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From "Leaky Gut" to Impaired Glia-Neuron Communication in Depression.
In the last three decades, the robust scientific data emerged, demonstrating that the immune-inflammatory response is a fundamental component of the pathophysiology of major depressive disorder (MDD). Psychological stress and various inflammatory comorbidities contribute to such immune activation. Still, this is not uncommon that patients with depression do not have defined inflammatory comorbidities, and alternative mechanisms of immune activation need to take place. The gastrointestinal (GI) tract, along with gut-associated lymphoid tissue (GALT), constitutes the largest lymphatic organ in the human body and forms the biggest surface of contact with the external environment. It is also the most significant source of bacterial and food-derived antigenic material. There is a broad range of reciprocal interactions between the GI tract, intestinal microbiota, increased intestinal permeability, activation of immune-inflammatory response, and the CNS that has crucial implications in brain function and mental health. This intercommunication takes place within the microbiota-gut-immune-glia (MGIG) axis, and glial cells are the main orchestrator of this communication. A broad range of factors, including psychological stress, inflammation, dysbiosis, may compromise the permeability of this barrier. This leads to excessive bacterial translocation and the excessive influx of food-derived antigenic material that contributes to activation of the immune-inflammatory response and depressive psychopathology. This chapter summarizes the role of increased intestinal permeability in MDD and mechanisms of how the "leaky gut" may contribute to immune-inflammatory response in this disorder.
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Microbiota-Induced Epigenetic Alterations in Depressive Disorders Are Targets for Nutritional and Probiotic Therapies.
Major depressive disorder (MDD) is a complex disorder and a leading cause of disability in 280 million people worldwide. Many environmental factors, such as microbes, drugs, and diet, are involved in the pathogenesis of depressive disorders. However, the underlying mechanisms of depression are complex and include the interaction of genetics with epigenetics and the host immune system. Modifications of the gut microbiome and its metabolites influence stress-related responses and social behavior in patients with depressive disorders by modulating the maturation of immune cells and neurogenesis in the brain mediated by epigenetic modifications. Here, we discuss the potential roles of a leaky gut in the development of depressive disorders via changes in gut microbiota-derived metabolites with epigenetic effects. Next, we will deliberate how altering the gut microbiome composition contributes to the development of depressive disorders via epigenetic alterations. In particular, we focus on how microbiota-derived metabolites such as butyrate as an epigenetic modifier, probiotics, maternal diet, polyphenols, drugs (e.g., antipsychotics, antidepressants, and antibiotics), and fecal microbiota transplantation could positively alleviate depressive-like behaviors by modulating the epigenetic landscape. Finally, we will discuss challenges associated with recent therapeutic approaches for depressive disorders via microbiome-related epigenetic shifts, as well as opportunities to tackle such problems.
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Pick fecal microbiota transplantation to enhance therapy for major depressive disorder.
In recent years, fecal microbiota transplantation (FMT) has emerged as a promising therapy for major depressive disorder (MDD). The goal of the operation is to restore a healthy gut microbiota by introducing feces from a healthy donor into the recipient's digestive system. The brain-gut axis is thought to have a significant role in regulating mood, behavior, and cognition, which supports the use of FMT in the treatment of MDD. Numerous studies have shown a correlation between abnormalities of the gut microbiota and MDD, whereas FMT has demonstrated the potential to restore microbial equilibrium. While FMT has shown encouraging results, it is crucial to highlight the potential hazards and limits inherent to this therapeutic approach. Stool donor-to-recipient disease transfer is a concern of FMT. Furthermore, it still needs to be determined what effect FMT has on the gut microbiota and the brain in the long run. This literature review provides an overview of the possible efficacy of FMT as a therapeutic modality for MDD. There is hope for patients who have not reacted well to typical antidepressant therapy since FMT may become an invaluable tool in the treatment of MDD as researchers continue to examine the relationship between gut microbiota and MDD.
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Gut Microbiota and Metabolites: Orchestrating Depression Pathogenesis Through the Microbiota-Gut-Brain Axis's Neural, Immune, and Metabolic Routes.
Depression (major depressive disorder, MDD) is a globally prevalent, highly disabling, and complex mental disorder whose pathogenesis has not been fully elucidated. In recent years, the role of the gut microbiota in depression via the "microbiota-gut-brain axis" (MGB axis) has attracted increasing attention. A large body of evidence indicates that the gut microbiota and its metabolites can engage in bidirectional communication with the central nervous system through three core pathways-neural, immune, and metabolic-thereby profoundly influencing the onset and progression of depression. This article reviews the specific mechanisms by which the gut microbiota affects depression through the aforementioned pathways, including regulating the balance of neurotransmitters (e.g., GABA and 5-HT), mediating neuroinflammatory responses, and adjusting the levels of metabolites such as short-chain fatty acids. This study aims to provide a theoretical basis for an in-depth understanding of the pathophysiological mechanisms of depression and the development of novel microbiota-based intervention therapeutic strategies.
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Nutritional Strategies in Major Depression Disorder: From Ketogenic Diet to Modulation of the Microbiota-Gut-Brain Axis.
Major depressive disorder (MDD) is a leading cause of disability worldwide. While traditional pharmacological treatments are effective for many cases, a significant proportion of patients do not achieve full remission or experience side effects. Nutritional interventions hold promise as an alternative or adjunctive approach, especially for treatment-resistant depression. This review examines the potential role of nutrition in managing MDD through addressing biological deficits and modulating pathways relevant to its pathophysiology. Specifically, it explores the ketogenic diet and gut microbiome modulation through various methods, including probiotics, prebiotics, synbiotics, postbiotics, and fecal microbiota transplantation. Numerous studies link dietary inadequacies to increased MDD risk and deficiencies in nutrients like omega-3 s, vitamins D and B, magnesium, and zinc. These deficiencies impact neurotransmitters, inflammation, and other biological factors in MDD. The gut-brain axis also regulates mood, stress response, and immunity, and disruptions are implicated in MDD. While medications aid acute symptoms, nutritional strategies may improve long-term outcomes by preventing relapse and promoting sustained remission. This comprehensive review aims to provide insights into nutrition's multifaceted relationship with MDD and its potential for developing more effective integrated treatment approaches.
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Ginkgo biloba extract protects against depression-like behavior in mice through regulating gut microbial bile acid metabolism.
Depression is a mental disorder with high morbidity, disability and relapse rates. Ginkgo biloba extract (GBE), a traditional Chinese medicine, has a long history of clinical application in the treatment of cerebral and mental disorders, but the key mechanism remains incompletely understood. Here we showed that GEB exerted anti-depressant effect in mice through regulating gut microbial metabolism. GBE protected against unpredictable mild stress (UMS)-induced despair, anxiety-like and social avoidance behavior in mice without sufficient brain distribution. Fecal microbiome transplantation transmitted, while antibiotic cocktail abrogated the protective effect of GBE. Spatiotemporal bacterial profiling and metabolomics assay revealed a potential involvement of Parasutterella excrementihominis and the bile acid metabolite ursodeoxycholic acid (UDCA) in the effect of GBE. UDCA administration induced depression-like behavior in mice. Together, these findings suggest that GBE acts on gut microbiome-modulated bile acid metabolism to alleviate stress-induced depression.
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The Gut Connection: A Narrative Review on the In-depth Analysis of Gut Microbiota and Metabolites in Depression.
Depression is a prevalent mood disorder with significant public health implications. Despite extensive research, its precise causes remain inadequately understood. Recently, interest has surged in the role of the gut microbiome and its metabolites in the pathophysiology of depression. This review aims to provide a comprehensive overview of the relationship between gut microbiota, its metabolites, and depression while exploring potential mechanisms influencing the efficacy of antidepressant medications. A narrative review methodology was employed, synthesizing recent studies utilizing a multi-omics approach. We examined alterations in gut microbiome composition and metabolite production in individuals diagnosed with depression, discussing the technical tools and methods commonly applied in this research area. The findings indicate that individuals with depression show significant alterations in gut microbiome composition, notably an imbalance in Firmicutes, Bacteroidetes, and Actinobacteria. Changes in metabolite production, including short-chain fatty acids, tryptophan, and bile acids, were also observed. Moreover, the review highlights that antidepressant medications may exert their therapeutic effects by modulating gut microbiota and its metabolites. This review emphasizes the intricate interplay between gut microbiota, its metabolites, and depression, revealing critical insights into the mechanisms underlying antidepressant efficacy. We recommend that future research focus on elucidating these interactions to develop innovative therapeutic strategies, potentially transforming the management of depression through microbiota-targeted approaches.
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The role of gut microbiota in psychiatric disorders: current findings.
PURPOSE OF REVIEW: Gut microbiota and its alterations have been increasingly implicated in the pathophysiology of major psychiatric disorders via the microbiota-gut-brain axis. This narrative review aims to highlight current findings from recent systematic reviews and meta-analyses (published between September 2023 and March 2025), addressing the role of gut microbiota in major depressive disorder (MDD) and schizophrenia, with particular attention to the effects of psychotropic medications and microbiota-targeted interventions. RECENT FINDINGS: In MDD, consistent changes in gut microbiota composition, such as depletion of Faecalibacterium and enrichment of Bifidobacterium, have been reported, although alpha diversity findings remain inconsistent. Antidepressants may modulate microbiota in both humans and animal models, while probiotic and synbiotic interventions yield modest reductions in depressive symptoms and inflammatory markers. In schizophrenia, observational studies showed stable alpha diversity, but altered beta diversity, with taxa like Bifidobacterium , Lactobacillus , and Roseburia linked to symptom severity, cognition, and antipsychotic exposure. Interventional studies, though limited, suggest small-to-moderate clinical improvements with probiotic supplementation, and emerging evidence supports potential benefits for both cognition and reducing metabolic side effects of psychotropic medications. SUMMARY: Across depressive and psychotic disorders, growing evidence supports a multifaceted and indispensable role of gut microbiota in clinical symptomatology, treatment response, and cognition of patients. However, substantial variability of methodological frame, limited sample sizes, lack of mechanistic precision, and heterogeneity between published studies result in unequivocal conclusions on the exact effect of microbiota on mental health in general, and on major psychiatric disorders. While microbiota-targeted therapies remain adjunctive and exploratory, recent findings reinforce them as a promising target for more successful treatment of mental health disorders in the near future. In order to reach that goal, we need more rigorous, longitudinal, and integrative studies to guide the clinical implementation.
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Latroeggtoxin-VI improves depression by regulating the composition and function of gut microbiota in a mouse model of depression.
Introduction. Depression has become one of the mental diseases that seriously affect human health. Its mechanism is very complex, and many factors influence the condition. An imbalance of the gut microbiota is being considered as a factor that impacts the occurrence and progression of depression. Future therapies may therefore tap into this connection, treating depression through manipulation of the gut microbiome.Hypothesis/Gap Statement. Latroeggtoxin-VI (LETX-VI), a proteinaceous neurotoxin from Latrodectus tredecimguttatus eggs, was previously demonstrated to inhibit excessive inflammation and improve depression behaviours, suggesting that it might be able to regulate the balance of gut microbiota. The aim of this study was to explore the effects of LPS and LETX-VI on depressive behaviours and gut microbiota and to analyse correlations between changes in the gut microbiota and depressive behaviours.Methodology. A murine model of depression was established, and the effects of LPS and LETX-VI treatment on depressive behaviours and gut microbiota were investigated.Results. In the murine model, depressive behaviour was induced by LPS; the ratio of Firmicutes to Bacteroidetes (F/B) and the number of pro-inflammatory bacteria in the gut microbiota increased (P<0.01), while butyric acid-producing bacteria with anti-inflammatory effect decreased (P<0.05). Furthermore, the metabolic function of the gut microbiota was disrupted, and the level of virulence factors among gut microbiota was up-regulated (P<0.05). Association analysis showed that the changes in the composition and function of gut microbiota were closely related to the depression phenotype of mice, suggesting that the abnormal function of gut microbiota is linked to depression. However, when LETX-VI was applied before LPS injection, the LPS-induced changes in the gut microbiota were alleviated, and the depressive behaviour greatly improved.Conclusion. LETX-VI can prevent depressive behaviour by regulating the composition and/or function of the gut microbiota.
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Microbiota-Driven microglia reprogramming reverses depressive-like behaviors through Peripheral-to-Central immune crosstalk.
Major depressive disorder (MDD) is a major psychiatric condition associated with neuroimmune dysregulation. Microglia, the principal innate immune cells of the central nervous system, have been implicated in MDD. Nevertheless, the specific subpopulations involved and the mechanisms that govern their responses are still elusive. Here, we found that gut microbiota intervention using bedding from control non-stressed mice reverses chronic unpredictable mild stress (CUMS)-induced alterations in behavior. Using CD45+ immune cell sorting and single-cell RNA sequencing (scRNA-seq), we built an atlas of brain-resident microglia and non-microglial immune cells in the central and peripheral compartments. CUMS primarily induced transcriptional alterations in microglia and monocytes, while the reversed changes induced by bedding exchange mainly detected in microglia (85%). Among the microglial subtypes, homeostatic microglia 2 (HM2) primarily responded to CUMS. HM2 shaped microglial states through activation trajectory: the HM2→chemokine-related microglia 3→inflame microglia 1, which could be reversed by bedding exchange. Brain Mdcs served as the mainly immune cells interact with microglia. Furthermore, we systematically characterized alterations in the myeloid-derived cells across the brain, skull, and peripheral blood mononuclear cells (PBMC). Meanwhile, CUMS disrupted immune cell differentiation by suppressing chromatin openness in global accessibility sequencing analyses, and Krüppel-like factors Klf2 emerged as a master regulator expressed in monocytes and HM2 microglial subtype. Remarkably, microbiota remodeling partially reversed this epigenetic dysregulation, restoring immune cell migration and activation processes. In summary, this study revealed that gut microbiota intervention ameliorates depressive phenotypes by dynamically reprogramming microglia via the "periphery-CNS immune" axis, providing a novel entry for antidepressant strategies targeting neuro-immune interactions.