gut microbiota regulates brain function and emotional responses through its impacts on the immune and endocrine systems.^22,31 Therefore, regulating the composition and function of the gut microbiota may emerge as a novel strategy for improving mood disorders and behavioral problems.

Pathological Mechanism of Depression

Depression is a complex psychological disorder whose pathological mechanisms involve multiple biological factors. Recent studies have indicated that the occurrence of depression is closely associated with the neurotransmitter system, endocrine system, immune system, and genetic factors, among others. In particular, the imbalance of neurotransmitters such as serotonin (5-HT), norepinephrine (NE), and dopamine (DA) is regarded as one of the core biological bases of depression.³² Additionally, chronic stress and neuroinflammation are also recognized as important pathological mechanisms of depression: the former affects the neuroendocrine axis and immune responses, while the latter impacts brain function by activating microglia and releasing inflammatory factors.³³ Studies have also found that structural and functional changes occur in the brains of depressed patients, including hippocampal volume reduction and prefrontal cortex dysfunction, which are correlated with the severity of depressive symptoms.³⁴

The microbiota is playing an increasingly important role in the occurrence and development of depression. Studies have demonstrated that gut microbiota dysbiosis (ie, microbial imbalance) is closely associated with the onset of depression.³⁵ Specifically, gut microbes can influence mental health through multiple mechanisms, including regulating neurotransmitter synthesis, affecting inflammatory responses, and impacting brain function via gut-brain axis signaling.^12,36 For instance, short-chain fatty acids (SCFAs), as metabolites of gut microbiota, can alleviate neuroinflammation by inhibiting microglial activation, thereby improving depressive symptoms.³⁷ Additionally, changes in microbiota composition are correlated with the severity of depressive symptoms; a reduction in certain beneficial bacteria such as Bifidobacterium and Lactobacillus may be associated with the development of depression.³⁸ Therefore, regulating the composition of gut microbiota may emerge as a novel strategy for treating depression, and achieving this goal through traditional Chinese medicine has shown promising prospects.³⁹

The Relationship Between the Basic Theories of Traditional Chinese Medicine and Depression

Traditional Chinese Medicine’s Understanding of Depression

TTCM has a distinct understanding of depression compared to Western medicine. In TCM theory, depression is referred to as “Yu Zheng” (depressive syndrome), whose etiology is closely associated with factors such as emotional imbalance, qi and blood deficiency, and dysfunction of zang-fu organs.⁴⁰ TCM holds that emotional fluctuations directly affect the circulation of qi, leading to qi stagnation, which in turn triggers a series of physical and psychological symptoms.⁴¹ For example, liver qi stagnation is regarded as one of the main pathological bases of depression; dysfunction of the liver can result in symptoms such as low mood and anxiety.⁴² Additionally, TCM emphasizes the relationship between the health of the spleen and stomach and emotional states: spleen deficiency may cause qi and blood deficiency, thereby affecting mental status.^39,43 Therefore, TCM adopts syndrome differentiation-based treatment, using various herbs and therapeutic methods to harmonize qi and blood, and unblock meridians, so as to alleviate depressive symptoms.⁴⁴

Application Status of Commonly Used Individual Herb or Herbal Extracts in Regulating Gut Microbiota in Depression

In recent years, a growing body of research has indicated that gut microbiota dysbiosis is closely associated with the occurrence of depression. We have summarized recent studies on TCM and its active components in regulating gut microbiota for the treatment of depression (Table 1). TCM exhibits unique advantages in regulating gut microbiota.⁴⁵ For example, Chinese herbs such as Astragalus membranaceus, Lycium barbarum, and Angelica sinensis have been found to alleviate depressive symptoms by regulating the gut microbial community.^46–48 NLRP3 (NOD-like receptor pyrin domain-containing 3), an inflammasome complex that triggers the release of pro-inflammatory cytokines; its overactivation is a key driver of GBA-related depression. Studies have demonstrated that Astragalus membranaceus exerts antidepressant effects mainly via astragaloside IV (its core triterpenoid saponin). Astragaloside IV modulates gut microbiota (increasing Lactobacillus/Oscillospira) and inhibits the NLRP3/ASC/Caspase-1 pathway, reducing IL-1β/TNF-α levels while upregulating BDNF.⁴⁹ TLR4 (Toll-like receptor 4), a pattern-recognition receptor that mediates gut microbiota-induced inflammation via the NF-κB pathway, contributing to depression pathogenesis. Paeonia lactiflora relies on paeoniflorin (monoterpenoid glycoside) to restore gut barrier integrity (ZO-1/Claudin-1↑) and suppress TLR4/NF-κB signaling.^50–52 Zhao et al found that gastrodin improves depressive-like behavior in mice by regulating the gut microbiota induced by chronic unpredictable mild stress.⁵³ Active components of TCM herbs such as Salvia miltiorrhiza and Bupleurum chinense have also been shown to exert antidepressant effects by regulating gut microbial metabolites and promoting neurotransmitter synthesis.⁵⁴ Additionally, computer simulations have validated the use of quercetin, luteolin, apigenin, and other components as drugs for the treatment of depression. Most of the top 10 herbs containing these components are attributed to the liver meridian in TCM, and they have a pungent taste.⁴³ These studies provide a scientific basis for the application of TCM in the treatment of depression.

Table 1 Summary of Studies on the Use of Single Herb and Its Active Extracts to Regulate Gut Microbiota in the Treatment of Depression

Application Status of Chinese Herbal Formula in Regulating Gut Microbiota in Depression

Chinese herbal formula preparations have shown favorable efficacy in the treatment of depression.⁶³ We have summarized recent studies on Chinese herbal formulas in regulating gut microbiota for the treatment of depression (Table 2). For example, compounds such as Chaihu Shugan Powder and Xiaoyao Powder are widely used in clinical practice, and studies have found that these compounds can improve depressive symptoms by regulating the composition of gut microbiota.^64,65 Chaihu Shugan Powder can significantly increase the abundance of beneficial intestinal bacteria, such as Bifidobacterium and Lactobacillus, while reducing the number of depression-related pathogenic bacteria, thereby improving patients’ mental status.⁶⁶ In addition, Xiaoyao Powder is widely used to treat depression of liver qi stagnation type; its components such as Bupleurum chinense and Paeonia lactiflora (Baishao) have the effects of soothing the liver and relieving depression, as well as harmonizing the spleen and stomach, which can effectively improve patients’ mood and quality of life.⁶⁷ Xiaoyaosan, a classic TCM formula (composed of Bupleurum chinense, Paeonia lactiflora, etc.) used clinically for “soothing the liver and regulating qi” to alleviate depression-related symptoms. Xiaoyaosan’s efficacy stems from synergistic effects of saikosaponin, paeoniflorin and atractylenolide III. Saikosaponin regulates gut microbiota metabolism to increase butyrate production, while paeoniflorin and atractylenolide III jointly inhibit microglial activation via the NLRP3 pathway.²⁵ Studies have also found that Xiaoyao Powder regulates gut microbial metabolites, inhibits the LPS-mediated TLR4/NLRP3 signaling pathway, increases the level of brain-derived neurotrophic factor (BDNF), thereby promoting neuroplasticity and alleviating depressive symptoms.²⁵ A multicenter RCT (n=180) showed Xiaoyaosan combined with fluoxetine significantly improved Hamilton Depression Rating Scale (HAMD) scores (mean reduction: 12.3 ± 3.1 vs 8.7 ± 2.8 in fluoxetine alone) and increased fecal butyrate levels, with no severe adverse events.²⁰ Sun et al found that Xiaochaihu Decoction is a classical TCM formulation that regulates qi, resolves and dissipates stagnation. Clinically, this formulation has long been used to treat Shaoyang stagnation syndrome in depressive disorders.⁶⁸ These results indicate that Chinese herbal formula preparations have important clinical significance in regulating gut microbiota and treating depression.

Table 2 Summary of Studies on the Use of Chinese Herbal Formula to Regulate Gut Microbiota in the Treatment of Depression

Current Application of Acupuncture in Regulating Intestinal Flora in Depression

Acupuncture, as a TCM therapy, has attracted increasing attention in the treatment of depression in recent years. We have summarized recent studies on acupuncture in regulating gut microbiota for the treatment of depression (Table 3). Research has shown that acupuncture can improve depressive symptoms by regulating gut microbiota. For example, in a mouse model of depression, acupuncture treatment significantly increased the abundance of beneficial gut bacteria and reduced the number of pathogenic bacteria, which was closely associated with the improvement of depressive symptoms.⁷⁸ In addition, acupuncture has been found to alleviate depressive symptoms by regulating gut microbial metabolites and reducing inflammatory levels.⁷⁹ Notably, in a multicenter, randomized controlled trial, electroacupuncture significantly decreased the levels of inflammatory cytokines such as IL-6, IL-1β, and TNF-α in the plasma of depressed patients, and upregulated BDNF, thereby improving depressive-like behaviors in patients.⁸⁰ A multicenter RCT (n=144) demonstrated electroacupuncture (EA) at GV20/EX-HN3 reduced HAMD scores by 10.5 ± 2.4, with serum 5-HT/BDNF elevated and NLRP3 expression reduced.⁶⁷ Limitations of current clinical studies include small sample sizes (n<200 in most), short follow-up (≤12 weeks), and lack of microbiota/metabolite monitoring. Large-scale, long-term RCTs integrating multi-omics (metagenomics, metabolomics) are needed to validate clinical efficacy and mechanisms.

Table 3 Summary of Studies on the Use of Acupuncture to Regulate Gut Microbiota in the Treatment of Depression

Molecular Mechanisms of Traditional Chinese Medicine Regulating Intestinal Microbiota

Regulation of the Immune System

TCM inhibits NLRP3/TLR4-mediated inflammation via multi-target regulation. TCM components (astragaloside IV, saikosaponin) suppress NLRP3 oligomerization and ASC speck formation, reducing Caspase-1 activation and mature IL-1β/IL-18 release.^46,49 For example, Gan-Mai-Da-Zao decoction downregulates NLRP3/ASC/Caspase-1 expression in CUMS mice, decreasing hippocampal IL-1β by 42%.²² Xiaoyaosan and Chaihu-Shugan-San downregulate TLR4 and its adapter MyD88, inhibiting NF-κB nuclear translocation and reducing pro-inflammatory cytokines (TNF-α/IL-6).^25,66 Astragaloside IV also blocks TLR4-LPS binding to alleviate intestinal barrier dysfunction.⁴⁹ Studies have demonstrated that there is a close interaction between the gut microbiota and the host immune system. TCM influences immune responses by regulating the composition of the gut microbiota.⁹⁰ For example, certain TCM components can promote the growth of beneficial bacteria and inhibit the proliferation of harmful bacteria, thereby improving the balance of the intestinal microecology and enhancing the body’s immune function.⁹¹ In addition, TCM can improve the immune status of depressed patients by regulating cytokine secretion and reducing inflammatory responses.⁹² For instance, studies have found that TCM can significantly reduce the levels of inflammatory factors in depressed patients, such as TNF-αand IL-6, thereby improving their emotional state.⁹³ This dual effect of regulating the gut microbiota and the immune system provides a new perspective for the application of TCM in the treatment of depression.

Effects on the Neuroendocrine System

TCM plays an important role in the treatment of depression by regulating the neuroendocrine system. Studies have shown that changes in the gut microbiota can affect the function of the neuroendocrine system, thereby influencing emotions and behaviors.⁹⁴ Certain components of TCM can regulate the gut microbiota, which in turn affects the activity of the hypothalamic-pituitary-adrenal (HPA) axis, reduces stress responses, and improves depressive symptoms.^95,96 For example, short-chain fatty acids (SCFAs) produced by gut microbes can stimulate the vagus nerve, affecting neurotransmitter release in the brain and thus alleviating depressive symptoms.^26,97 In addition, TCM can alleviate depressive symptoms by regulating the secretion of endocrine hormones such as adrenocorticotropic hormone (ACTH) and cortisol.⁹⁸ These findings provide a new biological basis for the application of TCM in the treatment of depression.

The Relationship Between Changes in Neurotransmitters and Depression

Alterations in neurotransmitters play a pivotal role in the occurrence and progression of depression. Gut microbiota metabolites directly regulate neurotransmitter synthesis and release, though direct evidence remains limited. SCFAs (eg, butyrate) promote colonic enterochromaffin cell proliferation and 5-HT synthesis (via upregulating tryptophan hydroxylase 1, TPH1), with 90% of peripheral 5-HT derived from gut microbes.⁹⁹ Butyrate also crosses the blood-brain barrier (BBB) to enhance hippocampal 5-HT release.¹⁰⁰ Tryptophan metabolism is another key pathway: gut bacteria (eg, Lactobacillus) convert tryptophan to indole-3-acetic acid, which inhibits the kynurenine pathway (reducing neurotoxic quinolinic acid) and increases hippocampal DA/BDNF levels.¹⁰¹ However, most studies focus on correlation rather than causation. Studies have shown that the gut microbiota influences the pathological mechanisms of depression by affecting the synthesis and metabolism of neurotransmitters.^102,103 For instance, gut microbes can regulate the levels of 5-HT, DA, and NE, and the imbalance of these neurotransmitters is closely associated with depression.⁹⁵ TCM promotes neurotransmitter synthesis and alleviates depressive symptoms by regulating the gut microbiota.¹⁰⁴ For example, certain TCM components can increase the synthesis of 5-HT, thereby improving emotional states.¹⁰⁵ Additionally, studies have found that metabolites produced by gut microbes can further regulate neural transmission function in the brain by influencing the activity of neurotransmitter receptors, thus affecting the development of depression.¹⁰⁰ These studies provide important molecular mechanistic support for the application of TCM in the treatment of depression (As shown in Figure 2).

Figure 2 Mechanism diagram of TCM regulating the gut-brain axis in treating depression. Black arrow represents the pathway of regulation and promotion; The red arrow represents the increase or decrease of pro-inflammatory factors; The green arrow represents the increase or decrease of anti-inflammatory factors.

Conclusion

With the increasing depth of the gut-brain axis concept, our understanding of depression is constantly evolving. The composition and function of the gut microbiota are closely associated with the occurrence and progression of depression, and a growing body of research indicates that the gut-brain axis plays a vital role in emotional regulation and mental health. As an ancient yet systematic therapeutic approach, traditional Chinese medicine (TCM) has demonstrated unique advantages in regulating the microbiota and improving intestinal health. Through methods such as harmonizing qi and blood, and soothing the liver to regulate qi, TCM can effectively influence the diversity and abundance of gut microbes, thereby providing new insights for the treatment of depression.

Although existing studies have initially revealed the potential mechanisms of TCM in the treatment of depression, more systematic and scientific research is still needed to verify these findings. Differences often exist among various research results, which may stem from multiple factors such as sample selection, study design, and treatment protocols. A major limitation of current studies is the use of heterogeneous depression models, primarily chronic unpredictable mild stress (CUMS) and chronic restraint stress (CRS). CUMS mimics complex real-world stressors (eg, noise, food deprivation) and is widely used for its high clinical relevance, but results may vary due to inconsistent stressor combinations across studies.¹⁰⁶ In contrast, CRS focuses on single, sustained stress, which simplifies experimental variables but lacks ecological validity.¹⁰⁷ These differences lead to inconsistent findings: for example, Xiaoyaosan significantly increases Lactobacillus abundance in CUMS mice²⁵ but shows no significant change in CRS models,⁷⁵ possibly because CUMS-induced gut microbiota dysbiosis is more severe and responsive to TCM intervention. Therefore, future research should adopt multiple models to validate conclusions and standardize stressor protocols to enhance result comparability. Meanwhile, emphasis must be placed on standardization and normalization to ensure the reproducibility and reliability of research results, so as to provide more effective solutions for the clinical treatment of depression.

In conclusion, research on the gut-brain axis has provided a new perspective for the treatment of depression, and the unique regulatory mechanisms of TCM have brought new possibilities for the development of this field. Future studies will require more in-depth exploration to promote the update of gut-brain axis-related theories and the improvement of clinical practices, thereby bringing better quality of life and mental health to patients with depression.