Gut microbiota dysbiosis and depression: Bidirectional interactions, mediating pathways, and microecological therapeutics

Abstract

The microbiota-gut-brain axis (MGBA) is increasingly recognized as a key target for ameliorating major depressive disorder (MDD). This review systematically synthesizes evidence on the bidirectional relationship between gut microbiota dysbiosis and MDD, and delineates the core mechanisms—such as neuroinflammation, neurotransmitter metabolism, and hypothalamic-pituitary-adrenal (HPA) axis dysregulation—through which this axis influences depressive pathogenesis. Further, the intestinal microbiota characteristics related to MDD, the main regulatory pathways, and the potential efficacy of microbiome-targeted intervention measures—including psychobiotics, prebiotics, fecal microbiota transplantation (FMT), and dietary strategies—were sorted out. In the clinical assessment and drug research of depression, the assessment tools are mainly divided into two categories: clinician-rated and self-reported. These two types are often used together to provide multi-dimensional evidence of therapeutic efficacy. Evidence suggests that stress-related intestinal permeability may initiate gut dysbiosis, which in turn can impair barrier function, promote neuroinflammation, disrupt neurotransmitter synthesis, and overactivate the HPA axis, potentially exacerbating depressive symptoms. Interventions targeting the gut microbiota may help reshape microbial communities, increase short-chain fatty acids (SCFAs) and 5-Hydroxytryptamine (5-HT), and dampen inflammatory and stress responses, thereby offering a promising, non-pharmacological avenue for alleviating MDD. This review not only offers a theoretical foundation for microbiota-based therapeutics in MDD but also highlights pathways toward developing safe, effective non-pharmacological strategies for depression management.

Graphical abstract

Abstract Figure. (5-hydroxytryptamine, 5-HT; Short-chain fatty acids, SCFAs; hypothalamic-pituitary-adrenal, HPA; Hamilton Depression Rating Scale, HDRS/HAMD; Montgomery-Åsberg Depression Rating Scale, MADRS; Beck Depression Inventory, BDI; Patient Health Questionnaire-9, PHQ-9; Depression Anxiety Stress Scale, DASS-21.)

Highlights

• •Gut microbiota dysbiosis and Major Depressive Disorder bidirectional link clarified.
• •Three mechanisms of gut-brain axis in Major Depressive Disorder summarized.
• •Antidepressant potential of 4 microecological interventions was evaluated.

1. Introduction

Major depressive disorder (MDD) is a common mental disorder, primarily characterized by low mood, anhedonia, eating disturbances, social anxiety, and impaired cognitive function (Li et al., 2023). According to statistics, in 2019, the global number of people suffering from mental disorders was approximately 970 million, among which the number of people suffering from depression was about 279 million (GBD 2019 Mental Disorders Collaborators, 2022). The lifetime prevalence of depressive disorders among Chinese adults is 6.8%, corresponding to 95 million MDD patients (People's Daily Health ClientHealth Times, 2022). This indicates that 1 out of every 15 adults experiences at least one depressive episode in their lifetime, and this number has continued to rise since the COVID-19 pandemic. More critically, MDD is often comorbid with anxiety, insomnia, and physical pain, leading to a significant decline in patients' quality of life. For this reason, the World Health Organization (WHO) has ranked MDD as the second leading cause of global disease burden, second only to ischemic heart disease (World Health Organization, 2017). Although traditional antidepressants can alleviate symptoms, research shows that the non-adherence rate to these medications can be as high as 46%–83%, and side effects such as weight gain can significantly undermine treatment adherence (Niarchou et al., 2024). Therefore, the search for safe, effective, and sustainable long-term intervention strategies has become a crucial focus requiring breakthroughs in the field of psychiatry.

Gut microbiota plays a vital role in human health. It is closely associated with the body's immune, nervous, and endocrine systems, and is involved in physiological processes such as nutrient metabolism, immune regulation, and neural development (Zhao et al., 2024). Studies have shown that gut microbiota contributes significantly to the occurrence and progression of various diseases, primarily relying on bacterial diversity, the stability of microbial community structure, and microecological balance (Chen et al., 2017). Studies have shown that in the gut microbiota of patients with depression, the relative abundance of Bacteroidetes is significantly increased, while the relative abundance of Firmicutes is decreased, and the alpha diversity is significantly lower than that of healthy controls (Zheng et al., 2016). A complex bidirectional communication system, known as the microbiota-gut-brain axis (MGBA), exists between the gut microbiota and the brain (Bhatt et al., 2023). Think of it as a high-speed information superhighway: this axis involves four pathways—vagal nerve, immune, endocrine, and metabolic—enabling gut-to-central signal transmission on a millisecond timescale (60–800 ms) (Kaelberer et al., 2018), thereby facilitating a “gut microenvironment–immune–neural–behavior” cascade. Recent animal experiments have further confirmed that germ-free mice exhibit "depression-like" behaviors after receiving fecal microbiota transplantation from MDD patients (Cao et al., 2025), suggesting that gut microbiota dysbiosis is not merely an accompanying phenomenon but also one of the key driving factors of the disease.

In this context, interventions targeting the gut microecology, particularly psychobiotics (i.e., probiotics with mental health benefits) supplementation, have shown great promise. After entering the intestinal tract, probiotics can modulate the intestinal microecological balance. Beneficial bacteria influence the synthesis and release of mood-related neurotransmitters such as 5-Hydroxytryptamine (5-HT), serotonin, and dopamine (DA) through the production of metabolites including short-chain fatty acids (Bhattarai et al., 2017). For example, butyrate-producing Clostridium species can increase hippocampal 5-HT levels by approximately 25% through upregulating the expression of tryptophan hydroxylase 2 (TPH2), while Lactobacillus can induce an 18% increase in DA release in the prefrontal cortex (Sun et al., 2018; Bravo et al., 2011). In addition, probiotics can regulate the intestinal immune system and reduce inflammatory responses (Burokas et al., 2017). For instance, fatigue in depressed patients has been associated with elevated IL-1 levels (Bower et al., 2002). Clinical randomized double-blind trials provide direct evidence: an 8-week intervention study showed that supplementation with a probiotic combination containing Lactobacillus helveticus and Bifidobacterium longum significantly reduced patients' Beck Depression Inventory (BDI) scores from 17.39 to 9.1 compared to the placebo group (Kazemi et al., 2019). Therefore, the rational use of probiotics may serve as a novel adjuvant therapeutic strategy for depression.

Market trends reflect this therapeutic potential, with the global gut health-related market size surpassing $14 billion by the end of 2025 and projected to exceed $32 billion by 2035 (Eastlake, 2025). As shown in Fig. 1, this review aims to summarizes the characteristics of gut microbiota in patients with depression,systematically explores the mechanisms and application prospects of microecological interventions, such as probiotics, in the treatment of depression, thereby providing new ideas and methods for the clinical management of depression.

Fig. 1.

Abstract Figure. (5-hydroxytryptamine, 5-HT; Short-chain fatty acids, SCFAs; hypothalamic-pituitary-adrenal, HPA; Hamilton Depression Rating Scale, HDRS/HAMD; Montgomery-Åsberg Depression Rating Scale, MADRS; Beck Depression Inventory, BDI; Patient Health Questionnaire-9, PHQ-9; Depression Anxiety Stress Scale, DASS-21.)

2. Bidirectional interaction between depression and gut microbiota

Gut microbiota and depression are not linked by a unidirectional causal relationship but form a dynamic bidirectional regulatory connection through the MBGA. Gut microbiota dysbiosis can drive the development of depression via pathways such as neuroimmunity and metabolism, while depressive states can inversely reshape the structure of gut microbiota by altering the intestinal microenvironment (Zheng et al., 2016; Alli et al., 2022). These two factors interact to form a vicious cycle of "dysbiosis-depression".As depicted in Fig. 2, the mechanisms of this bidirectional interplay primarily encompass two core pathways: (1) gut dysbiosis can compromise the intestinal barrier, leading to the translocation of pro-inflammatory substances like lipopolysaccharide, which triggers systemic and neuroinflammation, ultimately manifesting as depressive behaviors; (2) the depressive state itself can, through immune activation and elevated inflammatory cytokines, in turn reduce microbial diversity and alter its composition, forming a vicious cycle (Osimo et al., 2020; Cao et al., 2025). The figure also summarizes the characteristic shifts in microbial abundance commonly observed in depression.

Fig. 2.

Diagram of the Bidirectional Interaction Mechanisms Between Gut Microbiota and Depression. (Lipopolysaccharide, LPS; Pathogen-associated molecular patterns, PAMPs; Interleukin-6, IL-6; Tumor necrosis factor-α, TNF-α.) Data sources: (Jain et al., 2001; Wu et al., 2024).

2.1. The impact of gut microbiota dysbiosis on depression

Gut microbiota dysbiosis is associated with various neuroinflammation-related diseases (Alli et al., 2022). Evidence from rodent studies involving fecal microbiota transplantation (FMT) has suggested that alterations in gut microbiota may precede the onset of depression-like behaviors (Zheng et al., 2016). This finding emphasizes that gut microbiota dysbiosis is not merely an accompanying phenomenon but may contribute to the pathogenesis of depression by affecting brain function through neuroimmune and neuroendocrine pathways. Specifically, dysbiotic microbiota impairs is thought to the integrity of the intestinal barrier, potentially allowing the translocation of pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) into the bloodstream (Jain et al., 2001). Experiments have demonstrated that intraperitoneal injection of LPS (50 μg per mouse) can prolong the immobility time of mice in the forced swim test in a time-dependent manner (Jain et al., 2001). Importantly, this direct LPS administration bypasses the initial dysbiosis stage, thereby experimentally validating the hypothesis that systemic LPS exposure—mimicking barrier leakage—can induce depressive-like behaviors.

Changes in gut microbiota diversity have been correlated with mood-related behaviors in animal studies (Zheng et al., 2016). For example, in animal models, recipient rodents exhibit the onset of depressive behaviors following FMT from patients with MDD (Han et al., 2023). Knudsen et al. (2021) found that when FMT was performed on Flinders Resistant Line (FRL) rats using fecal microbiota from MDD patients and healthy individuals, the FMT-Healthy group displayed significantly fewer depression-like behaviors than the FMT-MDD group. Further analysis via 16S rRNA sequencing revealed differences in gut microbiota composition between the two groups: the FMT-MDD group showed significantly increased relative abundances of three taxa belonging to the Ruminococcaceae family and one taxon of the Lachnospira genus, while the relative abundance of the Coprococcus genus was significantly decreased. Some of these changes can be traced back to the human MDD donors, indirectly echoing the microbiota characteristics observed in human MDD studies (Alli et al., 2022). This cross-species phenotype transfer observed in animal models has led to the suggestion that depressive-like phenotypes might be influenced by microbiota-host interactions, providing a platform for mechanistic studies.

Current research status indicates that although the association between gut microbiota dysbiosis and depression has been supported by experimental evidence, particularly from animal models, a direct causal relationship in humans remains to be further clarified. The bidirectional communication system suggests that depressive states may also induce changes in the microbiota. Therefore, future studies require more longitudinal data and multi-omics analyses to distinguish the temporal sequence of these interactions.

2.2. The impact of depression on gut microbiota

Current research has indicated that significant differences exist in the composition and abundance of gut microbiota between patients with depression and healthy individuals in cross-sectional studies (Zheng et al., 2016). These differences are mainly reflected in alterations in gut microbiota diversity and the abundance of specific bacterial taxa—specifically, beneficial bacteria in the gut microbiota are reduced and harmful bacteria are increased following the onset of depression (Wang et al., 2022). Among Chinese patients with depression, the alpha diversity of the gut microbiota (e.g., ACE and Chao indices) has been reported to be significantly different from that in healthy control groups, which reflects changes in species richness (Han et al., 2023). Meanwhile, studies based on animal models have shown that induction of depressive states can lead to decreased richness and diversity of the gut microbiota, suggesting a potential impact of depression on the overall structure of the microbiota (Winter et al., 2018).

Specifically, at the phylum level, patients with depression have exhibited increased abundances of Bacteroidetes, Actinobacteria, and Proteobacteria, accompanied by a decreased abundance of Firmicutes; at the genus level, elevated abundances of Prevotella and Klebsiella, as well as reduced abundances of Faecalibacterium and Ruminococcus, have been observed (Wu et al., 2024). Naseribafrouei et al. (2014) found that the number of operational taxonomic units (OTUs) in the gut microbiota of depressed patients was slightly higher than that in healthy controls; at the phylum level, the abundance of Bacteroidales was decreased, while at the genus level, certain clades within Alistipes and Oscillibacter showed significant associations with depression. Through UniFrac analysis, Zheng et al. (2016) revealed distinct differences in gut microbial community composition between depressed patients and healthy controls, with an increased relative abundance of Actinobacteria and a decreased relative abundance of Bacteroidetes in the former group. A study by Yang et al. (2020) identified significant differences in 3 phages, 47 bacterial species, and 50 fecal metabolites between depressed patients and healthy individuals; notably, the abundance of Bacteroides was increased, while the abundances of Blautia and Eubacterium were decreased in depressed patients.

Evidence from both animal and human studies suggests a link between gut microbial diversity and depressive behaviors: depressive states may be associated with changes in specific bacterial species, while alterations in the microbiota may in turn potentially influence mood regulation via the MBGA (Wang et al., 2022). Additionally, host genetic factors may play a role in regulating gut microbial diversity. Current research status indicates that the relationship between depression and gut microbiota has received extensive attention, but the causal relationship remains to be further explored. Future studies require more longitudinal data and multi-omics approaches to clarify the underlying mechanisms and provide new directions for therapeutic interventions.

3. Mechanisms of depression regulation based on the microbiota-gut-brain axis

The MGBA constitutes a bidirectional communication network linking the gut and the brain, primarily through multiple pathways including the vagus nerve, neuroendocrine, and immune systems (Bhatt et al., 2023). These pathways collectively maintain the balance of the central nervous system (CNS), gastrointestinal system, and gut microbiota (Alli et al., 2022). Meanwhile, the brain can also influence gut microbiota by altering gastrointestinal motility, intestinal barrier permeability, and the release of bioactive substances. A schematic diagram of this mechanism is illustrated in Fig. 3, and this dynamic interaction plays a crucial role in the pathogenesis of depression (Liu et al., 2024). As depicted in Fig. 3, this schematic elucidates the core mechanisms of MGBA in depression regulation by comparing normal and dysbiotic gut states. It particularly highlights the intricate bidirectional interactions among the hypothalamic-pituitary-adrenal axis, gut barrier and immune homeostasis, and neurotransmitter metabolic pathways. For instance, low-grade chronic neuroinflammation forms the basis of depression, which is manifested through the interaction between psychological stress, gut microbiota dysbiosis, and depression (Evrensel et al., 2020).

Fig. 3.

Schematic Diagram of the Gut-Brain Axis-Mediated Regulatory Mechanisms in Depression. (Corticotropin-releasing hormone, CRH; Adrenocor ticotropi hormore, ACTH; Glucocorticoid receptor, GR; Short-chain fatty acids, SCFA; Dopamine, DA; γ-aminobutyric acid, GABA; 5-hydroxytryptamine, 5-HT; 3-Hydroxykynurenine, 3-HK; Indoleamine-2,3-dioxygenase, IDO; Zona Occludens 1, ZO-1; Interleukin-6, IL-6; Tumor necrosis factor-α, TNF-α; Interferon-gamma, IFN-γ; Toll-like receptor 4, TLR4; Nuclear factor kappa B, NF-κB; Purinergic receptor P2X, P2X7R; NOD-like receptor family pyrin domain containing 3, NLRP3; C-reactive protein; CRP; Interleukin-4, IL-4; Interleukin-10, IL-10.) Data sources: HPA axis (Wang and Wang, 2025); Neurotransmitter (Xu, 2021; Chen, 2024) ; Barrier - Immunity (Li et al., 2025; Zhang et al., 2023).

Short-chain fatty acids (SCFAs), end products of gut microbiota metabolism, serve as important mediators the MGBA (Cryan et al., 2019). They can influence nervous system function and modulate neurotransmitters including 5-HT, thereby affecting the host's physiological and psychological states (Bhattarai et al., 2017). Research has confirmed that gut microbiota dysbiosis is often observed in depressed patients, and this change leads to a reduction in SCFAs production (Chang et al., 2025). For example, butyrate levels show potential as a biomarker to distinguish depressed patients from healthy controls (Henning et al., 2023), and in patients with inflammatory bowel disease (IBD), the abundance of SCFA-producing bacteria (such as Odoribacter, Anaerotruncus, Alistipes, Intestinimonas, Eubacterium, and Clostridium) is negatively correlated with depressive symptoms (Thomann et al., 2022). Animal studies further elucidate the potential mechanisms of SCFAs: in a chronic unpredictable mild stress (CUMS) rat model, supplementation with different SCFAs, particularly sodium butyrate, improved gut microbiota structure and alleviated depression-like behaviors (Chen et al., 2024). However, the actions of SCFAs are not linear or universally applicable; host genetics, baseline dietary patterns, and depression subtypes may substantially influence their metabolic levels and final effects.

A decrease in SCFAs levels impairs the integrity of the intestinal immune barrier (Liu et al., 2024). Specifically, gut dysbiosis can induces microleakage of intestinal epithelial, lowialng endotoxin translocation into the bloodstream and subsequent immune system activation. Furthermore, it can activate microglia via signaling pathways such as P2X7R/NLRP3, leading to neuroinflammation and neural damage (Wang and Zeng, 2021; Li et al., 2025). For instance, through analysis of 5166 depressed patients and 5083 controls, Osimo et al. (2020) found that significantly elevated serum levels of various pro-inflammatory factors, including CRP, IL-6, IL-12, IL-18, sIL-2R, and TNF-α, while the level of IL-4 is significantly reduced in depressed patients. Similar changes in the inflammatory factor profile were also observed in the first-episode depressed patients (Zhang et al., 2023). The serum level of IFN-γ significantly increased, while the level of IL-4 significantly decreased; and these changes occurred as the disease progressed (Zhang et al., 2023). It should be noted that the magnitude of neuroinflammatory responses and the specific cytokine profiles involved exhibit significant inter-individual variability, potentially linked to genetic predisposition, comorbidities (e.g., metabolic syndrome), and different depressive endophenotypes.

The gut microbiota also directly influences the central nervous system (CNS) by synthesizing and metabolizing neurotransmitters, including 5-HT, brain-derived neurotrophic factor (BDNF), dopamine (DA), γ-aminobutyric acid (GABA), acetylcholine, and glutamate (Evrensel and Ceylan, 2015). Studies have shown that gut microbiota dysbiosis significantly affects host tryptophan metabolism, towards the kynurenine pathway at the expense of 5-HT synthesis, leading to 5-HT depletion (Roth et al., 2021). Furthermore, kynurenine induces the production of neurotoxic metabolites such as quinolinic acid and 3-hydroxykynurenine, which further damage neurons (Xu, 2021). Sulforaphane (SFN) and its derivatives may alleviate neuroinflammation by modulating the microbiota, inhibiting the NF-κB/NLRP3 pathway, thereby enhancing gut barrier function, reducing inflammatory factors, and increasing levels of IL-10, DA, 5-HT, and BDNF (Chen et al., 2024). The modulation of neurotransmitter metabolism by the gut microbiota is complex and influenced by the interplay of specific bacterial strains, host diet (e.g., tryptophan precursor intake), and individual genetic differences in metabolic enzymes, contributing to variability in therapeutic response.

The hypothalamic-pituitary-adrenal (HPA) axis represents another core component of the MGBA, engaged in bidirectional communication with the gut microbiota (Wang et al., 2022). Alterations in the microbiota can activate the HPA axis, promoting the release of cortisol (CORT) and adrenocorticotropic hormone (ACTH), which in turn affects neuroimmune responses and intestinal barrier integrity (Wang and Wang, 2025). Tian et al. (2024) discovered that Zhizi Chi Decoction can exert pleiotropic antidepressant effects by regulating the microbiota and HPA axis in mice, influencing neuroactive ligand-receptor interactions, and interfering with inflammatory pathways such as MAPK and TNF. The sensitivity of the HPA axis to gut signals and stress response patterns vary greatly among individuals and can be modified by early-life stress, epigenetic modifications, and current psychosocial context.

Notably, appetite alteration—a cardinal symptom of depression—mediates the bidirectional interactions within the MGBA. Dietary changes resulting from anorexia or emotional eating directly modify the substrate availability for gut microbiota, while microbiota-derived signals (e.g., SCFAs, gut peptides) reciprocally regulate hypothalamic appetite circuits via vagal and humoral pathways. This bidirectional crosstalk between appetite dysregulation and gut microbial perturbation forms a self-reinforcing loop in depressive states. Anorexic behavior associated with depression leads to reduced intake of dietary fiber and nutrients, which directly depletes the carbon and nitrogen sources essential for the growth of SCFA-producing beneficial bacteria, thereby exacerbating gut dysbiosis and reducing microbial diversity (Mukhopadhya and Louis, 2025). In contrast, emotional overeating, often characterized by high consumption of processed foods and refined sugars, promotes the proliferation of pro-inflammatory taxa such as Proteobacteria (Hills et al., 2019), which in turn impairs intestinal barrier function and triggers a state of low-grade inflammation. This inflammatory milieu not only amplifies depressive symptoms but also disrupts the secretion of gut-brain peptides that regulate satiety and hunger. Consequently, persistent appetite dysregulation ensues, perpetuating the dysfunction of the MGBA in depression.

In summary, the MGBA plays a crucial role in the pathogenesis of depression through neuroinflammation, neurotransmitter metabolism, and HPA axis regulation. Based on these mechanisms, regulating gut microbiota via probiotics, nutritional interventions, or physical exercise may provide novel strategies for the treatment of depression., but future research needs to incorporate perspectives from precision nutrition and precision psychiatry, fully considering host genetics, microbiome baseline, dietary context, and clinical heterogeneity to optimize personalized interventions.

4. Instruments for depression assessment

In the clinical assessment and drug research of depression, it is of vital importance to select appropriate, standardized and highly sensitive assessment tools, as this directly affects the reliability and comparability of the research conclusions. Assessment tools are primarily categorized into clinician-rated and self-reported measures, often used in combination to provide multi-dimensional evidence of efficacy (Fried, 2017).

The clinician-rated tools are typically evaluated by trained professionals through structured interviews, including the Hamilton Depression Rating Scale (HDRS/HAMD) and the Montgomery-Åsberg Depression Rating Scale (MADRS) (HAMILTON, 1960; Montgomery and Asberg, 1979).They provide a more objective and comprehensive assessment of core depressive symptoms (e.g., mood, retardation, somatic anxiety) and are sensitive to change, frequently serving as primary endpoints in registered clinical trials. A significant reduction in HAMD scores has been consistently used as a key efficacy measure in randomized controlled trials (RCTs) validating the antidepressant effects of specific probiotics (Wallace and Milev, 2017).

The Self-reported tool can be filled out by the subjects based on their own feelings, including the BDI, the Patient Health Questionnaire-9 (PHQ-9), and the Depression Anxiety Stress Scale-21 (DASS-21) (Kroenke et al., 2001).They are easy to administer, cost-effective, and effectively capture the patient's subjective experience, making them widely used in community-based studies and initial screening.

In future clinical studies, it is necessary to clearly report the version selected, its cultural adaptability, and the inter-rater reliability. Furthermore, a multimodal assessment approach that integrates biomarkers (e.g., BDNF, inflammatory cytokines, fecal microbiota composition) with psychological scales will be crucial for elucidating the mechanisms of the MGBA and establishing personalized response prediction models (Cryan et al., 2019).

5. Gut-based interventions for improving depression

Currently, depression is mainly treated with tricyclic and tetracyclic antidepressants, but these treatments are associated with limitations such as slow onset of action, long treatment courses, drug resistance, and numerous adverse reactions (Masand, 2003). Therefore, there is an urgent need to explore more effective and safe novel approaches for treating depression (Hu et al., 2025). Based on the MGBA theory, the gut microbiota modulates central nervous system function via neural, immune, and metabolic pathways, opening up a novel direction for depression intervention. As illustrated in Fig. 4, the primary gut microbiota-targeted antidepressant strategies include probiotics, prebiotics, FMT, and dietary interventions; this figure further delineates the core pathways underlying their antidepressant effects, which center on modulating the gut microbiota, enhancing intestinal barrier function, alleviating neuroinflammation, and regulating neurotransmitter systems.

Fig. 4.

Schematic Diagram of Gut Microbiota-Targeted Antidepressant Interventions. (Short-chain fatty acids, SCFAs; 5-hydroxytryptamine, 5-HT; Brain-derived neurotrophic factor, BDNF; Nuclear factor kappa B, NF-κB; Acyl-CoA synthetase short-chain family member 2, ACSS2; Peroxisome proliferator-activated receptor γ, PPARγ; Tryptophan hydroxylase 2, TPH2; NOD-like receptor family pyrin domain containing 3, NLRP3; Lipopolysaccharide, LPS; hypothalamic-pituitary-adrenal, HPA.) Data sources: Probiotics (Kim et al., 2021; Chen, 2024; Osimo et al., 2020); Prebiotics (Chen, 2024; Burokas et al., 2017); Fecal Microbiota Transplantation (Green et al., 2023; Doll et al., 2022); Dietary Interventions (Bayes et al., 2022; Sánchez-Villegas et al., 2006).

5.1. Probiotics

Probiotics are authoritatively defined by the International Scientific Association for Probiotics and Prebiotics (ISAPP) as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”. This definition underscores the importance of strain specificity, adequate dosage, and clinically substantiated benefits. Notably, psychobiotics represent a subcategory of probiotics specifically targeting mental health, but all probiotics must meet the fundamental ISAPP definition requirements.Currently reported psychobiotics—probiotics with potential antidepressant effects mainly include Lactobacillus plantarum, Lactobacillus casei, Lactobacillus helveticus, and Bifidobacterium species (Ma et al., 2024).

A large number of preclinical and clinical studies have supported the antidepressant effects of probiotics (Kim et al., 2021; Alli et al., 2022). At the clinical level, RCTs provide more direct evidence. For instance, a 12-week RCT conducted by Kim et al. (2021) showed that supplementation with a probiotic combination containing Bifidobacterium BGN4 and Bifidobacterium longum BORI significantly reduced the relative abundance of pro-inflammatory bacteria in the gut and significantly increased serum brain-derived neurotrophic factor (BDNF) levels in elderly participants. In addition, a systematic review of 24 observational studies and 19 intervention trials by Alli et al. (2022) revealed that probiotics and synbiotics could moderately improve depressive symptoms within 4–9 weeks. These clinical studies highlight the importance of intervention duration and sample size in demonstrating translatable benefits.

In terms of mechanistic exploration, preclinical studies provide crucial insights into the pathways of probiotic action. Yao et al. (2024) investigated the antidepressant potential of GABA-high-yielding Lactobacillus brevis YSJ2 in CUMS model mice. They found that this strain upregulated the expression of the glucocorticoid receptor (GR) gene in the hippocampus, regulated the levels of HPA axis stress hormones (ACTH and CORT), and alleviated depression-like and anxiety-like behaviors in CUMS mice. Additionally, research by Luo et al. (2014) indicated that probiotics could improve depressive and anxiety-like symptoms in rodents by acting on depression-related neurons. These animal studies elucidate mechanisms through which probiotics may exert effects, such as modulating the MGBA, inhibiting inflammation, and regulating neuroendocrine function. However, these findings are primarily derived from small-scale preclinical studies and require further validation in human trials.

The growing scientific interest is mirrored by a robust and expanding global market. The global probiotics market size was valued at approximately USD 70.52 billion in 2023 and is projected to grow, reflecting increasing consumer awareness and application of probiotics for health and well-being (Grand View Research, 2023).

In summary, probiotics, especially Lactobacillus and Bifidobacterium species, have shown potential therapeutic effects on depressive and anxiety symptoms through multiple mechanisms.The current evidence base encompasses both clinical studies offering direct efficacy evidence and preclinical studies clarifying biological mechanisms. Future research should focus on conducting larger-scale, longer-duration randomized controlled trials to clearly establish the clinical robustness of specific psychobiotic interventions.

5.2. Prebiotics

Prebiotics are defined as dietary supplements that can be fermented by gut microbiota, selectively stimulate the growth and activity of one or more beneficial bacterial species in the intestine, and thereby exert beneficial effects on host health. Common prebiotics include fructans (e.g., inulin, fructooligosaccharides), galactooligosaccharides (GOS), xylooligosaccharides, chitooligosaccharides, lactulose, resistant starch, and polyphenols (Alli et al., 2022). They can influence the MGBA by regulating neurotransmitters and proteins that are crucial for the balance of neural excitation and inhibition, mood, cognitive function, and memory processes (Cheng et al., 2019).

In recent years, studies have emphasized the importance of the gut microbiota in the development and maintenance of brain function. As an intervenable regulatory tool, prebiotics have shown potential in the prevention and treatment of brain-related diseases. In human clinical trials, randomized controlled trials provide relatively robust evidence (Cheng et al., 2020; Johnstone et al., 2021). A study in individuals simulating shift work showed that supplementation with a prebiotic mixture containing β-glucan and inulin significantly improved emotional state, including reduced depression and anxiety scores, and modulated the gut microbiota (Cheng et al., 2020). Another double-blind, placebo-controlled trial by Johnstone et al. (2021) found that GOS prebiotic intervention exert positive effects on emotional state and attentional processing in healthy women with high trait anxiety by regulating the gut microbiota (e.g., increasing Bifidobacterium). These clinical studies, typically lasting several weeks, offer direct insights into the applicability of prebiotics in human populations.

For mechanistic insights, preclinical animal studies provide in-depth biological understanding. Burokas et al. (2017) administered chronic prebiotic treatment to male C57BL/6J mice for 3 weeks, demonstrating that supplementation with prebiotics such as GOS and fructooligosaccharides (FOS) reduced anxiety and depression-like behaviors, regulated stress-related CORT levels, and reversed the negative effects of chronic stress on the gut microbiota and neuroinflammation. Research by Chen (2024) found that long-term administration or a single gavage dose of 20% D-mannose to chronically stressed depressed mice reversed gut microbiota dysbiosis, increased hippocampal short-chain fatty acids, and promoted 5-hydroxytryptamine synthesis by activating the ACSS2-PPARγ-TPH2 axis, thereby significantly improving depression-like behaviors in mice. These studies illuminate mechanisms through which prebiotics may exert effects by modulating microbiota composition, short-chain fatty acids, and neurotransmitter synthesis to influence hippocampal neurogenesis and neural plasticity, although these conclusions are derived from animal models and require further validation in humans.

In summary, prebiotics provide a novel non-invasive strategy for the treatment of neuropsychiatric and neurodegenerative diseases through the MGBA. The existing evidence encompasses both human clinical trials demonstrating their mood-modulating potential and animal studies clarifying underlying mechanisms. Future studies should focus on optimizing prebiotic intervention regimens, including combinations with probiotics, dietary adjustments, and fecal microbiota transplantation, to achieve personalized treatment.

5.3. Fecal microbiota transplantation (FMT)

FMT is a therapeutic approach in which the fecal microbiota from healthy individuals is transplanted into patients with certain diseases to achieve therapeutic effects by replacing or correcting the pathology-associated microbiota (Liu et al., 2020). Initially, FMT was mainly used for the treatment of recurrent Clostridium difficile infection (CDI), but recent studies have explored its application in other diseases, including psychiatric disorders such as MDD (Browne and Kelly, 2017). The gut microbiota is closely linked to depressive symptoms via the MGBA, with bidirectional communication influencing the host's metabolic, immune, endocrine, and nervous systems (Lin et al., 2024).

In clinical research directly targeting depressed patients, randomized controlled trials provide the most robust evidence available (Green et al., 2023; Doll et al., 2022). Green et al. (2023) conducted an 8-week triple-blind RCT comparing FMT with placebo in patients with moderate-to-severe MDD, which demonstrated that FMT is safe and feasible and may improve gut microbiota composition. In contrast, case reports or very small-scale studies offer preliminary exploratory findings. Doll et al. (2022) administered oral frozen FMT capsules administered to two patients reported significant improvements in depressive symptoms within 4 weeks, with the effect sustained for 8 weeks in one participant; however, this study was limited by its minimal sample size and the inability to exclude confounding effects from treatment as usual. Supportive data also come from studies on comorbid populations (Huang et al., 2019). A 6-month follow-up study evaluating FMT in patients with refractory irritable bowel syndrome (IBS) found that it improved gastrointestinal symptoms as well as depressive and anxiety (Huang et al., 2019).

For mechanistic insights, preclinical animal studies provide a fundamental understanding. In a postpartum depression model, FMT from healthy donors reversed depression-like behaviors and regulated the NLRP3-mediated neuroinflammatory pathway (Xu et al., 2024). These investigations reveal the biological mechanisms through which FMT may alleviate depression by altering microbial composition to influence neurotransmitters and inflammatory responses, although these conclusions are derived from animal models.

In summary, although clinical trials directly targeting FMT in depression are limited, based on the overall evidence of gut microbiota regulation, FMT may alleviate depression by altering microbial composition to influence neurotransmitters and inflammatory responses (Lin et al., 2024). However, current research mainly focuses on basic mechanisms and case reports, and large-scale randomized controlled trials are still lacking. Therefore, the application of FMT in depression treatment remains in the exploratory stage, and more high-quality studies are needed to verify its safety and efficacy.

5.4. Dietary interventions

Diet serves as a key regulator of intestinal microecology, and rational dietary interventions hold promise for alleviating depressive symptoms. The Mediterranean diet—a holistic dietary pattern centered on unprocessed plant-based foods—has emerged as a promising intervention for depression due to its richness in various components potentially beneficial for gut microecology and brain health (such as B vitamins, omega-3 fatty acids, and polyphenols) that can improve intestinal microecological imbalance through different mechanisms, thereby exerting positive effects (Gui et al., 2025).

The Mediterranean diet exerts antidepressant effects partly through direct modulation of gut microbiota composition and function. This dietary pattern is rich in polyphenols, dietary fiber, and omega-3 fatty acids, which serve as substrates for beneficial bacteria and promote the growth of SCFA-producing taxa (Ghosh et al., 2020). Additionally, the high intake of fermented foods and complex carbohydrates enhances microbial diversity and reduces the Firmicutes/Bacteroidetes ratio, a marker frequently associated with depression (Bayes et al., 2022). These microbiota-mediated pathways operate synergistically with the diet's anti-inflammatory and neuroprotective properties.

Observational studies and preclinical experiments provide important foundational evidence and preliminary leads for intervention. A workplace-based nutritional intervention study showed that implementing a plant-based dietary pattern emphasizing the intake of vegetables, legumes, fruits, nuts, and whole grains for 6 weeks led to significant improvement in participants' depressive symptoms (Sutliffe et al., 2018). In earlier study analyzed the association between the Mediterranean diet pattern and depression, suggesting that adequate intake of B vitamins and ω-3 fatty acids might contribute to depression prevention (Sánchez-Villegas et al., 2006). Furthermore, Gould et al. (2017) focused on perinatal period has explored the role of specific nutrients, indicating that supplementation of omega-3 polyunsaturated fatty acids during pregnancy may have a positive effect on reducing the risk of postpartum depression, although the role of vitamin D remains unclear.

In confirmatory clinical research, the results of RCTs are particularly important. Cabrera-Suárez et al. (2024) conducted a 2-year randomized PREDIDEP trial and found that Mediterranean diet intervention rich in extra virgin olive oil significantly improved subsyndromic depressive symptoms in patients recovering from depression, with effects observed at follow-ups of 4, 8, and 20 months. Similarly, Bayes et al. (2022) conducted the AMMEND RCT targeting young male patients with (aged 18–25) with depression confirmed that adhering to a Mediterranean diet for 12 weeks significantly reduced Beck Depression Inventory scores and improved quality of life. These RCTs, lasting from several months to years, provide relatively robust support for the clinical efficacy of the Mediterranean diet due to their controlled design and defined intervention protocols.

In summary, the Mediterranean diet, as a holistic and feasible dietary intervention strategy, may alleviate depression through anti-inflammatory effects, modulation of the microbiota, and improvement of nutritional status, thereby ameliorating depressive symptoms from multiple dimensions. As a feasible dietary intervention, it provides new ideas and methods for the prevention and treatment of depression.

6. Conclusion and outlook

In summary, the MGBA provides a crucial framework for understanding the complex pathophysiology of depression. Gut microbiota dysbiosis contributes to depressive symptoms via interconnected mechanisms, including neuroinflammation, neurotransmitter metabolism, and HPA axis dysregulation. Interventions targeting the gut microbiome, including psychobiotics, prebiotics, FMT, and dietary interventions have shown promising mood-improving and anti-inflammatory potential in preclinical and early clinical research.

Looking ahead, the translation of these findings into robust clinical applications requires a concerted effort to bridge significant evidence gaps. Future research must prioritize large-scale, long-term randomized controlled trials to substantiate efficacy and safety in diverse patient populations. Concurrently, a deeper mechanistic understanding is needed to elucidate how specific microbial changes translate into psychiatric benefits. Ultimately, the goal is to move beyond one-size-fits-all approaches towards personalized microbiome-based strategies, integrating multi-omics data to predict individual treatment responses. This review underscores the transformative potential of the MGBA in psychiatry while highlighting the rigorous scientific pathway necessary to realize its promise for patients with depression.

CRediT authorship contribution statement

Yufan Su: Conceptualization, Methodology, Software, Data curation, Investigation, Funding acquisition, Writing-original draft, Preparation, Editing. Yanan Xia: Project administration, Validation, Supervision, writing-review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Handling Editor: Dr. Yeonhwa Park