One critical neural pathway is the vagus nerve, which acts as a primary conduit for signal transmission between the gut and brain, influencing emotional regulation and stress responses (Bonaz et al., 2018). Animal studies indicate that vagus nerve stimulation (VNS) effectively alleviates depression, playing a pivotal role in stress modulation and mood regulation (Breit et al., 2018). Research has demonstrated that repetitive VNS (rVNS) produces anxiolytic effects through the noradrenergic pathway. This treatment is associated with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated excitatory neurotransmission in the central amygdala (CeL), achieved via AMPAR transport activation (Zhang et al., 2022; Toader et al., 2024). Microglia, the primary immune cells of the central nervous system (CNS), initiate immune responses when recognizing neurotransmitter signals (Gao H. et al., 2022; Agirman et al., 2021). Recent studies suggest that gut microbiota in animals experiencing stress activate microglia in the dentate gyrus. This response may interfere with hippocampal neurogenesis and increase depression-related behaviors (He et al., 2024). GM significantly affect brain function through the synthesis of neurotransmitters such as serotonin and gamma-aminobutyric acid (GABA), which are essential for maintaining emotional balance (Dinan and Cryan, 2020). VNS therapy also reduces peripheral blood TNF-α levels, which are elevated in depressed patients (Toader et al., 2024; Koopman et al., 2016). Brain-derived neurotrophic factors (BDNF), as a growth factor associated with the gut microbiota, can be influenced by the gut microbiota through neuroendocrine pathways to regulate its expression, thereby modulates hippocampal neurogenesis and contributes to the onset and progression of depression (Han et al., 2025). Thus, neural modulation represents an innovative clinical approach to treating depression and anxiety.

The HPA axis is a central mediator of the body’s stress response and is significantly influenced by the gut microbiota (Bear et al., 2021). The hippocampus plays a key role in regulating the HPA axis, primarily by controlling corticotropin-releasing hormone (CRH) secretion. This effect is mainly exerted by regulating the hypothalamic paraventricular nucleus (PVN), which prompts the anterior pituitary gland to secrete adrenocorticotropic hormone (ACTH). ACTH subsequently induces glucocorticoid (cortisol in humans) secretion from the adrenal cortex (Misiak et al., 2020; Ding et al., 2024). Cortisol, a glucocorticoid produced by the adrenal cortex (Rehman et al., 2022), increases in response to gut microbiota alterations affecting the HPA axis (Misiak et al., 2020). These hormones significantly influence anxiety and depression (Martin et al., 2019; Sun et al., 2022). Chronic stress negatively affects gut microbiota composition, elevating cortisol levels and exacerbating anxiety and depression. This cascade results from dysfunction of the HPA axis, disturbing gut bacterial balance (Hassamal, 2023). Additionally, gut microbiota modulates neuropeptide and hormone secretion, including mood-regulating hormones such as ghrelin and leptin (Zheng et al., 2016).

The gut microbiota in healthy individuals typically remains balanced and stable. When pathogens invade and disrupt host-microbial homeostasis, dysbiosis occurs, increasing intestinal barrier permeability (“leaky gut”). This increased permeability allows microbial metabolites, toxins, and pathogens to enter circulation, triggering systemic inflammation (Alhasson et al., 2017; Kociszewska and Vlajkovic, 2022). Intestinal permeability is intricately linked to systemic inflammation and psychiatric disorders (Ma et al., 2022). The enteric nervous system (ENS) plays a crucial role in modulating intestinal immune functions by mediating associated immune responses (Lu et al., 2024). Further research indicates that immune responses are closely associated with neuroinflammation, a major contributor to mood disorders (Sittipo et al., 2022). During inflammatory responses, the body produces numerous pro-inflammatory cytokines. These cytokines, upon entering the brain, modulate neural circuits and neurotransmitter systems related to mood, potentially causing depressive symptoms (Zhu R. et al., 2024). Disruption of gut microbiota also increases lipopolysaccharide (LPS) production (Li W. et al., 2020). LPS-induced inflammation can provoke depressive symptoms through the release of pro-inflammatory cytokines and inflammatory mediators (Shi et al., 2019). Consequently, LPS exacerbates inflammation and disrupts the blood–brain barrier (Logsdon et al., 2020). LPS and similar molecules activate immune cells to release pro-inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α), which directly contribute to depression onset (Medina-Rodriguez et al., 2018; Simpson et al., 2021). Additionally, GM imbalance and HPA axis dysfunction mutually influence each other, jointly promoting inflammation (Warren et al., 2024). Microglia, the primary resident macrophages of the CNS, play a key role in brain immune defense (Thangaraj et al., 2018). The gut microbiota may impact microglia via inflammatory signaling along the MGB axis, affecting brain function and modulating depressive-like behaviors (Agirman et al., 2021; Donoso et al., 2023). Studies indicate an increased prevalence of depression and anxiety among patients with ulcerative colitis (UC). Preventive anti-inflammatory treatment effectively alleviates depressive behaviors and reduces systemic inflammatory cytokine levels in colitis models (Yuan et al., 2021).

Key metabolites of the intestinal microbiota, SCFAs, including butyrate, acetate, and propionate (Dong et al., 2022). SCFAs can cross the BBB, providing neuroprotection by regulating neuroinflammation and enhancing barrier integrity (Dalile et al., 2019). SCFAs predominantly inhibit histone deacetylase (HDAC) activity, thereby dampening inflammation and mitigating overzealous immune reactions in microglia, or triggering free fatty acid receptors (e.g., FFAR2/3), to augment microglial activation (Cao et al., 2025). Human trials indicate that an almond-based low-carbohydrate diet (a-LCD) promotes the growth of SCFA-producing gut microbiota, thereby increasing SCFA production, activating the GPR43 receptor, and enhancing GLP-1 secretion to alleviate depressive symptoms (Ren et al., 2020). Butyrate is essential for maintaining intestinal barrier function in mammals. Reduced butyrate levels may trigger depressive symptoms by disrupting gut-derived metabolite balance and altering the expression of G protein-coupled receptors (GPCRs) and BDNF in the CNS (Nohesara et al., 2023). Butyrate stimulates BDNF secretion (Romo-Araiza et al., 2018), a gene potentially associated with anxiety and depression (Chu et al., 2022). Research indicates that sodium butyrate alters gene expression in hippocampal microglia, thereby eliminating lipopolysaccharide-induced depressive-like behavior (Yamawaki et al., 2018). Valeric acid, another gut microbial metabolite, influences MGB axis metabolism (Lin et al., 2021), has demonstrated potential to modulate anxiety and depression (Mann et al., 2014; Bhandage et al., 2019). This finding offers new insights into treating related neurological conditions. Moreover, GM significantly contributes to tryptophan metabolism (Zhao et al., 2022), a crucial precursor of serotonin (Emmerzaal et al., 2020), which profoundly affects mood and emotional regulation (Li Z. et al., 2020). During inflammatory states, tryptophan is metabolized by IDO1 (indoleamine 2,3-dioxygenase) into kynurenine, simultaneously producing neurotoxic metabolites that reduce 5-HT synthesis and promote depression and anxiety (Tahiri et al., 2024). Research indicates that patients who orally administered the probiotic B. breve CCFM1025 exhibited a significant increase in fecal concentrations of multiple tryptophan derivatives, such as 5-hydroxytryptophan (5-HTP). These changes in derivative concentrations were significantly correlated with improvements in patients’ depressive symptoms and gastrointestinal symptoms (Tian et al., 2022). Another metabolite, bile acids, showed in randomized controlled trials that elevated glycine-conjugated bile acids were significantly associated with decreased anxiety scores (HADA) (Martin et al., 2024). A study has demonstrated for the first time in humans that the probiotic strain LP299v can significantly reduce plasma homocysteine levels by modulating the tryptophan-homocysteine metabolic pathway. This reduction in homocysteine levels was significantly associated with improvements in cognitive function (Rudzki et al., 2019). Gut peptides are peptide hormones capable of regulating gastrointestinal motility through brain-gut axis interactions (Li et al., 2015; Młynarska et al., 2022). Certain intestinal peptides, including peptide YY (PYY), glucagon-like peptide-1 (GLP-1), cholecystokinin, CRH, growth inhibitory-releasing peptide, and oxytocin, are especially important, as they modulate depressive and anxiety-related behaviors (Młynarska et al., 2022; Dockray, 2014).

The MGB axis functions as a dynamic hub, through which gut microbial communities communicate via multiple signaling pathways (Figure 2), significantly influencing mental health. Clarifying these relationships is essential for developing novel therapeutic approaches to mental health disorders through GM modulation (Shoubridge et al., 2022).

Given the correlation between gut microbiota and anxiety/depression, probiotics may alleviate symptoms by regulating dysbiosis (Jang et al., 2019). Probiotics, as a safe and well-tolerated non-pharmacological therapy, represent a promising therapeutic option for mood disorders (Merkouris et al., 2024). Research has shown that probiotics can enhance cognitive function and reduce depressive symptoms, suggesting their potential role in depression treatment (He et al., 2023). Timothy G et al. defined the concept of psycholbiotics as live microorganisms that, when ingested in sufficient quantities, confer health benefits to individuals with mental disorders. These probiotics belong to a class capable of producing and delivering neuroactive substances such as GABA, serotonin, and dopamine, thereby influencing brain function through the MGB axis (Dinan et al., 2013). Probiotic preparations commonly used in clinical practice include beneficial strains such as Lactobacillus casei, Lactobacillus acidophilus, and Bifidobacteria (Zhang et al., 2023). Research by Kirsten Tillisch et al. has demonstrated for the first time in humans that chronic consumption of fermented dairy products containing five probiotic strains—including Bifidobacterium lactis CNCM I-2494—significantly modulates the brain’s response to emotional stimuliation (Tillisch et al., 2013). In addition, Gu et al. (2020) confirmed that Lactobacillus casei exert significant antidepressant effects in rat models by regulating gut microbiota and the brain-derived neurotrophic factor-tyrosine kinase receptor (BDNF–TrkB) signaling pathway. Certain strains, such as Lactobacillus NK41, Bifidobacterium longum NK46, and their combinations, can alleviate stress-induced anxiety/depression-like behaviors. These effects involve reduced neuroinflammation (e.g., hippocampal NF-κB and microglial activation), increased neuroplasticity markers (e.g., BDNF), and improved peripheral stress/inflammation indicators (e.g., cortisol, TNF-α, and IL-6) (Han and Kim, 2019). Similarly, Sara Ferrari reported that probiotic combinations (e.g., Bifidobacterium longum novaBLG2) can mitigate glutamate-induced anxiety/depression symptoms and enhance cell survival by regulating gut-brain axis metabolites (Ferrari et al., 2024). Research also indicates that daily supplementation with Bifidobacterium breve Bif11 for 21 consecutive days can prevent LPS-induced depressive behavior in mice (Sushma et al., 2023). Bifidobacterium bifidum has demonstrated positive preventive and therapeutic effects on depression in animal models and humans (Li et al., 2023). Regarding dosage, studies have indicated that psychobiotics require a minimum daily dose of 1 billion CFU, with optimal results achieved using doses exceeding 10 billion CFU for at least 8 weeks (Jach et al., 2023). The following are partial experimental results from human studies (Table 2).

In recent years, multiple meta-analyses have attempted to comprehensively evaluate the efficacy of probiotics for mood disorders. For example, Liu’s analysis revealed no statistically significant difference between the probiotic group and the placebo group in alleviating anxiety symptoms (SMD = −0.12, 95% CI: −0.28 to 0.04, p = 0.14; Liu et al., 2018). However, Moshfeghinia et al. (2025) analysis indicates that probiotics, prebiotics, or synbiotics can significantly alleviate depressive and anxiety symptoms in individuals with depression, despite high heterogeneity among studies (I²: 96.29%). Notably, nearly all meta-analyses emphasize significant heterogeneity among included studies (I² > 50%), underscoring the need for extreme caution in interpreting results.

Despite these promising findings, probiotic applications still face several limitations. Although evidence supports probiotics’ benefits for mood regulation, specific biological mechanisms remain unclear. Additionally, probiotic efficacy varies among individuals, likely due to differences in gut microbiota composition, lifestyle, and genetic background. Therefore, considering that the gut microbial composition of individuals with mental illness differs from that of healthy individuals, personalized intervention strategies can be designed to address specific microbial dysbiosis for therapeutic purposes (Vindegaard et al., 2021). Furthermore, probiotics used in different studies vary in strain, dosage, and administration protocols, reducing comparability across studies. Crucially, the effects of probiotics exhibit a high degree of strain specificity. This means that different strains-even of the same species-may have completely different effects on their hosts. For example, experiments have demonstrated that Lactobacillus johnsonii (NCC 533) or Lactobacillus paracasei (NCC 2461)—two strains of intestinal lactobacilli exhibiting similar characteristics in vitro—can elicit different immune responses (Ibnou-Zekri et al., 2003). Even the same bacterial strains exhibit differences in dosage and treatment duration across different experiments. Therefore, it is unscientific to summarize the results of probiotic research in general. Future research and clinical applications must operate accurately at the strain level. Although some studies have shown positive effects, research in this field is extremely heterogeneous, resulting in different studies often reaching conflicting conclusions. This heterogeneity mainly comes from inconsistent intervention plans, different study populations, diverse outcome measures, and lack of standardization.

Prebiotics are substrates selectively utilized by host microorganisms to confer health benefits (Gibson et al., 2017). Non-digestible oligosaccharides, including fructan, galactan, and resistant starch, are the primary prebiotic components. Recently, the scope of the term has broadened to include dietary compounds such as polyphenols (Medina-Larqué et al., 2022). Prebiotics affect depression by modulating neurotransmitter production, SCFA production, and immune regulation (Yang Y. et al., 2023). SCFA production is closely linked to prebiotic intake and the composition of intestinal microbiota (Godínez-Méndez et al., 2021). SCFAs can cross the BBB, influencing brain function (Wang J. et al., 2022). Additionally, studies suggest that SCFAs regulate emotional states through the MGB axis and produce anti-inflammatory effects (Liu et al., 2021; Van de Wouw et al., 2018). Recently, Igor Henrique Rodrigues de Paiva succeeded in reversing depressive and anxiety symptoms in mice fed a high-fat diet through therapeutic intervention with fructooligosaccharides (FOS) and galactooligosaccharides (GOS) (Paiva et al., 2024). The administration of FOS and GOS not only demonstrated benefits in probiotic treatment for stress-related behaviors but also effectively reduced stress-induced increases in corticosterone and pro-inflammatory cytokines, attenuating depressive-like and anxiety-like behaviors (Burokas et al., 2017). Antonio Leo’s research confirmed that in the chronic unpredictable mild stress (CUMS) model, the combination of prebiotic α-lactalbumin (ALAC) and postbiotic sodium butyrate (NaB) effectively regulates the MGB axis. This synergy indicates potential for treating anxiety and depression (Leo et al., 2021). However, clinical data on prebiotics remain scarce. Thus, large-scale clinical trials are necessary to determine their sustained therapeutic effects, optimal dosage, and mechanisms of action against depression and anxiety (Asad et al., 2025).

The International Scientific Association for Probiotics and Prebiotics (ISAPP) defines postbiotics as formulations containing non-viable microorganisms or their constituents that provide health benefits to the host (Salminen et al., 2021). Given the limitations associated with probiotic research, postbiotic compositions derived from probiotics may represent promising new microbial therapeutic approaches (Nataraj et al., 2020; Suez et al., 2019). Postbiotics comprise inactivated cell components (e.g., cell wall fragments and surface proteins) and bacterial cell metabolites (e.g., SCFAs and bacteriocins), collectively mediating physiological effects (Mehta et al., 2023). Postbiotics have been employed to regulate intestinal microbiota, showing effectiveness in resolving dysbiosis (Gao M. et al., 2022), which may positively impact mental health. A review by Icer et al. (2024) noted that GABA produced by lactic acid bacteria (LAB) may exert neuroprotective effects, improving depression. Another study reported that cell-free supernatant (CFS) obtained from Lactobacillus rhamnosus UBLR-58 and Bifidobacterium breve UBBr-01 can reduce nerve damage by inhibiting neuroinflammation and regulating the MGB axis pathway (Rahman et al., 2024). Additionally, SCFAs produced as postbiotics by probiotics play an important role in the MGB axis (Ragavan and Hemalatha, 2024). Increasing research into postbiotics and neurological dysfunction disorders suggests that modulation of the gut-brain axis offers promising future applications in mental health.

Synbiotics, dietary supplements combining probiotics and prebiotics to deliver synergistic health benefits, demonstrate therapeutic potential in mood disorders (Ke et al., 2019). A 2020 double-blind randomized controlled trial (RCT) showed that Synbiotic 2000 supplements can improve emotional regulation in adults with attention deficit hyperactivity disorder (ADHD) (Skott et al., 2020; Arteaga-Henríquez et al., 2024). A multicenter, randomized, placebo-controlled “basket” trial by Arteaga-Henríquez et al. (2024) also demonstrated that synbiotics specifically improved mood symptoms and abnormalities in mood regulation, consistent with Scott’s findings. A preclinical mechanistic study by Lapmanee et al. (2024) revealed that synbiotics have neuroprotective and gut benefits in stressed rats. Sanjay Noonan et al. found that supplementation with Synbiotic produced statistically significant improvements in measures of depression (Noonan et al., 2020). Synthetic probiotics possess both probiotic and prebiotic properties, and combining these elements primarily enhances probiotic survival during gastrointestinal transit. When properly combined, they may produce better results than probiotics or prebiotics alone (Yoo et al., 2024; Markowiak and Śliżewska, 2018).

Fecal microbiota transplantation (FMT) is a therapeutic intervention involving the transfer of fecal material from a healthy individual to the intestinal tract of a recipient. This approach has recently gained attention as a potential treatment for depressive disorders by recalibrating intestinal microbiota (Joo et al., 2024). Multiple academic analyses indicate that FMT interventions reduce bacteria associated with psychiatric disorders (e.g., Lactobacillus acidophilus), thereby alleviating psychiatric symptoms (Yang C. et al., 2023). A recent RCT of patients with diarrhea-predominant irritable bowel syndrome (IBS-D) and comorbid anxiety/depression demonstrated that oral FMT capsules significantly alleviated both IBS-D and associated psychological symptoms (Guo et al., 2021). Critically, these clinical improvements were accompanied by the restoration of gut microbial communities, suggesting microbiota modulation as a potential underlying mechanism. A pilot RCT by Green et al. (2023) demonstrated the feasibility of a different FMT administration route (enema) for patients with major depressive disorder (MDD). Baske et al. (2024) reviewed evidence showing significantly elevated Escherichia-Shigella levels in patients with generalized anxiety disorder (GAD) and proposed that FMT might reduce these bacteria, positively affecting the gut-brain axis and providing a promising avenue for novel GAD therapies. Xu Qi et al. showed that FMT from healthy mice to postpartum depression (PPD) model mice improved depression/anxiety-like behaviors by regulating the NLRP-3/caspase-1 pathway in the gut and hippocampus (Campbell and Macqueen, 2004). Cai et al. (2022) confirmed that FMT improved CUMS-induced depressive behavior in rats, with mechanisms involving coordinated actions of the 5-HT system, BDNF, neurotransmitters (GABA/Glu), inflammatory factors (IL-6/LPS), and SCFAs. Rao et al. (2021) observed increased 5-HT and decreased IL-1β and TNF-α after FMT treatment, leading to improved depressive symptoms. An international consensus meeting convened by the American Gastroenterological Association (AGA) indicated that FMT demonstrates favorable short-term safety in treating Clostridium difficile infection, but long-term safety data remain insufficient and require ongoing follow-up studies (Cammarota et al., 2019). Moreover, evidence is lacking regarding its safety in extremely immunocompromised individuals (Yadegar et al., 2024). Mark Hofmeister’s recent meta-analysis ultimately included 62 studies, with only one evaluating the impact of FMT on depressive symptoms. The conclusion was that this intervention did not demonstrate a statistically significant benefit for depression (Hofmeister et al., 2021). However, the author has only included one relevant study thus far. Due to factors such as small sample size, it is currently not possible to draw definitive conclusions on this matter.

The goal shared by FMT and FVT is to treat diseases by reshaping gut microbiota. Mao et al. (2024) suggested that the success of FMT may largely be attributed to the role played by its transferred viral components in reprogramming the host microbiota. Meanwhile, a double-blind randomized placebo-controlled trial demonstrated that FMT significantly alters the recipient’s intestinal phage community and promotes the long-term stable colonization of donor phages (Zuppi et al., 2024). Therefore, we have incorporated FVT as a novel transplant intervention into this chapter. FVT has emerged as an innovative therapeutic strategy focused specifically on transferring viral components of the donor’s gut microbiota (Castells-Nobau et al., 2024). FVT involves transplanting the viral components present in feces, specifically bacteriophages (Rasmussen et al., 2020). Experiments by Ritz et al. (2024) demonstrate that FVT can alleviate stress-induced behavioral, immunological, and neurobiological changes by modulating the MGB axis. FVT significantly reduces the risk of pathogen transmission associated with FMT through physical filtration and processing while maintaining therapeutic efficacy. Compared to FMT, it represents a safer potential treatment strategy capable of accommodating donor variability (Rasmussen et al., 2024). At present, few studies have been conducted in this area, and more research is required to clarify the underlying mechanisms.

Although FMT and FVT are promising therapeutic approaches, their clinical application poses significant safety concerns. Regarding FMT, reports of serious adverse events, including the transmission of multidrug-resistant infections resulting in fatalities—have prompted regulatory warnings (Kuijper et al., 2019). The long-term consequences of introducing intact foreign microbial communities remain unclear, and adverse reactions such as diarrhea, bloating, and abdominal pain may occur. For FVT, although the risk of bacterial infection is significantly reduced during preparation by eliminating bacteria, the possibility of eukaryotic virome transmission and potential microbial contamination cannot be completely ruled out. As invasive therapeutic procedures, FMT and FVT require strict screening of microbiota donors and necessitate long-term follow-up in clinical trials. Furthermore, these therapies face significant regulatory hurdles. Neither FMT nor FVT fits neatly into traditional drug or medical device classifications, creating regulatory ambiguity. The absence of standardized protocols for donor screening, material preparation, and efficacy assessment complicates quality control and approval processes. Establishing safe, high-quality donor banks involves complex ethical and legal challenges. Crucially, current evidence supporting the efficacy of FMT/FVT for treating mood disorders primarily stems from small-scale or open-label studies, which are highly susceptible to bias and placebo effects. Before considering any clinical application recommendations, large-scale randomized double-blind placebo-controlled trials are imperative.

Oral antidepressants and anxiolytics continue to dominate the treatment of anxiety and depression. SSRIs and SNRIs serve as primary medications for managing depression and anxiety, while benzodiazepines are restricted to short-term anxiety management (Neil-Sztramko et al., 2025). Antidepressants are generally categorized into novel antidepressants, tricyclic antidepressants, traditional antidepressants, and SSRIs, collectively offering various therapeutic options for depression treatment (Hockenberry et al., 2019). Studies have shown that antidepressants affect gut microbiota composition and function (Tan et al., 2022). SSRIs modulate gut microbiota, potentially contributing to symptom relief in depressed individuals. Individuals treated with SSRIs showed significant alterations in gut microbiota composition, which might explain improvements in mood symptoms (Gao M. et al., 2023). Fluoxetine, an SSRI antidepressant, exerts effects beyond emotional stabilization, particularly in pregnant and nursing women. This drug alters gut microbiota balance and fundamentally modifies the metabolic functions of these microorganisms (Ramsteijn et al., 2020). Venlafaxine exerts antidepressant effects by inhibiting serotonin and norepinephrine reuptake, regulating serotonin and glutamate levels in mouse models of depression, and influencing gut microbiota diversity, particularly affecting key bacterial genera such as Blautia, Oscillibacter, Tyzzerella, Butyricoccus, and Enterorhabdus (Shen et al., 2023). Dexipramine, a tricyclic antidepressant, exhibited notable antimicrobial activity; notably, Mucinophilic Immobilized Bacillus and Escherichia coli were highly susceptible to this drug (Ait Chait et al., 2020). Evidence suggests antidepressants can regulate gut microbiota composition and function, which may be critical for their efficacy. Future research exploring this interaction could inform improved treatment strategies.

Currently, an increasing number of studies indicate that TCM treatments can alleviate psychological disorders, including depression and anxiety, by modulating the gut microbiota. The effectiveness of acupuncture (including electroacupuncture and manual acupuncture) in treating depression and anxiety has long been demonstrated (Zheng et al., 2019). Several studies show acupuncture can alleviate depression by modulating gut microbiota (Wang et al., 2024). Recent studies suggest acupuncture may ameliorate depressive-like behaviors in post-stroke depression (PSD) by modulating gut microbiota and inhibiting NLRP3 inflammasome overactivation in the colon (Cai et al., 2024). Electroacupuncture (EA) has minimal side effects, combining electrical stimulation and acupuncture. This innovative therapy has attracted attention in the field of neurological disorders, especially depression (Duan et al., 2024). EA may exert antidepressant effects by regulating gut microbiota (Duan et al., 2024), experimentally demonstrated by the upregulation of BDNF and increased abundance of SCFA-producing bacteria (Li S. et al., 2024). Umbilical moxibustion helps rebalance intestinal microbiota by promoting beneficial bacteria growth and inhibiting harmful strains. This microbial regulation plays an important role in alleviating subclinical depressive symptoms. The therapy creates a healthier intestinal environment, supporting mental health (Yu et al., 2024).

In addition, TCM herbal formulas have demonstrated efficacy in treating mental illnesses, including depression and anxiety, through alterations in gut microbiota (Table 4). Research indicates that Xiaoyao San alleviates depressive-like symptoms in rats subjected to chronic unpredictable mild stress (CUMS) by modulating gut microbiota, especially, it exerts antidepressant effects by inhibiting the TLR4/NLRP3 inflammatory pathway and enhancing intestinal barrier function (Liu et al., 2024). Similarly, data confirms that Gegen Qinlian decoction significantly alleviates depression-like behaviors in CUMS rats, also by regulating gut microbiota and metabolites such as oleanolic acid (Peng et al., 2024). Li J. L. et al. (2024) evaluated the efficacy and safety of Kaixin Powder in treating depression. The results showed that KXS was comparable to or superior to antidepressants in treating depression, with fewer side effects. KXS alleviates intestinal inflammation by modulating microbiota composition and reducing LPS levels, thereby decreasing pro-inflammatory cytokines and protecting both the intestinal barrier and blood–brain barrier. Simultaneously, it lowers HPA axis hormone levels to mitigate excessive HPA axis activation, thereby improving anxiety and depression (Cao et al., 2020). Dan Zhi Xiao Yao San exerts its antidepressant effects through a multi-component, multi-target, multi-pathway mechanism. Its primary active constituents are quercetin and luteolin, with key targets including AVPR2, EGFR, F2, and CDK6. Therapeutic effects are achieved by regulating LPA and the gut microbiota-brain axis (Zhu X. et al., 2024). Zhi-zi-chi decoction not only regulates intestinal microbiota but also delivers multiple bioactive compounds (such as oleanolic acid) that act on multi-target genes. This ultimately modulates the HPA axis (by reducing CRH, ACTH, etc.), elevates neurotransmitter levels (5-HT, GABA, etc.), reduce pro-inflammatory factors (IL-1β, TNF-α), and increase anti-inflammatory factors (IL-10) to alleviate anxiety and depression (Tian et al., 2024). In summary, robust evidence supports the efficacy of TCM interventions in alleviating depression and anxiety symptoms through gut microbiota regulation.

However, translating these promising research findings into evidence-based medicine faces significant challenges, primarily due to the lack of standardization in traditional Chinese medicine formulations, which leads to substantial heterogeneity across studies. Future research must prioritize identifying key active components and developing standardized, quality-controlled TCM formulations to ensure reproducibility and reliability of results. Furthermore, experimental findings from animal models cannot be directly applied to human clinical settings due to species-specific differences in gut microbiota composition, host metabolism, and drug pharmacokinetics. Animal experiments can only partially replicate the complexity of human emotional disorders. Therefore, while our data provides strong mechanistic evidence, they cannot directly predict human efficacy. Future research should integrate systems biology approaches to elucidate the precise mechanisms of action and active components of TCM. In summary, rigorously designed human clinical trials using standardized TCM formulations are essential for validating their efficacy and safety in treating anxiety and depression.