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Intestinal γδ T17-IL-17A signaling disrupts hippocampal mitophagy in stress-induced depression and is restored by arketamine.
Chronic stress precipitates depression, yet how gut-immune-brain interactions translate stress into mood pathology remains unclear. We tested the hypothesis that stress-primed small intestinal γδ T cells drive hippocampal mitochondrial dysfunction and depression-like behavior via interleukin-17A (IL-1A). In mice exposed to chronic restraint stress (CRS), we combined behavioral assays (open-field, sucrose-preference, tail-suspension, forced-swim), 16S rRNA profiling, fecal microbiota transplantation, Kaede photoconversion, conditional CD8α deletion in γδ T cells, hippocampal IL-17A overexpression, rapamycin treatment, and administration of the antidepressant arketamine. CRS increased gut and brain permeability, induced gut-microbiota dysbiosis, and promoted migration of small intestinal CD8α⁺ γδ T17 cells to the meninges and brain; γδ T cells were the predominant IL-17A source in the brain. Kaede tracing confirmed an intestinal origin, and CRS-associated microbiota alone transferred γδ T cell trafficking and depression-like behavior to recipients. In the hippocampus, CRS elevated IL-17A and impaired PINK1/Parkin-mediated mitophagy (decreased PINK1, Parkin, Beclin-1, and LC3B-II/I; increased p62), reduced ATP, and produced mitochondrial and synaptic ultrastructural deficits. IL-17A overexpression further worsened mitophagy and behavior, whereas rapamycin restored both. Conditional deletion of CD8α in γδ T cells reduced brain γδ T17 infiltration, lowered hippocampal IL-17A, rescued mitophagy and synapses, and improved behavior. Arketamine normalized dysbiosis and barrier markers, curtailed γδ T cell trafficking, decreased hippocampal IL-17A, restored mitophagy, and alleviated depression-like behavior in both sexes. These findings delineate a stress-responsive microbiota-γδ T cell-IL-17A pathway that compromises hippocampal mitophagy and identify arketamine as a candidate modulator of this axis, nominating mitophagy and γδ T cell trafficking as translational targets.
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The Intestinal Microbiota in Acute Anorexia Nervosa and During Renourishment: Relationship to Depression, Anxiety, and Eating Disorder Psychopathology.
OBJECTIVE: The relevance of the microbe-gut-brain axis to psychopathology is of interest in anorexia nervosa (AN), as the intestinal microbiota plays a critical role in metabolic function and weight regulation. METHODS: We characterized the composition and diversity of the intestinal microbiota in AN, using stool samples collected at inpatient admission (T1; n = 16) and discharge (T2; n = 10). At T1, participants completed the Beck Depression and Anxiety Inventories and the Eating Disorder Examination-Questionnaire. Patients with AN were compared with healthy individuals who participated in a previous study (healthy comparison group; HCG). Genomic DNA was isolated from stool samples, and bacterial composition was characterized by 454 pyrosequencing of the 16S rRNA gene. Sequencing results were processed by the Quantitative Insights Into Microbial Ecology pipeline. We compared T1 versus T2 samples, samples from both points were compared with HCG (n = 12), and associations between psychopathology and T1 samples were explored. RESULTS: In patients with AN, significant changes emerged between T1 and T2 in taxa abundance and beta (between-sample) diversity. Patients with AN had significantly lower alpha (within-sample) diversity than did HCG at both T1 (p = .0001) and T2 (p = .016), and differences in taxa abundance were found between AN patients and HCG. Levels of depression, anxiety, and eating disorder psychopathology at T1 were associated with composition and diversity of the intestinal microbiota. CONCLUSIONS: We provide evidence of an intestinal dysbiosis in AN and an association between mood and the enteric microbiota in this patient population. Future directions include mechanistic investigations of the microbe-gut-brain axis in animal models and association of microbial measures with metabolic changes and recovery indices.
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Preventive effects of GABA-producing postbiotics derived from Levilactobacillus brevis against chronic sleep deprivation-induced gut-brain axis dysfunction, neuroinflammation, and behavioral impairments in mice.
Chronic sleep deprivation (CSD) is increasingly recognized as a contributor to gut dysbiosis, systemic inflammation, and neurobehavioral impairments via the gut-brain axis. γ-Aminobutyric acid (GABA)-producing postbiotics, derived from microbial fermentation, offer potential in mitigating such dysfunctions. This study investigates the effects of GABA-producing postbiotics produced by Levilactobacillus brevis on CSD-induced gut and brain disturbances in mice. Male C57BL/6 mice were subjected to 30 days of sleep fragmentation and treated with low (250 mg/kg) or high (500 mg/kg) doses of postbiotics. Behavioral tests revealed that GABA-producing postbiotics significantly alleviated anxiety- and depression-like behaviors. Postbiotic treatment restored intestinal tight junction protein expression (ZO-1, Claudin-1), increased glutathione peroxidase activity, and reduced serum lipopolysaccharide and TNF-α levels, indicating improved intestinal barrier function and attenuated systemic inflammation. Postbiotic treatment promote the growth of beneficial genera such as Ruminococcus and Akkermansia, while also elevating fecal propanoic acid concentrations. In the brain, postbiotics upregulated blood-brain barrier (BBB) associated genes and reduced neuroinflammatory gene expression. Correlation analysis highlighted microbial signatures linked to short-chain fatty acids, intestinal tight junction proteins, serum LPS and TNF-α levels, as well as hypothalamic inflammatory, BBB gene expressions and anxiety. These findings suggest that GABA-producing postbiotics ameliorate CSD-induced gut-brain axis disruption by modulating the microbiota, restoring barrier functions, and suppressing systemic and neuroinflammation. This study supports the potential application of GABA-producing postbiotics as a dietary strategy to mitigate sleep loss-related physiological and behavioral impairments.
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OVA-Induced Food Allergy Leads to Neurobehavioral Changes in Mice and the Potential Role of Gut Microbiota and Metabolites Dysbiosis.
The neurobehavioral changes in food allergy mice have not been comprehensively studied, and the mechanism underlying them remains unclear. Our study aims to fully investigate neurobehavioral changes in OVA (ovalbumin)-sensitized food allergy mice and explore the potential mechanism via the gut microbiota-brain axis. We established the food allergy mouse (C57BL/6J male) model with OVA, evaluating the anaphylactic symptoms and the levels of Th2 signature cytokine and allergy-related antibodies in serum. Using behavioral tests, we measured anxiety, depression, social behavior, repetitive behavior, attention, and spatial memory in control and OVA mice. In addition, we analyzed the prefrontal cortex for measuring inflammation-related indicators and gathered serum for untargeted metabolomics analysis and feces for 16S rDNA sequencing. OVA mice exhibited anaphylactic symptoms and significantly elevated serum IgE and Th2 signature cytokine levels. In addition to anxiety-like, depression-like, and repetitive behaviors, OVA mice also displayed less social interest and damaged attention. TNF-α, IL-1β, and IL-6 levels and the activation of microglia in the prefrontal cortex of OVA mice were significantly increased, which might explain the neuronal damage. Using multi-omics technology, amino acid metabolism disruption, particularly carboxylic acids and derivatives, was observed in OVA mice, which was remarkably correlated with the altered abundance of gut microbiota related to food allergy. Behaviors in OVA-induced food allergy mice were extensively impaired. The disruption of amino acid metabolism associated with gut microbiota dysbiosis in OVA mice might play a pivotal role in impairing neural immune homeostasis and neuronal damage, which could be responsible for behavioral abnormalities.
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Acute effect of a Mediterranean-style dietary pattern (MDP) on mood, anxiety and cognition in UK adults with mild to moderate anxiety and depression: the MediMood randomised controlled trial protocol.
INTRODUCTION: Psychological disorders including depression and anxiety are significant public health concerns. A Mediterranean-style dietary pattern (MDP) has been associated with improved mental well-being in observational studies. Evidence of the acute (defined as postprandial to 1 week) effects of an MDP on brain function, mood, cognition and important modulators, including sleep and the gut microbiota is limited. The current intervention aims to examine whether an MDP, compared with a Western diet (WD), improves mood, cognition and anxiety symptoms, postprandially, at 24-hour and after 5 days in adults with mild to moderate anxiety and depression. METHODS AND ANALYSIS: Twenty-five UK adults (aged 18 or over) with mild to moderate anxiety and/or depression and low adherence to an MDP were recruited to a cross-over randomised controlled trial. Each participant undergoes a 5 day MDP and a 5 day WD in a randomised order with all meals provided. The co-primary outcomes are mood and anxiety, with secondary outcomes including cognitive function, brain perfusion (as assessed by MRI), sleep quality, blood pressure, plasma glucose, insulin, lipids, C-reactive protein, cortisol, brain-derived neurotrophic factor, gut microbiota speciation and microbial metabolites including short chain fatty acids. A linear mixed model and/or paired analysis will be used to compare the effects of treatments over time. ETHICS AND DISSEMINATION: The study has received a favourable ethics opinion from the National Health Service London Queen Square Research Ethics Committee (22/LO/0796). The results will be disseminated through scientific journals and conferences. TRIAL REGISTRATION NUMBER: NCT05927376.
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Effect of dietary live microbe intake on the prevalence and mortality risks of depression and suicidal ideation in adults: Evidence from a nationwide population-based study.
BACKGROUND: Gut microbial dysbiosis has been implicated in the pathogenesis of depression. Dietary interventions offer promising microbial-targeted therapeutics for depression. However, limited evidence exists regarding the associations between dietary live microbe intake and the prevalence of depression, as well as its impact on mortality risks. METHODS: This study included 28,133 participants from the U.S. National Health and Nutrition Examination Survey (2005-2018), and ascertained their underlying causes of death. Weighted logistic regression was utilized to assess the relationships between live microbe intake and risks of depression and suicidal ideation. Independent and joint associations between live microbe and mortality outcomes were evaluated using multivariable Cox regression and Kaplan-Meier survival curves to calculate relative risks. RESULTS: In the fully adjusted model, participants with high dietary live microbe intake had a significantly lower prevalence of depression (OR = 0.727, 95%CI: 0.627,0.844) and suicidal ideation (OR = 0.778, 95%CI: 0.648,0.935) than those with low intake. The multivariable-adjusted HRs for individuals in the G1 were 1.217 (95%CI, 1.081, 1.370) for all-cause mortality and 1.307 (95%CI, 1.029,1.661) for cardiovascular disease mortality, compared to participants in the G3. Kaplan-Meier survival analysis revealed that cumulative hazard of cardiovascular mortality was progressively lower among participants with depression in the G3 than those without depression. CONCLUSIONS: Higher live microbe intake was associated with a lower prevalence of depression and suicidal ideation, and was linked to significantly decreased risks of all-cause and cardiovascular mortality. Further larger prospective studies are essential to verify the health effects of live microbes, and personalized dietary recommendations are necessary.
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From association to causality: mechanistic pathways linking the gut microbiome to psychiatric disorders.
The microbiota-gut-brain axis (MGBA) has emerged as a key framework for understanding how peripheral biological systems influence brain function and behaviour. However, despite extensive associative evidence linking gut microbiome to psychiatric disorders, robust causal and mechanistic insights remain limited. This review critically evaluates current evidence to determine whether microbiome alterations contribute to psychiatric pathophysiology and inform therapeutic strategies. We outline methodological frameworks for causal inference, highlighting the limitations of cross-sectional designs and the need for convergent evidence from longitudinal studies, experimental models, and human genetic approaches. We then synthesize mechanistic pathways linking the microbiota to brain function, including immune signaling, neuroendocrine regulation via the hypothalamic-pituitary-adrenal (HPA) axis, neural communication through vagal and enteric pathways, and intestinal and blood-brain barrier (BBB) integrity. Across these systems, microbial metabolites and immune mediators emerge as key mediators, although direct causal mechanisms in humans remain incompletely established. Disorder-specific evaluation across major depressive disorder (MDD), anxiety disorders, bipolar disorder (BD), schizophrenia (SCZ), and post-traumatic stress disorder (PTSD) reveals heterogeneous but converging evidence for microbiome involvement. Although preclinical and interventional studies support biological plausibility, human evidence remains constrained by confounding, variability, and limited mechanistic validation. Translational strategies, including psychobiotics, dietary interventions, fecal microbiota transplantation (FMT), and microbiome-based biomarkers, show promise but remain methodologically limited. Overall, the gut microbiome represents a biologically plausible and modifiable contributor to psychiatric disorders. Advancing toward clinical application will require integrative, longitudinal, and mechanism-driven research to enable precision psychiatry grounded in causal evidence.
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Involvement of the gut-brain axis in vascular depression via tryptophan metabolism: A benefit of short chain fatty acids.
Cerebral hemodynamic dysfunction and hypoperfusion have been found to underlie vascular depression, but whether the gut-brain axis is involved remains unknown. In this study, a rat model of bilateral common carotid artery occlusion (BCCAO) was adopted to mimic chronic cerebral hypoperfusion. A reduced sucrose preference ratio, increased immobility time in the tail suspension test and forced swim test, and compromised gut homeostasis were found. A promoted conversion of tryptophan (Trp) into kynurenine (Kyn) instead of 5-hydroxytryptamine (5-HT) was observed in the hippocampus and gut of BCCAO rats. Meanwhile, 16S ribosomal RNA gene sequencing suggested a compromised profile of the gut SCFA-producing microbiome, with a decreased serum level of SCFAs revealed by targeted metabolomics analysis. With SCFA supplementation, BCCAO rats exhibited ameliorated depressive-like behaviors and improved gut dysbiosis, compared with the salt-matched BCCAO group. Enzyme-linked immunosorbent assays and quantitative RT-PCR suggested that SCFA supplementation suppressed the conversion of Trp to Kyn and rescued the reduction in 5-HT levels in the hippocampus and gut. In addition to inhibiting the upregulation of inflammatory cytokines, SCFA supplementation ameliorated the activated oxidative stress and reduced the number of microglia and the expression of its proinflammatory markers in the hippocampus post BCCAO. In conclusion, our data suggested the participation of the gut-brain axis in vascular depression, shedding light on the neuroprotective potential of treatment with gut-derived SCFAs.
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The Use of Nutritional Psychiatry in the Treatment of a Patient With Treatment-resistant Depression: A Biopsychosocial Case Report.
This case study describes a 30-year-old patient with recurrent depressive disorder and pharmacological treatment resistance. After 2 courses of electroconvulsive therapy without significant improvement, the illness was classified as treatment-refractory. A comprehensive nutrient analysis and dietary history identified malnutrition, nutrient deficiencies, and gastrointestinal issues. By supplementing the treatment-as-usual approach with personalized nutritional and nutrient therapy, a significant reduction in depressive symptoms was achieved, and the pharmacological medication could be reduced. This case suggests that targeted nutritional and nutrient interventions may help enhance the effectiveness of pharmacological treatment and support mental health by promoting metabolic processes.
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Estrogenic Effect of Probiotics on Anxiety and Depression: A Narrative Review.
Anxiety and depression are mental disorders with significant global impact, and are especially prominent in women during times of hormonal fluctuations. The microbiota-gut-brain axis (MGB axis) has emerged as a crucial pathway in the pathogenesis of these disorders, as it directly influences the production of neurotransmitters such as serotonin (5-HT), gamma-aminobutyric acid (GABA) and dopamine (DA). In addition, they have shown estrogenic effects through enzymes such as β-glucuronidase, which modulate hormone metabolism and consequently mood. A comprehensive search of recent preclinical studies has found that probiotic intake in female rats led to significant improvements in anxiety- and depression-related behaviors. Similarly, clinical trials in certain populations, particularly women with hormonal imbalances during menopause or premenstrual syndrome, have shown promising results. However, there are still significant problems, such as the individual variability of responses and the need for controlled long-term studies. The development of specific probiotics for hormonal modulation and the implementation of personalized approaches integrating omics and neuroimaging technologies to optimize therapeutic interventions in the field of mental health are promising. Accordingly, a comprehensive search was conducted in scientific databases such as PubMed, ScienceDirect, Scopus and Web of Science. Preclinical studies investigating the estrogenic effects of different probiotic strains in animal models and in controlled clinical trials during chronic treatment were selected, excluding those studies that did not provide access to full text.