Major depressive disorder (MDD) is a prevalent and disabling mental health condition, characterized by persistent low mood, anhedonia, cognitive impairments, and disruptions in sleep, appetite, and energy regulation lasting for a minimum of 2 weeks (Otte et al., 2016). With an estimated global prevalence affecting over 320 million individuals, MDD represents a leading cause of disability worldwide. The World Health Organization (WHO) anticipates it will become the foremost contributor to the global burden of disease in the near future (Nik Ramli et al., 2024; Zainal Abidin et al., 2023). Unlike transient experiences of sadness or grief, depression is marked by chronicity and functional impairment, often persisting long after triggering events have passed and significantly affecting quality of life and social participation (Belmaker and Agam, 2008).

The pathogenesis of depression is multifactorial, resulting from the intricate interaction of biological, psychological, and environmental influences. Neurobiological research has highlighted structural and functional changes in brain regions involved in emotion and cognition, particularly the prefrontal cortex (PFC), hippocampus, and amygdala (Sun et al., 2023). Neuroimaging consistently reveals reduced volume and hypoactivity in these areas among individuals with depression, impairing executive functioning and memory (Zhang et al., 2018). Concurrently, hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis and elevated cortisol levels contribute to neuronal atrophy and symptom exacerbation (Jesulola et al., 2018; Rafiee Sardooi et al., 2020). In addition to monoaminergic deficits, newer evidence implicates dysregulation in glutamate and gamma-aminobutyric acid (GABA) pathways both vital to synaptic plasticity and emotional stability (Sarawagi et al., 2021).

Moreover, psychosocial stressors, such as trauma, chronic stress, and limited social support, further intensify vulnerability to depression, particularly among individuals with genetic predispositions. This gene-environment interaction reinforces the individualized and dynamic nature of MDD’s etiology and progression (Belmaker and Agam, 2008).

While traditional treatments target central nervous system (CNS) dysfunction using pharmacological and psychotherapeutic modalities, growing attention has turned toward peripheral contributors to mental health, most notably the gut microbiota. The gut-brain axis (GBA), a bidirectional communication system connecting the gastrointestinal tract with the CNS, has emerged as a critical regulator of mood, cognition, and behavior (Carabotti et al., 2015; Morys et al., 2024).

Emerging research suggests that gut microbiota composition shaped by diet, environment, age, sex, and genetic factors can significantly impact neurophysiological and immune pathways relevant to depression (Ullah et al., 2024). Germ-free animal models have demonstrated altered brain structure, behavior, and emotional regulation in the absence of a functional microbiome, reinforcing its developmental importance (Nakhal et al., 2024). Certain microbial species contribute directly to the synthesis of key neurotransmitters, including serotonin and GABA, while also regulating inflammation via cytokine signaling processes increasingly recognized as central to MDD pathophysiology (Foster and McVey Neufeld, 2013; Irum et al., 2023).

Crucially, the gut microbiota is more amenable to modulation than central neural pathways. Interventions such as dietary adjustments, probiotic and prebiotic supplementation, and fecal microbiota transplantation (FMT) represent accessible, non-invasive strategies for restoring microbial balance and potentially mitigating depressive symptoms (Zhang et al., 2025). These emerging approaches offer promising adjuncts or alternatives to conventional antidepressant therapy and underscore the need for more integrative mental healthcare frameworks.

Thus, in this review, we examine the mechanisms linking gut microbiota dysbiosis to MDD and evaluate the therapeutic potential of microbiota-targeted strategies including probiotics, prebiotics, synbiotics, dietary interventions, FMT, and gut-focused pharmacological agents. We also discuss the translational potential of these findings for health promotion and behavioral health interventions, particularly in the context of education, prevention, and community-level mental health strategies.

The gut microbiota plays a fundamental role in maintaining human health, influencing a wide range of physiological processes including hormone production, immune regulation, metabolism, and communication between the gut and the brain. Central to this dynamic interaction is the GBA, a complex bidirectional communication network that links the gastrointestinal tract and the CNS via neural, endocrine, immune, and metabolic pathways (Ullah et al., 2024).

This sophisticated system facilitates constant crosstalk between the gut microbiota and the brain, allowing microbial signals to influence cognition, emotion, and behavior. Conversely, psychological stress and neural activity can impact gut function and microbiota composition, illustrating the deeply interconnected nature of this axis. Dysbiosis (e.g., reduced Faecalibacterium, increased Eggerthella) has been linked to systemic inflammation, immune dysregulation, and neuropsychiatric conditions, including MDD, with implications for drug metabolism and treatment response (Foster and McVey Neufeld, 2013; Cheng et al., 2024).

The gut microbiome is a diverse ecosystem composed of bacteria, viruses, archaea, and eukaryotic microorganisms, with a collective gene pool that vastly exceeds that of the human host. It harbors approximately 1,000 bacterial species and 7,000 strains. Among the dominant phyla are Firmicutes (e.g., Lactobacillus, Eubacterium, Clostridium), Bacteroidetes (e.g., Bacteroides, Prevotella), Actinobacteria, Proteobacteria, and Verrucomicrobia, all of which play essential roles in metabolic and neuroimmune homeostasis (Ullah et al., 2024).

The gut microbiota communicates with the enteric nervous system (ENS) often referred to as the “second brain” and the CNS by producing key signaling molecules such as cytokines, SCFAs, and neurotransmitter precursors. These biochemical messengers can influence blood-brain barrier (BBB) integrity, modulate inflammatory pathways, and alter the synthesis of mood-related neurotransmitters such as serotonin and GABA (Ullah et al., 2024).

Disruptions in the GBA due to gut dysbiosis can impair these communication mechanisms, leading to increased systemic inflammation and altered neurotransmitter production, which have been implicated in the onset and severity of depressive symptoms (Foster et al., 2021). A growing body of research, including findings by Kumar et al. (2023) has identified specific alterations in microbial genera associated with depression. Consistent reductions have been observed in beneficial taxa such as Clostridia, Bacteroides, Alistipes, Roseburia, Coprococcus, Dialister, Faecalibacterium, and Butyricicoccus. These bacteria are often involved in the production of anti-inflammatory SCFAs and the regulation of neurotransmitter pathways. Conversely, increased levels of potentially pathogenic or pro-inflammatory genera such as Proteobacteria, Actinobacteria, Clostridium, Streptococcus, and Oscillibacter have been noted in individuals with depression. Among these findings, Firmicutes and Actinobacteria appear to exhibit consistent patterns, with a notable decline in Firmicutes (particularly SCFA-producing species like Faecalibacterium) and a proliferation of certain Actinobacteria (e.g., Eggerthella) in depressed populations. Interestingly, some genera like Bacteroides and Clostridium show variability, with their abundance fluctuating based on factors such as individual genetics, diet, and environmental exposures, as well as study design and population demographics. Table 1 summarized the classification of the bacteria genera towards human and animal studies.

Collectively, these data suggest that microbial signatures associated with MDD are not only diverse but also context-dependent, highlighting the importance of personalized approaches when examining microbiota-based interventions for mental health. Additionally, research has shown that exposure to specific microbial strains can protect against stress-induced behavioral changes and systemic immune alterations, offering compelling evidence for the potential of microbe-based therapies in treating stress-related disorders (Nakhal et al., 2024).

SCFAs, including acetate, propionate, and butyrate, are metabolites produced by a healthy gut microbiota during the fermentation of dietary fibers and resistant starch (Silva et al., 2020). These SCFAs play a crucial role in immune modulation (Cheng et al., 2024). Butyrate, in particular, is thought to influence the gut-brain axis, potentially by enhancing colonic serotonin production, a key neurotransmitter involved in mood and behavior regulation. Additionally, animal studies suggest that butyrate may exert antidepressant-like effects by stimulating the production of brain-derived neurotrophic factor (BDNF), a protein essential for neuronal development and survival (Mansuy-Aubert and Ravussin, 2023).

Moreover, SCFAs are vital for reducing inflammation, maintaining intestinal barrier integrity, and regulating central nervous system function. However, microbial imbalance, or dysbiosis, can reduce SCFA production, diminishing their anti-inflammatory effects and promoting inflammation. Research indicates that restoring SCFA levels through dietary interventions or probiotic supplementation can enhance immune function and alleviate depressive symptoms. These findings highlight the therapeutic potential of modulating gut microbiota for treating depression (Mansuy-Aubert and Ravussin, 2023).

Given the urgent need for novel treatments and preventative strategies for mental health (Viana, 2024). Understanding the influence of the gut microbiota on emotional and cognitive functions, neurotransmitter synthesis, neuroinflammation, and gut barrier integrity is critical (Singh et al., 2024). This complex relationship involves bidirectional communication between the gut and the brain, with brain regions such as the insula and anterior cingulate cortex playing key roles in regulating both gut function and psychological responses (Kano and Fukudo, 2025). Despite variations in gut microbiota composition across studies, all evidence consistently demonstrates significant alterations in the gut microbiota of individuals with depression, suggesting that the gut microbiota may be a promising target for both the prevention and treatment of this disorder (Xiong et al., 2023). A comprehensive understanding of the gut microbiota’s influence on psychiatric conditions is vital for developing innovative and effective therapeutic strategies, emphasizing the need for an integrated approach to mental healthcare (Singh et al., 2024).

The gut microbiota is integral to the synthesis and regulation of neurotransmitters such as serotonin, dopamine, and glutamate, which are critical for neurological and immunological functions in the brain. This complex microbial community is diverse, with certain species potentially promoting mental wellbeing, while others may contribute to the development and progression of mental disorders (Xiong et al., 2023). Studies have revealed significant alterations in the gut microbiota composition of individuals with depression compared to healthy controls. Depressed patients showed reduced levels of Dialister and Coprococcus species, alongside elevated levels of Prevotella, Klebsiella, Streptococcus, and Clostridium XI, as well as decreased levels of Bacteroidetes. Animal studies supported these findings, showing that fecal microbiota transplants from depressed individuals induced depression-like behaviors in mice, while transplants from healthy rats prevented depression in susceptible rats. These results suggest that gut microbiota dysbiosis plays a significant role in depression by influencing protein expression along the gut–brain axis. While microbial composition varies across studies, certain families (e.g., Paraprevotella-positive and Streptococcaceae and Gemella-negative) and genera (e.g., Prevotella, Klebsiella, and Clostridium) have been consistently associated with depression (Xiong et al., 2023). Emerging evidence suggests that gut microbiome dysbiosis plays a crucial role in the neurovascular pathophysiology of glymphatic system dysfunction and cerebral small vessel disease, which may exacerbate neuroinflammation and impair the BBB function, both of which are critical processes in the development and progression of depression (Che Mohd Nassir et al., 2024).

Depression alters the composition and activity of the gut microbiota through several interconnected pathways, particularly inflammation, neurotransmitter modulation, and stress responses. Depressive states promote pro-inflammatory conditions that favour gut microorganisms associated with inflammation while inhibiting species that exert anti-inflammatory effects (Liu et al., 2024). Research on human depression has shown that depressive moods are linked to an increase in Bacteroides (pro-inflammatory) and a decrease in Clostridium species (SCFA producers), which affects butyrate metabolism (Liu et al., 2023). A lack of butyrate contributes to intestinal barrier dysfunction, leading to endotoxemia and systemic inflammation, which are further exacerbated by the depressive state (Liu et al., 2024). Additionally, there is an increase in Eggerthella and Ruminococcaceae species, which are associated with impaired glutamate metabolism, and a decrease in Coprococcus and Dialister species, which are involved in dopamine production (Radjabzadeh et al., 2022).

Furthermore, stress hormone signalling plays a crucial role in gut microbiota alterations. Microbial changes may occur early in MDD and could be part of its onset. Over time, pathogenic shifts in the gut microbiota contribute to dysbiosis by altering the gut environment (Liu et al., 2023). The activation of the HPA axis in depression increases cortisol production, which in turn affects gastrointestinal motility and secretion (Averina et al., 2024). These stress hormones also alter the gut environment, favouring certain pathogenic bacteria while disrupting beneficial SCFA-producing species (Bevilacqua et al., 2024; Madison and Kiecolt-Glaser, 2019). As a result, intestinal permeability (also known as “leaky gut”) increases, facilitating bacterial translocation (Kumar et al., 2023; Madison and Kiecolt-Glaser, 2019).

Dysbiosis in depression is also linked to neurotransmitter disturbances. Specific microbiota associated with depression shows reductions in neurotransmitter synthesis. For example, the depletion of Coprococcus results in a diminished supply of dopamine precursors, and strains like Coprococcus comes and Coprococcus catus are involved in the synthesis of DOPAC, a dopamine metabolite (Hamamah et al., 2022). Additionally, reductions in Subdoligranulum have been correlated with disruptions in GABA production (Radjabzadeh et al., 2022). Likewise, Bellach et al. (2024) noted that depletion of Subdoligranulum and other genera, such as Coprococcus and Faecalibacterium, may potentially serve as transdiagnostic markers of psychopathologies (Bellach et al., 2024). Also, Park et al. (2023) found that dysbiosis with Subdoligranulum associated with depressive symptoms, providing further support for these findings. They suggested that certain bacterial taxa, including Subdoligranulum, participate in neurotransmitter biosynthesis including GABA synthesis (Park et al., 2023). This implies that the presence of these gut microbes is significant for emotional regulation. Inhibited tryptophan metabolism also negatively affects serotonin production. Serotonin (5-HT) has been implicated in the development and treatment of depression, and its levels are regulated by the gut microbiota (Irum et al., 2023).

Alterations in microbial metabolites further contribute to depression-related changes in the gut. Depression has been shown to alter the gut metabolome by reducing SCFA synthesis, with 40%–60% less butyrate present in MDD patients (Liu et al., 2023; Liu et al., 2024). Additionally, the accumulation of neurotoxic metabolites such as p-cresol sulphate contributes to gut microbiota alterations in depression. p-Cresol has been shown to inactivate dopamine beta-hydroxylase, an enzyme necessary for converting dopamine into norepinephrine. This disruption can lead to neurotransmitter imbalances, which affect mood regulation and cognitive functions (Flynn et al., 2025).

Further research indicates that depressed individuals often exhibit an overabundance of bacteria responsible for producing phosphatidylcholines, contributing to gut dysbiosis and systemic toxicity that impair normal brain functioning (Xie et al., 2024). Disrupted bile acid metabolism has also been associated with depression. Secondary bile acids, modulated by the gut microbiota, are negatively correlated with the severity of depressive symptoms, suggesting that higher levels of bile acids may have a protective effect against depression (Liu et al., 2023).

Studies on depression treatments also demonstrate the influence of gut microbiota. For example, FMT from depressed individuals to germ-free rats successfully transmits depression traits, providing evidence for a causal relationship between the gut microbiota and depression (Irum et al., 2023). Conversely, supplementation with Clostridium butyricum, a butyrate-producing bacterium, has shown antidepressant properties by restoring gut microbial balance and reducing inflammation (Liu et al., 2024). These alterations in the gut microbiota create a self-perpetuating cycle, in which the conditions of depression worsen gut dysbiosis, neuroinflammation, and neurotransmitter imbalances. Figure 2 illustrates the difference between a healthy brain and a depressed brain and emphasizes the role of the GBA.

Mounting evidence has highlighted gut microbiota’s role in influencing neurochemical pathways involved in depression specifically through the modulation of neurotransmitters such as butyrate, GABA, glutamate, and serotonin (Radjabzadeh et al., 2022). Preclinical and clinical studies increasingly support the idea that microbial dysbiosis may contribute to the onset and progression of depression by disrupting these pathways (Radjabzadeh et al., 2022).

Recent research has identified specific microbial taxa associated with depressive symptoms, underscoring the intricate relationship between gut microbiota and mental health. A consistent finding across studies is the reduced abundance of butyrate-producing bacteria in individuals with MDD (Radjabzadeh et al., 2022; Modesto Lowe et al., 2023; Zhu L.-B. et al., 2021). Butyrate, a SCFA, plays a key role in maintaining intestinal barrier integrity, modulating inflammation, and supporting neurogenesis. It is commonly produced by Gram-positive anaerobic bacteria in the human colon through the fermentation of dietary fibers (Louis and Flint, 2009).

Butyrate can modulate the GBA via epigenetic mechanisms, such as upregulating cholinergic neuron expression, and can influence brain function by crossing the BBB and activating the vagus nerve and hypothalamus (Radjabzadeh et al., 2022). Several bacterial genera, including Faecalibacterium, Butyricimonas, Coprococcus, and Dialister, have been identified as key butyrate producers. Their depletion has been consistently associated with depressive symptoms (Singh et al., 2024; Radjabzadeh et al., 2022; Modesto Lowe et al., 2023). In particular:

1. Eggerthella and Actinomyces are increased in depression and correlate with lower levels of butyrate-producing bacteria (Suda and Matsuda, 2022).

A large population-based study (Flemish Gut Flora Project, n = 1,054) and other investigations have shown that individuals with depression often exhibit reduced levels of Coprococcus and Dialister, alongside increased pro-inflammatory species such as Desulfovibrio (Modesto Lowe et al., 2023; Matsuzaki et al., 2024).

Multiple microbial taxa have been implicated in depression through their roles in neurotransmitter production, inflammation regulation, and GBA (Table 3). These include:

• Butyrate-producing taxa: Faecalibacterium, Butyricimonas, Coprococcus, Subdoligranulum, E. ventriosum, Ruminococcus gauvreauii group.

These associations reflect the dynamic and multifactorial nature of gut-brain interactions and suggest potential biomarkers or therapeutic targets for microbiota-based interventions in depression.

The interaction of psychotropic drugs and gut microbiota has increased attention in current research highlights, with conflicting findings between positive and negative for microbiota composition and health.

Recent research has increasingly focused on the complex interplay between gut microbiota, demographic factors (such as sex and age), and MDD. Given the well-established sex-based disparities in the prevalence and presentation of MDD, emerging evidence suggests that differences in gut microbiota composition may partly explain these disparities.

Several studies have reported significant alterations in the gut microbiota of individuals with MDD, a condition known as dysbiosis. A comprehensive scoping review identified five studies reporting significant sex-specific differences in both alpha and beta diversity of gut microbiota among MDD patients compared to healthy controls (Niemela et al., 2024). Specifically, certain bacterial taxa appear to be more prevalent in women than in men. For example, female patients with MDD show higher relative abundances of specific bacteria compared to male patients under similar conditions (Niemela et al., 2024). In particular, women tend to have elevated levels of Actinobacteria, whereas men with MDD display lower levels of Bacteroidetes (Chen et al., 2018). Moreover, the severity of depressive symptoms has been linked to unique microbial signatures in each sex, suggesting that sex-specific biological processes may mediate the gut-brain connection in mood disorders (Niemela et al., 2024; Hu et al., 2023).

These findings underscore the importance of incorporating sex-stratified analyses in both the diagnosis and treatment of MDD. Gut microbial markers may hold potential as sex-specific diagnostic tools or treatment targets, highlighting the need for personalized approaches in mental health interventions (Niemela et al., 2024). In addition to sex differences, age-related changes in gut microbiota also appear to influence MDD pathogenesis. Notably, young adults (18–29 years) with MDD exhibit lower levels of Firmicutes and higher levels of Bacteroidetes, while middle-aged adults (30–59 years) demonstrate the opposite trend (Chen et al., 2020). In a study of young adults with depression, specific taxa such as Neisseria spp. and Prevotella nigrescens were found in significantly greater abundance among depressed individuals compared to healthy controls (Wingfield et al., 2021).

Furthermore, alterations were observed in the oral microbiome, with 21 bacterial species exhibiting significant differences in abundance, suggesting a broader microbial dysregulation involving both oral and gut environments (Wingfield et al., 2021). These microbial patterns may reflect underlying inflammatory mechanisms or contribute directly to the etiology of mood disorders (Kerff et al., 2024). In older adults, particularly those experiencing late-life depression, distinct microbial signatures have also been identified. Although taxonomic changes in this population are less well-defined, certain microbial alterations have been linked to both gastrointestinal symptoms and depressive mood (Miyaho et al., 2022). A common finding among elderly individuals is a decline in beneficial bacteria, such as Lactobacillus and Bifidobacterium, which has been associated with increased vulnerability to depression (Kumar et al., 2023). These age-related shifts may be influenced by cumulative health issues, diet, medication use, and systemic inflammation, all of which can affect gut-brain axis functioning (Zhang Q. et al., 2021).

Beyond age and sex, body mass index (BMI) and lifestyle-related factors such as ethnicity and urbanization also appear to shape gut microbiota composition. Higher BMI has been associated with reduced microbial diversity, a change that may contribute to both metabolic dysfunction and altered gut-brain communication (Cryan et al., 2019). Ethnicity, which often correlates with specific dietary and cultural practices, has also been linked to distinct gut microbial profiles, reflecting differences in environmental exposures and genetic backgrounds (Ren et al., 2023). Similarly, living environment urban versus rural plays a significant role. Urbanization is associated with reduced intra-individual gut microbiota diversity and increased variability between individuals, likely due to changes in diet, stress levels, antibiotic exposure, and environmental microbiota contact (Ren et al., 2023).

Taken together, these findings illustrate the critical role of demographic factors in shaping gut microbial ecosystems and influencing the onset, severity, and manifestation of depression. Recognizing and accounting for these variables is essential in developing more targeted, personalized strategies for mental health assessment and treatment.

Lifestyle factors including high-fibre diets, fermented foods, and prebiotics can promote microbiome diversity and may complement psychobiotic treatments by supporting mood and resilience to stress (Appleton, 2018; Aziz et al., 2024; Leeuwendaal et al., 2022). While behavioural frameworks and cultural tailing such as age, gender, ethnicity, surroundings) may impact adherence, these factors are less significant than the pharmacological modulation which is the focus of this research. Broader measures, such as microbiome-informed food policy or educational campaigns, may help to increase adoption, although they are only addressed here to offer context for psychobiotic therapies.

Nonetheless, despite progress we have barriers that inhibit GBA findings integrated into clinical practice. Human based studies often utilize small number of subjects or lack demographic diversity, and microbiota and targeted therapies are variable in strain, dosing and duration. This variability limits the comparability of studies, and we lack standardisation of microbial characterisation and classification of our intervention. Most studies have identified correlation rather than causation and we have unknown confounders, for example nutrient composition, treatment or regimens, sleep and socio-economic status.

Importantly, comprehensive strain-dose-duration-specific data are inconsistently recorded and hence cannot be provided systematically in this study. This omission emphasises are critical need that future research must fill. Large, well-controlled, and demographically varied cohorts, together with standardised methods and multi-omics techniques, are required to elucidate pathways and improve clinical translation.

The next hurdle in the research of GBA is to turn foundational insights into functional therapeutics. Microbiome-based biomarkers could allow earlier identification and monitoring of potential therapies in depression, but repeatability is an issue due to changing effects of diet, medications and host physiology (Sochacka et al., 2024). Personalised microbiome-targeted therapeutics using custom probiotics, prebiotics, and synbiotics, are promising, but need to be thoroughly assessed on causative mechanisms, strain specific efficacy, and long-term safety (Ma et al., 2023). Regulatory conditions and quality assurance mechanisms are similarly even more important.

Psychobiotics with established mental health benefits are emerging as adjunct therapies to standard psychiatric treatments, but widespread application will require evidence of reliable efficacy and safety. The adoption of these ideas into clinical practice will require standardized methods of protocols, longitudinal assessments, and equitable availability.

Ultimately, improving clinical translation will require not just technical innovation but also collaborative, multidisciplinary work that links neurology with psychiatry. Gastrointestinal, dietic science and behavioural health. By bridging these disciplines, the field is ready to make advances with new, individualized solutions for depression prevention and management.

GBA represents a promising frontier in understanding and managing MDD. Emerging evidence underscores the role of gut microbiota in modulating mood through neuroimmune pathways, neurotransmitter production, and HPA axis regulation. Microbial imbalances are consistently linked to depressive symptoms, suggesting that restoring gut health may offer novel therapeutic opportunities. Microbiota-targeted strategies such as probiotics, prebiotics, and dietary interventions show potential as adjuncts to conventional treatments. However, progress is limited by small sample sizes, methodological inconsistencies, and a lack of causal evidence. Future research should focus on identifying reliable microbial biomarkers, leveraging advanced omics technologies, and developing personalized, evidence-based interventions. Integrating gut-focused approaches with existing therapies may enhance treatment outcomes, reduce resistance, and support holistic mental healthcare. Addressing regulatory, ethical, and implementation challenges will be essential to translating gut-brain research into effective, accessible clinical practice. Future research should prioritize human randomized controlled trials to validate microbial biomarkers (e.g., Coprococcus abundance) and explore pharmacomicrobiomics how gut microbes modulate drug pharmacokinetics and pharmacodynamics in depression.