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Gut microbiota dysbiosis and depression: Bidirectional interactions, mediating pathways, and microecological therapeutics.
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.
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Serotonin and tryptophan metabolites, autoantibodies and gut microbiome in APECED.
Objective Intestinal autoimmunity with gastrointestinal (GI) dysfunction has been shown in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Patients lack entero-endocrine (EE) cells and have circulating autoantibodies (Aabs) against critical enzymes in serotonin (5-HT) biosynthesis. Design We sought to determine the serum levels of 5-HT, tryptophan (Trp) metabolites and L-DOPA in 37 Finnish APECED patients and to correlate their abundance with the presence of TPH and AADC Aabs, GI dysfunction and depressive symptoms. We also performed an exploratory analysis of the gut microbiome. Methods Serum 5-HT, L-DOPA and Trp metabolite levels were determined by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). TPH and AADC Aabs were measured by ELISA. Depression was assessed with a structured RBDI questionnaire. The V3-V4 regions of the bacterial 16S rRNA gene were sequenced for gut microbiome exploration. Results Serum 5-HT levels were significantly decreased (130 ± 131 nmol/L vs 686 ± 233 nmol/L, P < 0.0001) in APECED patients with TPH-1 (±AADC) Aabs compared to controls and patients with only AADC Aabs. Reduced 5-HT levels correlated with constipation. The genus Escherichia/Shigella was overrepresented in the intestinal microbiome. No correlation between serum Trp, 5-HT or l-DOPA levels and the RBDI total score, fatigue or sleep disorders was found. Conclusions This exploratory study found low serum levels of 5-HT to be associated with constipation and the presence of TPH-1 and AADC Aabs, but not with symptoms of depression. Hence, serum 5-HT, TPH1 and AADC Aabs should be determined in APECED patients presenting with GI symptoms.
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Targeting the gut-immune-brain axis: pharmacological insights from depression in inflammatory bowel disease.
Inflammatory Bowel Disease (IBD), comprising Crohn's Disease and Ulcerative Colitis, is a chronic inflammatory condition of the gastrointestinal tract with a remarkably high prevalence of psychiatric comorbidities, particularly Major Depressive Disorder (MDD). The traditional monoaminergic hypothesis of depression is insufficient to explain the complex etiology of MDD, paving the way for new paradigms, such as the inflammatory hypothesis of depression. This narrative review critically explores IBD as a human clinical model to investigate the connection between chronic inflammation and depression. It is argued that gut dysbiosis, a central feature of IBD, is a fundamental trigger that, through a compromised gut barrier, drives systemic inflammation and, subsequently, neuroinflammation. We detail the molecular and cellular mechanisms that link intestinal inflammation to central nervous system (CNS) dysfunction, including microglial activation, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and kynurenine pathway activation, which diverts tryptophan metabolism from serotonin synthesis to the production of neurotoxic metabolites. Robust epidemiological evidence demonstrating a bidirectional association between IBD and depression is discussed, suggesting a shared pathophysiology rather than a simple cause-and-effect relationship. Furthermore, we review the implications and emerging therapeutics, highlighting the antidepressant effects of immunobiologicals, such as anti-TNF therapies, and the potential of emerging interventions that target the microbiome, such as probiotics, psychobiotics, fecal microbiota transplantation, and anti-inflammatory diets. Furthermore, we address the limitations of the current literature, such as the lack of a quantitative definition for dysbiosis and the scarcity of clinical trials with integrated neuropsychiatric outcomes, and propose directions for future translational research. We conclude that IBD should be considered a systemic disease with significant psychiatric repercussions, advocating for an integrated therapeutic approach that combines immunomodulatory, neuromodulatory, and microbiological interventions to treat both gut and brain pathology effectively.
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Estrogen-Gut-Brain Axis: Examining the Role of Combined Oral Contraceptives on Mental Health Through Their Impact on the Gut Microbiome.
Combined oral contraceptives (COCs) possess the ability to alter the normal composition of the gut microbiome and the permeability of the gastrointestinal (GI) tract, which may cause both gut-related and non-gut-related complications. The gut-estrogen axis examines the relationship between estrogens (particularly the active form, estradiol) and the gastrointestinal system and can be attributed to the maintenance of the estrobolome and circulating estradiol levels. The gut-brain axis involves the relationship between the brain and the gastrointestinal system and can be attributed to the gut microbiome in relation to the enteric nervous system (ENS) and serotonin levels. Overall, the introduction of exogenous hormones into an endogenous environment alters the normal balance of both hormones and bacteria. Currently, there is a gap in knowledge regarding the link between COCs and mental health complications such as anxiety and depression, and the diversity in these complications may be related to different types of COCs, their composition, and variations in study populations. This article reviews existing evidence from animal and human studies on the role of COCs in the development of mental health issues through their impact on the gut microbiome.
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Intestinal Flora Reconfiguration via Electroacupuncture: A Strategy to Counteract Depressive-Like Symptoms in Rats.
BACKGROUND: Depression is a global health concern, and acupuncture has emerged as an effective treatment. The role of intestinal microbiota in depression remains unclear. This study, utilizing 16S rRNA high-throughput sequencing, aimed to explore the relationship between electroacupuncture (EA) and depressive behavior by examining changes in the intestinal microbiota. MATERIALS AND METHODS: Forty-eight male Sprague-Dawley rats were utilized, with 13 assigned to the normal control (NC) group. The remaining rats underwent a 28-day depression modeling process, and those exhibiting depressive symptoms were randomly divided into chronic unpredictable mild stress (CUMS) and EA groups. The EA group received 14 days of treatment. Behavioral analyses were conducted on rats from the NC, CUMS, and EA groups to assess EA's effectiveness. Additionally, 16S rRNA sequencing was performed on randomly selected rats from each group. RESULTS: By examining the behavior of 39 rats and the intestinal microbiota of 18 rats, we found that EA may alter the composition of the intestinal microbiota community structure in CUMS rats, particularly modulating the abundance of Akkermansia in a manner potentially linked to gut-brain axis regulation, including stress- and inflammation-related pathways that may influence microbial composition. CONCLUSION: The potential antidepressant impact of electroacupuncture (EA) might be linked to the modulation of Akkermansia abundance within the brain-gut axis.
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Circulating metabolites modulated by diet are associated with depression.
Metabolome reflects the interplay of genome and exposome at molecular level and thus can provide deep insights into the pathogenesis of a complex disease like major depression. To identify metabolites associated with depression we performed a metabolome-wide association analysis in 13,596 participants from five European population-based cohorts characterized for depression, and circulating metabolites using ultra high-performance liquid chromatography/tandem accurate mass spectrometry (UHPLC/MS/MS) based Metabolon platform. We tested 806 metabolites covering a wide range of biochemical processes including those involved in lipid, amino-acid, energy, carbohydrate, xenobiotic and vitamin metabolism for their association with depression. In a conservative model adjusting for life style factors and cardiovascular and antidepressant medication use we identified 8 metabolites, including 6 novel, significantly associated with depression. In individuals with depression, increased levels of retinol (vitamin A), 1-palmitoyl-2-palmitoleoyl-GPC (16:0/16:1) (lecithin) and mannitol/sorbitol and lower levels of hippurate, 4-hydroxycoumarin, 2-aminooctanoate (alpha-aminocaprylic acid), 10-undecenoate (11:1n1) (undecylenic acid), 1-linoleoyl-GPA (18:2) (lysophosphatidic acid; LPA 18:2) are observed. These metabolites are either directly food derived or are products of host and gut microbial metabolism of food-derived products. Our Mendelian randomization analysis suggests that low hippurate levels may be in the causal pathway leading towards depression. Our findings highlight putative actionable targets for depression prevention that are easily modifiable through diet interventions.
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Acupuncture Modulation of the Microbiota-Gut-Brain Axis in Major Depressive Disorder: Integrative Mechanisms, Emerging Evidence, and Future Therapeutic Perspectives.
Major depressive disorder (MDD) is a prevalent and disabling psychiatric condition. Its pathophysiology extends beyond monoamine deficiency to encompass systemic dysregulation of the gut-brain axis-a bidirectional network integrating neural, immune, endocrine, and microbial signals. Accumulating evidence indicates that MDD patients frequently exhibit gut microbiota dysbiosis, impaired intestinal mucosal barrier integrity, and systemic low-grade inflammation. These gut-derived pathological alterations may collectively contribute to the onset and progression of depression through complex interactions involving microbial metabolites, immune signaling, and neuroendocrine pathways. Although several recent reviews have addressed gut-brain axis dysfunction in depression or the therapeutic effects of acupuncture individually, a systematic synthesis integrating neuroimmune, neuroendocrine, and microbiome mechanisms within a unified framework remains lacking. This review integrates three key regulatory dimensions-neuroimmune regulation, hypothalamic-pituitary-adrenal (HPA) axis homeostasis, and gut microbiota remodeling-through which acupuncture is proposed to modulate the gut-brain axis in MDD. Acupuncture, a core modality of Traditional Chinese Medicine (TCM), offers unique advantages in intervening in this complex system due to its multi-target regulatory properties. Modern studies have linked classical TCM principles to the vagus-adrenal axis, the endocannabinoid system, the HPA axis, and the TLR4/NF-κB pathways. Specifically, preclinical evidence suggests that acupuncture may induce systemic anti-inflammatory responses, suppress NLRP3 inflammasome activation, restore HPA axis negative feedback, and repair the intestinal barrier, while also reshaping gut microbiota composition, promoting short-chain fatty acid synthesis, and regulating tryptophan metabolism. These coordinated actions may generate synergistic multi-system antidepressant effects. Clinical evidence further suggests that acupuncture combined with pharmacotherapy may outperform medication alone, although high-quality clinical trials remain limited. This review critically appraises current evidence and methodological limitations, and proposes future directions including rigorous randomized controlled trials, multi-omics integrative approaches, and microbiome-guided precision acupuncture strategies, aiming to advance individualized acupuncture treatment for MDD.
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Glutamate and depression: Reflecting a deepening knowledge of the gut and brain effects of a ubiquitous molecule.
The versatility of glutamate as the brain's foremost excitatory neurotransmitter and modulator of neurotransmission and function is considered common knowledge. Years of research have continued to uncover glutamate's effects and roles in several neurological and neuropsychiatric disorders, including depression. It had been considered that a deeper understanding of the roles of glutamate in depression might open a new door to understanding the pathological basis of the disorder, improve the approach to patient management, and lead to the development of newer drugs that may benefit more patients. This review examines our current understanding of the roles of endogenous and exogenous sources of glutamate and the glutamatergic system in the aetiology, progression and management of depression. It also examines the relationships that link the gut-brain axis, glutamate and depression; as it emphasizes how the gut-brain axis could impact depression pathogenesis and management via changes in glutamate homeostasis. Finally, we consider what the likely future of glutamate-based therapies and glutamate-based therapeutic manipulations in depression are, and if with them, we are now on the final chapter of understanding the neurochemical milieu of depressive disorders.
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An Analysis of the Intestinal Microbiome Combined with Metabolomics to Explore the Mechanism of How Jasmine Tea Improves Depression in CUMS-Treated Rats.
Recently, research has confirmed that jasmine tea may help improve the depressive symptoms that are associated with psychiatric disorders. Our team previously found that jasmine tea improved the depressive-like behavior that is induced by chronic unpredictable mild stress (CUMS) in Sprague Dawley (SD) rats. We hypothesized that the metabolic disorder component of depression may be related to the gut microbiota, which may be reflected in the metabolome in plasma. The influence of jasmine tea on gut microbiota composition and the association with depressive-related indexes were explored. Furthermore, the metabolites in plasma that are related to the gut microbiota were identified. SD rats were treated with control or CUMS and administrated jasmine tea for 8 weeks. The 16S rRNA gene amplicon sequencing was used to analyze the gut microbiota in feces samples, and untargeted metabolomics was used to analyze the metabolites in plasma. The results found that jasmine tea significantly ameliorated the depressive behavior induced by CUMS, significantly improved the neurotransmitter concentration (BDNF and 5-HT), and decreased the pro-inflammation levels (TNF-α and NF-κB). The intervention of jasmine tea also alleviated the dysbiosis caused by CUMS; increased the relative abundance of Bacteroides, Blautia, Clostridium, and Lactobacillus; and decreased Ruminococcus and Butyrivibrio in the CUMS-treated rats. Furthermore, the serum metabolites of the CUMS-treated rats were reversed after the jasmine tea intervention, i.e., 22 were up-regulated and 18 were down-regulated, which may have a close relationship with glycerophospholipid metabolism pathways, glycine serine and threonine metabolism pathways, and nicotinate and nicotinamide metabolism pathways. Finally, there were 30 genera of gut microbiota related to the depressive-related indexes, and 30 metabolites in the plasma had a strong predictive ability for depressive behavior. Potentially, our research implies that the intervention of jasmine tea can ameliorate the depression induced by CUMS via controlling the gut flora and the host's metabolism, which is an innovative approach for the prevention and management of depression.
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Integrated Inflammatory and Gut Microbial Signatures in Major Depressive Disorder: A Case-Control Study.
BACKGROUND/OBJECTIVES: Major depressive disorder (MDD) is increasingly recognized as involving inflammation and the microbiota-gut-brain axis. Few studies have simultaneously assessed systemic inflammatory markers and gut microbiota composition within the same cohort while accounting for metabolic confounders. Moreover, data from Middle Eastern and North African (MENA) populations remain limited, restricting our understanding of how diet may influence neuroimmune-microbiome interactions in depression. This study aimed to investigate associations between MDD, systemic inflammatory markers, and gut microbiota composition in Lebanese adults. To our knowledge, this is the first study of its kind in Lebanon, as well as in the MENA region. METHODS: In this cross-sectional case-control study, we examined circulating inflammatory markers and gut microbial profiles in 46 adults with DSM-5-confirmed MDD and 25 healthy controls. Plasma C-reactive protein (CRP) and interleukin-6 (IL-6) were measured, and the gut microbiota composition was characterized using 16S rRNA gene sequencing. Multivariable models were adjusted for age, sex, body mass index (BMI), Mediterranean diet adherence, and fluoxetine exposure. RESULTS: Depression status was not independently associated with CRP or IL-6 after adjustment, whereas BMI emerged as a significant determinant of systemic inflammation. At the genus level, MDD was associated with the enrichment of Dorea, Lachnoclostridium, Collinsella, Bilophila, and Klebsiella and the depletion of Christensenella, Mitsuokella, and Victivallis, independent of inflammatory biomarkers. Alpha diversity did not differ between groups, while beta diversity showed modest metric-dependent differences, primarily driven by presence/absence-based measures. CONCLUSIONS: Specific microbial taxa may contribute to gut-brain signaling pathways implicated in MDD and systemic inflammation. Further longitudinal and mechanistic studies are required to clarify causal interactions within inflammation-microbiome networks in MDD.