The gut–brain connection: microbes’ influence on mental health and psychological disorders

The gastrointestinal tract harbors trillions of microbial cells that produce key metabolites such as SCFAs and vitamins, which contribute to digestion, immune regulation, and gut barrier integrity (Lipski, 2020; Lee et al., 2022). These microbes’ impact metabolic functions and produce essential biomolecules that include SCFAs, vitamins such as menaquinone (vitamin K2), a bacterially produced form of vitamin K2 (Ellis et al., 2021), and neurotransmitters that contribute to the maintenance of the integrity of the gut barrier. Some clinical studies have suggested that supplementation with vitamin K2 may play a role in the treatment of depression, potentially through its involvement in anti-inflammatory and neuroprotective pathways (Liu et al., 2022; Tarkesh et al., 2022; Wang S.-T. et al., 2024). Notably, certain gut microbiota species can produce vitamin K2 within the colon, suggesting that microbiome composition may indirectly influence neurological health by contributing to the local synthesis of neuroactive vitamins. Therefore, a healthy microbiome is characterized by diversity and balance, and disruptions—commonly referred to as dysbiosis—have been linked to various health conditions (Fassarella et al., 2021).

The nervous system, which is composed of central and peripheral branches, plays a central role in regulating behavior, cognition, and vital physiological processes (Sabina et al., 2024). Increasing evidence highlights a strong, bidirectional relationship between the nervous system and the gastrointestinal tract, known as the gut–brain axis (Arneth, 2018). This connection is mediated by complex signaling networks involving the vagus nerve, neurotransmitters, immune signals, and microbial metabolites produced in the gut. The enteric nervous system, often referred to as the “second brain,” operates semi independently but remains in constant communication with the brain, allowing gut microbes to influence neural processes such as mood regulation, stress response, and neurodevelopment (Garzone et al., 2025). Understanding this dynamic interaction offers critical insights into how the gut microbiota may contribute to both neurological and psychological conditions. Bidirectional communication between the gut and the brain is facilitated by signaling pathways involving electrical impulses; neuroactive compounds such as serotonin, dopamine, and gamma-aminobutyric acid (GABA); and immune modulators such as cytokines and SCFAs, which are bacterial products. Gut–brain communication occurs through multiple interconnected pathways, including the vagus nerve, the immune system, microbial metabolites such as SCFAs, and endocrine signaling. These mechanisms enable the gut microbiota to influence neural activity, mood regulation, and stress responses. Immune signaling plays a key role in this axis, as the gut microbiota regulates systemic inflammation and immune cell activity, which can in turn affect brain function. This complex neurochemical and immunological crosstalk—often referred to as the gut–brain–immune axis—is a fundamental component of host physiology, highlighting the biological relevance of microbial communication beyond the gut.

The vagus nerve, the longest cranial nerve in the body, serves as a key communication pathway between the gut and the brain (Wang Y. et al., 2024). The vagus nerve enables bidirectional signaling between the gut microbiota and the CNS, allowing microbial activity to influence brain function and behavior (Liu and Forsythe, 2021). While vagus nerve stimulation has been shown to alleviate symptoms of depression and anxiety, it is not direct evidence of microbiome involvement (Karemaker, 2022). However, preclinical studies suggest that the vagus nerve may serve as a key communication route by which gut microbes influence brain function, linking microbial signals to neural and emotional regulation (Kong et al., 2018). In addition, certain probiotic strains—often termed “psychobiotics”—can modulate the gut microbiota composition and metabolic activity, enhancing the production of neuroactive compounds such as GABA, serotonin precursors, and SCFAs. These metabolites interact with enteroendocrine and epithelial receptors in the gut, stimulating afferent signaling via the vagus nerve and enteric nervous system (ENS) (Smith et al., 2021; Deng et al., 2024). Animal studies have demonstrated that the effects of probiotics on mood and behavior are abolished after subdiaphragmatic vagotomy, confirming this neural route (Needham et al., 2022). Metabolites such as SCFAs also act through free fatty acid receptors (e.g., FFAR2/3), modulating microglial activation, neuroinflammation, and neurotransmitter systems, further influencing emotional regulation (Mishra et al., 2020). Finally, these microbial signals may help restore stress axis balance by reducing hypothalamic pituitary adrenal (HPA) axis hyperactivity and proinflammatory cytokines—effects supported by rodent and early human clinical trials (Rusch et al., 2023).

Gut microbes play pivotal roles in the production and regulation of neurotransmitters—chemical messengers that influence mood, cognition, and behavior (Mittal et al., 2017). Several key neurotransmitters are either synthesized directly by gut bacteria or modulated through microbial activity:

Bacterially derived vitamins, particularly those from the B-complex group and vitamin K2, contribute to processes including neurotransmitter synthesis, energy metabolism, and neuroprotection. Emerging research suggests that deficiencies in these vitamins—often influenced by gut dysbiosis—may be linked to mood disorders, cognitive decline, and other psychiatric symptoms. While the underlying mechanisms vary, their importance in supporting brain health is increasingly recognized. A summary of these vitamins, their microbial sources, and mental health relevance—acknowledging that observed deficiencies often reflect overall systemic levels rather than microbiota-specific causes—is provided in Table 1.

In addition to directly influencing neurotransmitters, the gut microbiota produces a variety of metabolites that can impact brain function and mental health. The microbiome metabolome may act as a nexus of body-mind health. Among these metabolites, SCFAs and tryptophan metabolites play particularly significant roles:

Depression and anxiety disorders are among the most prevalent mental health conditions, and a growing number of human studies have identified significant associations among the gut microbiota composition, microbe-targeted interventions, and these disorders. Case–control studies have shown that individuals with depression and anxiety often exhibit increased pro-inflammatory bacteria and reduced SCFA-producing taxa (Liang et al., 2018; Du et al., 2020; Simpson et al., 2021; Mitrea et al., 2022). Studies have demonstrated that individuals with depression often have reduced microbial diversity and depletion of beneficial genera such as Lactobacillus and Bifidobacterium. Notably, FMT experiments have provided compelling causal evidence: when the gut microbiota from depressed human donors or mice subjected to chronic stress are transferred into germ-free or antibiotic-treated rodents, the recipients develop anxiety- and depression-like the behaviors of the donors. These animals also exhibit increased neuroinflammatory markers—such as elevated hippocampal IFN-γ, TNF-α, and IDO1—as well as changes in microbial taxa (e.g., decreased Lactobacillus and increased Bacteroides) that parallel donor profiles (Romijn et al., 2017; Han and Kim, 2019; Jang et al., 2019; Li et al., 2019). This body of evidence strongly supports a link between dysbiosis and behavioral phenotypes and highlights the mechanistic relevance of gut–brain–immune interactions in depression and anxiety.

Inflammation has been strongly implicated in depression and anxiety, with increased levels of proinflammatory cytokines, such as interleukin-6 (IL-6) and TNF-α, observed in affected individuals (Elgellaie et al., 2023). Dysbiosis contributes to this inflammatory state by disrupting immune homeostasis primarily through increased intestinal permeability, which allows bacterial components such as LPS to translocate into the systemic circulation. This translocation triggers a systemic immune response characterized by elevated proinflammatory cytokines, which can, in turn, influence brain function and behavior through signaling along the gut–brain axis (Rutsch et al., 2020). Additionally, a reduction in serotonin-producing microbes can negatively impact mood regulation, potentially contributing to the onset of depressive and anxious symptoms (Sarkar et al., 2020; Li et al., 2025).

Schizophrenia is a severe psychiatric disorder characterized by hallucinations, delusions, and cognitive impairments (McCutcheon et al., 2023). While its exact cause remains unclear, research suggests that imbalances in the gut microbiota may contribute to disease progression (Ma and Song, 2023). Studies comparing the microbiomes of individuals with schizophrenia to those of healthy controls have revealed significant differences in microbial composition, with an increase in proinflammatory bacteria, including Eggerthella, Lactobacillus, and Veillonella; a decrease in potentially beneficial bacteria, such as Faecalibacterium and Roseburia; and a reduction in beneficial microbes, including Coprococcus and Blautia (Yan et al., 2022; Gokulakrishnan et al., 2023).

The role of the gut microbiota in schizophrenia may be linked to neuroinflammation, oxidative stress, and altered neurotransmitter activity (Carlessi et al., 2021). Gut microbial metabolites, such as SCFAs, have been implicated in schizophrenia through both developmental and symptomatic pathways. Early-life alterations in SCFA production—particularly butyrate production—have been associated with neurodevelopmental changes that may predispose individuals to schizophrenia. Additionally, during the onset of symptoms, reduced SCFA levels have been linked to increased gut permeability, systemic inflammation, and disrupted blood–brain barrier integrity, all of which may contribute to the cognitive and behavioral symptoms characteristic of the disorder (Peng et al., 2022; Kowalski et al., 2023). FMT studies in animal models have demonstrated that transferring gut bacteria from individuals with schizophrenia to germ-free mice induces schizophrenia-like behaviors, further supporting the role of the microbiota in this disorder (Vasiliu, 2023).

ASD is a neurodevelopmental condition characterized by social communication deficits and repetitive behaviors (Bhat, 2021; Hirota and King, 2023). Mounting evidence suggests that the gut microbiome may play a role in autism, particularly during early development, when the microbiota is still forming (Vuong and Hsiao, 2017; Taniya et al., 2022). Autistic children often exhibit distinct gut microbiota profiles, broadly including reduced microbial diversity and an increased abundance of certain bacterial species, such as Clostridia, which are known to produce neurotoxic metabolites (Fattorusso et al., 2019; Zou et al., 2020).

One potential mechanism linking gut microbes to ASD involves alterations in gut permeability and immune function (Azhari et al., 2019). Studies have reported increased intestinal permeability, or a “leaky gut,” in children with ASD, which may allow bacterial metabolites, bacterial components themselves and inflammatory molecules to enter the bloodstream and affect brain development (Eshraghi et al., 2020; Al-Ayadhi et al., 2021). Additionally, disruptions in the microbial production of neurotransmitters, including GABA and serotonin, may contribute to ASD-related behavioral symptoms (Garcia-Gutierrez et al., 2020; Bamicha et al., 2024). These imbalances may influence excitatory-inhibitory signaling in the brain, potentially contributing to core behavioral symptoms such as social deficits, anxiety, and repetitive behaviors. Emerging interventions, such as probiotic supplementation, dietary modifications and FMT, have shown promise in improving gastrointestinal and behavioral symptoms in autistic children, further highlighting the influence of the microbiota on neurodevelopment (Tan et al., 2021).

Bipolar disorder is a mood disorder characterized by alternating episodes of mania and depression (McIntyre et al., 2020). Recent studies suggest that immune system dysfunction and alterations in the gut microbiota may contribute to the pathophysiology of this disorder (Levy et al., 2017). Individuals with bipolar disorder often exhibit increased levels of systemic inflammation, with elevated concentrations of inflammatory markers such as C-reactive protein (CRP) and IL-6. Dysbiosis may contribute to this inflammatory state by disrupting gut barrier integrity and triggering immune activation (Doney et al., 2022; Zhao N. O. et al., 2022).

In individuals with bipolar disorder, alterations in the gut microbial composition have been linked to dysregulation of serotonin and dopamine pathways—neurotransmitter systems that are central to mood stabilization and are commonly disrupted during manic and depressive episodes (González-Arancibia et al., 2019). Additionally, preliminary research suggests that probiotic supplementation may help reduce inflammation and stabilize mood symptoms in individuals with bipolar disorder, opening new avenues for microbiome-targeted therapeutic strategies (Zeng et al., 2022). These effects are thought to arise through several interconnected mechanisms: by enhancing gut barrier integrity and thereby reducing leaky gut, by downregulating proinflammatory cytokine production and modulating immune responses, and by influencing the synthesis and availability of key neurotransmitters such as serotonin, dopamine, and GABA—each of which plays a crucial role in mood regulation. Together, these pathways highlight the therapeutic potential of targeting the gut microbiome in the management of bipolar disorder (Borkent et al., 2025; Zeng et al., 2022).

Although research on the gut microbiota in patients with OCD is still in its early stages, emerging evidence suggests a meaningful connection between microbial composition and OCD symptomatology (Turna et al., 2016). Clinical studies have revealed a reduction in microbial diversity among individuals with OCD, particularly a decrease in beneficial butyrate-producing genera such as Oscillospira, Anaerostipes, and Odoribacter, which are known to play key roles in maintaining gut barrier integrity and anti-inflammatory signaling (Turna et al., 2020). Concurrently, an increased abundance of proinflammatory taxa such as Rikenellaceae—notably Alistipes—has been reported, indicating a shift toward a more inflammatory microbial profile (Parker et al., 2020; Tavella et al., 2021). These microbial alterations may contribute to increased intestinal permeability and systemic inflammation, both of which have been implicated in neuropsychiatric disorders. In support of a potential causal role, FMT from individuals with OCD into germ-free mice has been shown to induce compulsive-like behaviors and alter neurochemical pathways in recipient animals, including elevated succinic acid levels associated with neuroinflammatory responses (Zhang et al., 2024). In preclinical models, probiotic treatment with Lactobacillus casei Shirota has been found to attenuate compulsive grooming behavior in rodents, normalize BDNF expression, and modulate serotonin receptor levels, showing comparable effects to those of fluoxetine—a standard pharmacological treatment for OCD (Sanikhani et al., 2020). Collectively, these findings suggest that gut dysbiosis may contribute to the pathophysiology of OCD through immune modulation, microbial metabolite production, and effects on neurotransmitter systems. While human studies remain limited, this growing body of literature points to the gut microbiome as a promising target for future therapeutic interventions in patients with OCD.

Animal and preliminary human studies increasingly suggest that PTSD may involve disturbances in the gut microbial composition, intestinal barrier integrity, and downstream neuroimmune and neurochemical signaling. In a mouse model of repeated social defeat stress (RSDS), which induces PTSD-like behaviors, researchers reported significant gut dysbiosis, reduced gut microbial diversity, and disrupted barrier function characterized by altered tight junction proteins and increased permeability (He et al., 2024; Voigt et al., 2025). These mice also exhibited a proinflammatory gut milieu, supporting the hypothesis that repeated trauma induces a cascade from microbial imbalance to systemic immune activation (Yadav et al., 2023).

In humans, systematic reviews comparing PTSD patients to trauma-exposed controls have linked the reduced abundance of protective taxa—such as Actinobacteria, Lentisphaerae, and Verrucomicrobia—with PTSD symptom severity (Winder et al., 2025). Studies of specific populations, such as firefighters, revealed that individuals without PTSD symptoms presented greater gut microbial diversity and higher levels of SCFA-producing species, such as Alistipes putredinis, which has been associated with resilience to stress (Yoo et al., 2025). Therapeutically, pilot human trials using prebiotic supplementation in veterans with PTSD revealed modest increases in SCFA-producing bacteria and reductions in pro-inflammatory taxa, along with attenuated stress responses and trends toward decreased symptoms (Voigt et al., 2025). In rodent experiments, the administration of Lactobacillus reuteri DSM 17938 improved intestinal integrity, reduced systemic inflammation (e.g., lowered CRP), and reversed reductions in cortical BDNF linked to PTSD-like behaviors (Petakh et al., 2024). A separate mouse model using single prolonged stress (SPS) revealed that probiotic treatment mitigated anxiety- and depression-like behaviors, restored BDNF expression, and improved gut morphology (Khan et al., 2025).

Together, these findings suggest that PTSD may be associated with gut dysbiosis, increased intestinal permeability, and systemic inflammation—factors through which microbial metabolites and immune signaling influence neurobiology and behavior. While causal human data remain limited, these studies support the potential for microbiome-based adjunctive therapies in PTSD patients.

The immune system plays a critical role in maintaining brain health, and the gut microbiota is an important regulator of immune function. A balanced microbiome supports immune homeostasis, whereas dysbiosis can trigger chronic low-grade inflammation, which has been implicated in several neuropsychiatric disorders, including depression, schizophrenia, and bipolar disorder (Mundula et al., 2022; Perdijk et al., 2024).

Microbial metabolites, such as SCFAs, help regulate inflammation by influencing immune cells (Parada Venegas et al., 2019). However, an imbalance in gut bacteria can lead to increased intestinal permeability, allowing inflammatory molecules such as LPS, which are components of the outer membrane of gram-negative bacteria and potent immune activators, to enter the bloodstream (Candelli et al., 2021). These proinflammatory signals can activate microglia, the brain’s immune cells, leading to neuroinflammation and contributing to cognitive and emotional disturbances (Qin et al., 2007; Skrzypczak-Wiercioch and Sałat, 2022). Peripheral immune mediators, such as cytokines and LPS, can cross the blood–brain barrier when its integrity is compromised or can signal indirectly via the vagus nerve and endothelial cells lining the cerebral vasculature (Huang et al., 2021).

Moreover, certain bacterial species modulate the production of anti-inflammatory cytokines (e.g., interleukin-10) and proinflammatory cytokines (e.g., interleukin-6, tumor necrosis factor-alpha), further influencing brain function (Strle et al., 2001). Chronic inflammation has been linked to alterations in neurotransmitter signaling, oxidative stress, and impaired neuroplasticity, all of which are associated with mental health disorders (Hassamal, 2023). Studies have shown that certain gut bacteria modulate the production of anti-inflammatory cytokines—such as interleukin-10 (IL-10)—as well as proinflammatory cytokines, including IL-6 TNF-α, which can significantly influence brain function (Steen et al., 2020). For example, Faecalibacterium prausnitzii is known to increase IL-10 secretion while simultaneously inhibiting NF-κB activation, thereby suppressing the production of inflammatory cytokines (IL-6 and TNF-α) (Alameddine et al., 2019). Conversely, dysbiosis characterized by an increased abundance of gram-negative taxa elevates LPS levels and stimulates immune responses that increase systemic IL-6 and TNF-α, both of which are markers linked to mood disorders such as depression and anxiety (Chen et al., 2024). Elevated IL-6 has also been shown to repress BDNF expression via epigenetic mechanisms in the brain, leading to impaired neuroplasticity and emotional regulation (Jehn et al., 2015). Collectively, these findings support the concept that microbial modulation of cytokine profiles—through both anti- and proinflammatory pathways—can induce neuroimmune changes directly associated with mental health outcomes.

The gut microbiota is a key modulator of the body’s response to stress, primarily through its interaction with the HPA axis (Rusch et al., 2023). The HPA axis regulates the body’s stress response system by controlling the release of cortisol, a hormone involved in mood regulation, energy metabolism, and immune function (Dedovic et al., 2009). In terms of mood regulation, persistent activation of the HPA axis—common in chronic stress—can lead to elevated cortisol exposure. Chronic cortisol elevation damages brain regions such as the hippocampus and prefrontal cortex, which are important for emotional regulation and cognitive control; this damage contributes to mood disturbances and depressive symptoms (Bertollo et al., 2025). With respect to immune function, cortisol exerts both acute anti-inflammatory effects and, under prolonged exposure, paradoxical immune dysregulation. While it suppresses proinflammatory cytokines (e.g., IL-6 and TNF-α) and dampens T-cell activity in the short term, chronic cortisol elevation may impair immune cell responsiveness and promote a shift toward Th2 dominance, reducing cellular immunity and increasing susceptibility to infections (Alotiby, 2024). Importantly, the gut microbiota and immune signals influence the HPA axis: microbial components such as LPS and elevated cytokines (e.g., IL-6) can activate the axis, increasing cortisol levels (Liu and Zhu, 2018; Bertollo et al., 2025).

Beneficial gut bacteria, such as Lactobacillus and Bifidobacterium, have been shown to modulate the stress response by reducing cortisol levels and promoting the production of GABA, an inhibitory neurotransmitter that helps counteract stress-induced excitability (Liu and Zhu, 2018; Tette et al., 2022; Zhao N. et al., 2022). Conversely, an imbalance in gut microbes can increase the release of stress hormones, increasing susceptibility to anxiety and depression-like behaviors (Nie et al., 2024).

Animal studies have demonstrated that germ-free mice exhibit exaggerated HPA axis responses to stress, further highlighting the role of the microbiota in stress regulation. Restoring beneficial microbes through probiotic supplementation has shown potential for modulating stress hormone levels and enhancing behavioral resilience, particularly in populations with HPA axis dysregulation. For example, in a murine model colonized with microbiota from patients with Cushing’s disease—a condition characterized by excessive cortisol production—probiotic intervention attenuated depression- and anxiety-like behaviors and normalized corticosterone levels. Similarly, human and preclinical studies have demonstrated that specific probiotic strains can influence the microbiota–gut–brain axis, thereby regulating cortisol output and improving stress-related outcomes (Wiley et al., 2017; Nie et al., 2024).

Diet plays a crucial role in shaping the gut microbiome, which in turn influences mental health. Nutritional components such as fiber, polyphenols, and omega-3 fatty acids contribute to a balanced microbiota, supporting brain function and emotional well-being (Businaro, 2022). In contrast, diets high in saturated fats and refined sugars have been linked to dysbiosis, increased inflammation, and a greater risk of neuropsychiatric disorders (Leo and Campos, 2020).

Probiotics have been shown to positively impact brain function when this results in colonization in the gut. Specific probiotic strains, such as Lactobacillus rhamnosus and Bifidobacterium longum, help regulate neurotransmitter levels, particularly serotonin and GABA, and have been shown to be associated with reduced symptoms of depression and anxiety (Jarosz et al., 2024). These probiotics also play a role in reducing neuroinflammation, further supporting mental well-being (Meher et al., 2024).

Prebiotics, on the other hand, are nondigestible dietary fibers that serve as fuel for beneficial gut bacteria (Rezende et al., 2021). Compounds such as inulin and fructo-oligosaccharides promote the growth of bacteria that produce SCFAs (Birkeland et al., 2020), which have neuroprotective and anti-inflammatory properties. By fostering a healthier gut environment, prebiotics indirectly contribute to improved cognitive function and emotional stability. For example, Schmidt et al. reported that healthy volunteers who consumed galacto oligosaccharides (GOS) daily for three weeks presented a reduced cortisol awakening response and decreased attentional vigilance to negative stimuli, suggesting an anxiolytic effect (Schmidt et al., 2015). Similarly, a randomized controlled trial by Kato-Kataoka et al. demonstrated that prebiotic-containing fermented milk improved stress-related symptoms and sleep quality in medical students under academic stress (Kato-Kataoka et al., 2016).

Dietary patterns also play a significant role in mental health (Grajek et al., 2022). The Mediterranean diet—characterized by high intake of fiber, polyphenols, omega-3 fatty acids, and fermented foods—promotes microbial diversity and increases the abundance of beneficial taxa such as Bifidobacterium and Lactobacillus, as well as SCFA-producing species such as Faecalibacterium prausnitzii (Ghosh et al., 2020; Ventriglio et al., 2020). These microbial shifts are associated with reduced intestinal inflammation and improved blood–brain barrier integrity, both of which support cognitive function and emotional regulation (Jacka et al., 2017). In contrast, a Western diet—high in saturated fats, refined sugars, and low in fiber—has been shown to reduce microbial diversity and promote the expansion of proinflammatory bacteria such as Bilophila wadsworthia and Alistipes (David et al., 2014; Zhang et al., 2023). These findings highlight the importance of dietary interventions in promoting both gut and brain health, emphasizing the potential for nutritional strategies to help promote a healthy gut microbiome as a complementary treatment approach for managing psychological disorders.

Probiotics have been studied for their role in mental health because of their ability to influence neurotransmitter production and regulate the immune response. Some probiotics, known as psychobiotics, have been shown to have specific effects on brain function by modulating serotonin, dopamine, and GABA levels (Sharma et al., 2021).

Psychobiotics also influence the HPA axis, which regulates the body’s response to stress. By promoting a balanced stress response and reducing cortisol levels, these beneficial microbes may help alleviate mood disorders (Bermúdez-Humarán et al., 2019). Clinical studies suggest that probiotic supplementation can improve emotional well-being, although its efficacy depends on factors such as strain specificity, dosage, and an individual’s baseline microbiome composition (Pirbaglou et al., 2016).

The consumption of fiber-rich foods, fermented products, and essential nutrients such as omega-3 fatty acids can help maintain microbial balance and promote the production of beneficial metabolites (Nogal et al., 2021). Prebiotic-rich foods, including those containing inulin and fructo-oligosaccharides, provide nourishment for beneficial bacteria, stimulating their growth and increasing the production of SCFAs, which have neuroprotective and anti-inflammatory effects (Bornet and Brouns, 2002).

Additionally, certain dietary compounds, such as polyphenols found in plant-based foods, have been shown to support brain function by modulating gut bacteria and reducing oxidative stress (Shanmugam et al., 2022). Emerging research highlights the role of personalized nutrition in mental health, emphasizing the need for tailored dietary recommendations on the basis of an individual’s microbiome composition (Bianchetti et al., 2023).