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The Safety and Efficacy of Microbial Ecosystem Therapeutic-2 in People With Major Depression - A Phase 2, Double-Blind, Placebo-Controlled Study: Clinical Results: Innocuité et efficacité du traitement de l'écosystème microbien (met-2) dans la dépression majeure - une étude de phase 2 à double insu contrölée par placebo : résultats cliniques.
OBJECTIVES: This study examines the safety and efficacy of a fecal transplant alternative, Microbial Ecosystem Therapeutic-2 (MET-2), in improving symptoms of depression. The primary objective of this study is to assess changes in depressive symptoms before, during, and after administration of MET-2 in comparison to placebo. Mood-related symptoms such as anxiety and anhedonia, gastrointestinal symptoms, and safety of the therapeutic were also assessed using both self-report and clinician-rated measures. METHODS: Twenty-nine participants (n = 29) experiencing a major depressive episode were recruited from the Kingston and Toronto areas. Participants orally consumed MET-2, an encapsulated microbial therapeutic containing 40 different strains of bacteria, or placebo alternative, once daily for 6 weeks with a 2-week follow-up. Participants underwent a series of clinical assessments used to measure mood, anxiety, and gastrointestinal symptoms. RESULTS: There was a significant improvement in depressive symptomology over time as determined by Montgomery-Åsberg Depression Rating Scale scores (p < 0.0001); however there was no significant difference between placebo and MET-2 groups (p = 0.338). No serious adverse events were reported. The findings of this study are the first to provide evidence for the role of oral microbial therapeutics, such as MET-2, as treatment for symptoms of depression. CONCLUSIONS: Though there are positive trends suggesting a greater improvement in depressive symptomology among the MET-2 group compared to the placebo group, a larger sample size is needed for more conclusive results. CLINICALTRIALS: gov NCT04602715.
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Beneficial psychological effects of novel psychobiotics in diabetic rats: the interaction among the gut, blood and amygdala.
Type 2 diabetes mellitus (T2DM) can lead to major complications such as psychiatric disorders which include depressive and anxiety-like behaviors. The association of the gut-brain axis in the development of such disorders, especially in T2DM, has been elucidated; however, gut dysbiosis is also reported in patients with T2DM. Hence, the regulation of the gut-brain axis, in particular, the gut-amygdala, as a vital region for the regulation of behavior is essential. Thirty-five male Wistar rats were divided into six groups. To induce T2DM, treatment groups received high-fat diet and 35 mg/kg streptozotocin. Then, supplements of Lactobacillus plantarum, inulin or their combination were administered to each group for 8 weeks. Finally, the rats were sacrificed for measurement of blood and tissue parameters after behavioral testing. The findings demonstrated the favorable effects of the psychobiotics (L. plantarum, inulin or their combination) on oxidative markers of the blood and amygdala (superoxide dismutase, glutathione peroxidase, malondialdehyde and total antioxidant capacity), as well as on concentrations of amygdala serotonin and brain-derived neurotrophic factor, in the diabetic rats. In addition, beneficial effects were observed on the elevated plus maze and forced swimming tests with no change in locomotor activity of the rats. There was a strong correlation between the blood and amygdala oxidative markers, insulin and fasting blood sugar with depressive and anxiety-like behaviors. Our results identified L. plantarum ATCC 8014 and inulin or their combination as novel psychobiotics that could improve the systemic and nervous antioxidant status and improve amygdala performance and beneficial psychotropic effects.
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A metabolic "double hit" in prefrontal gray and white matter shapes microbiota-related visual learning memory impairment in major depressive disorder.
BACKGROUND: Visual learning memory deficits are key issues in major depressive disorder (MDD), but the specific gut microbiota involved are not well understood. While gut dysbiosis and metabolic alterations in the frontolimbic region are linked to MDD, the influence of regional neurochemistry on the microbiota-cognition relationship remains unknown. METHODS: Visual learning memory was assessed in 38 MDD patients and 41 healthy controls (HC) using the Brief Visuospatial Memory Test-Revised. Gut microbiota were analyzed via 16S rRNA gene sequencing of fecal samples, and neurochemical ratios N-acetylaspartate/Creatine (NAA/Cr) and Choline/Creatine (Cho/Cr) in anterior cingulate cortex (ACC) and prefrontal white matter (PWM) were quantified using proton magnetic resonance spectroscopy. RESULTS: MDD exhibited visual learning memory deficits, elevated NAA/Cr in the right ACC, reduced NAA/Cr in the right PWM compared to HC. Ruminococcus abundance was increased in MDD and negatively correlated with visual learning memory. The relationship between Ruminococcus abundance and visual learning memory was moderated by NAA/Cr ratios in the ACC and PWM in a configuration-dependent manner. Specifically, the most pronounced negative association emerged when the ACC NAA/Cr ratio was high and the PWM NAA/Cr ratio was low. CONCLUSIONS: The study indicates that simultaneous metabolic dysregulation in gray and white matter, shown by elevated ACC NAA/Cr and decreased PWM NAA/Cr, constitutes a "double hit" that exacerbated visual learning memory impairment associated with Ruminococcus in MDD. This dual impact underscores distinct yet interconnected vulnerabilities in gray and white matter, where microbiota-cognition associations are critically shaped by the broader neurochemical environment.
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Interleukin-6 Gene Expression Changes after a 4-Week Intake of a Multispecies Probiotic in Major Depressive Disorder-Preliminary Results of the PROVIT Study.
Major depressive disorder (MDD) is a prevalent disease, in which one third of sufferers do not respond to antidepressants. Probiotics have the potential to be well-tolerated and cost-efficient treatment options. However, the molecular pathways of their effects are not fully elucidated yet. Based on previous literature, we assume that probiotics can positively influence inflammatory mechanisms. We aimed at analyzing the effects of probiotics on gene expression of inflammation genes as part of the randomized, placebo-controlled, multispecies probiotics PROVIT study in Graz, Austria. Fasting blood of 61 inpatients with MDD was collected before and after four weeks of probiotic intake or placebo. We analyzed the effects on gene expression of tumor necrosis factor (TNF), nuclear factor kappa B subunit 1 (NFKB1) and interleukin-6 (IL-6). In IL-6 we found no significant main effects for group (F(1,44) = 1.33, p = ns) nor time (F(1,44) = 0.00, p = ns), but interaction was significant (F(1,44) = 5.67, p < 0.05). The intervention group showed decreasing IL-6 gene expression levels while the placebo group showed increasing gene expression levels of IL-6. Probiotics could be a useful additional treatment in MDD, due to their anti-inflammatory effects. Results of the current study are promising, but further studies are required to investigate the beneficial effects of probiotic interventions in depressed individuals.
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Integrative Proteomics Reveals Distinct Lipid Metabolic and Gut Microbiota-Associated Antidepressant Mechanisms of Two Herbal Medicines in a Chronic Stress Model.
Depression is a prevalent and disabling mental disorder associated with increased suicide risk and impaired quality of life. Herbal medicines such as Hypericum perforatum L. (St. John's Wort [SJW]) and Chaihu Shugan San (CSGS) have been widely used to treat depressive symptoms, yet their system-level molecular mechanisms remain incompletely understood. In this study, we applied a multi-omics strategy centered on quantitative proteomics, combined with metabolomics and microbiota profiling, to investigate the antidepressant mechanisms of CSGS and SJW in a chronic unpredictable mild stress rat model. Behavioral assessments confirmed that both treatments significantly alleviated depressive-like behaviors. Proteomic analysis identified 204 differentially expressed proteins (DEPs) in the CSGS group and 473 DEPs in the SJW group. Functional enrichment analyses suggested that CSGS was more closely associated with lipid metabolism, whereas SJW was linked to broader metabolic processes. Integrative metabolomic and microbiota analyses further supported these proteomics-driven pathway distinctions, with SJW showing stronger associations with gut microbiota alterations. CSGS and SJW alleviated depressive-like behaviors through divergent yet partially overlapping molecular mechanisms. These findings highlight the utility of multi-omics approaches for elucidating system-level mechanisms of complex herbal medicines.
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Fish Oil, but Not Olive Oil, Ameliorates Depressive-Like Behavior and Gut Microbiota Dysbiosis in Rats under Chronic Mild Stress.
BACKGROUND: This study investigated the effects of fish oil and olive oil in improving dysbiosis and depressive-like symptoms. METHODS AND RESULTS: Male rats were fed normal, fish oil-rich or olive oil-rich diets for 14 weeks. Chronic mild stress (CMS) was administered from week 2. The sucrose preference test (SPT) and forced swimming test (FST) were used to determine depressive-like behavior. The SPT results revealed that the CMS, CMS with imipramine (CMS+P) treatment, and CMS with olive oil diet (CMS+O) groups exhibited significantly reduced sucrose intake from week 8, whereas the fish oil diet (CMS+F) group exhibited significantly reduced sucrose intake from week 10. The FST results showed that the immobile time of the CMS+F group was significantly less than that of the CMS-only group. Next generation sequencing (NGS) results showed CMS significantly reduced the abundance of Lactobacillus and increased that of Marvinbryantia and Ruminiclostridium_6. However, the CMS+F group showed an increase in the abundance of Eisenbergiella, Ruminococcaceae_UCG_009, and Holdemania, whereas the CMS+O group showed an increase in the abundance of Akkermansia. CONCLUSIONS: CMS stimuli altered the gut microbiome in depressed rats. Fish oil and olive oil exerted part of a prebiotic-like effect to ameliorate dysbiosis induced by CMS. However, only fish oil ameliorated depressive-like symptoms.
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6'-Sialyllactose alleviates loperamide-induced constipation and depressive-like behaviors in mice by modulating gut microbiota and short-chain fatty acids.
Constipation is a common gastrointestinal disorder, which impairs the quality of life. This study investigated the ameliorative effects of 6'-sialyllactose (6'-SL) in a loperamide-induced murine model of constipation and associated depressive-like behaviors. Constipation was induced in mice by loperamide and subsequently treated by administering 6'-SL at doses of 100 or 300 mg per kg body weight for 14 days. The ameliorative effects of 6'-SL were evaluated through defecation-related parameters, histopathological and immunohistochemical analyses of colonic and hippocampal tissues, biochemical assays, behavioral tests, gut microbiota analysis, and short-chain fatty acid (SCFA) levels. The results showed that 6'-SL alleviated loperamide-induced constipation by improving defecation-related parameters, colonic histopathology, gastrointestinal neurotransmitter levels, and AQP3 and SCF/c-Kit levels. Moreover, 6'-SL ameliorated constipation-associated depressive-like behaviors and hippocampal alterations while modulating the gut microbiota composition and increasing the SCFA levels. Spearman's correlation analysis suggested that the alleviation of constipation and depressive-like behaviors may be associated with alterations in the gut microbiota and SCFA levels upon 6'-SL intervention. These results provide a theoretical and practical basis for developing functional foods and biomedical products based on 6'-SL.
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Possible association of Bifidobacterium and Lactobacillus in the gut microbiota of patients with major depressive disorder.
BACKGROUND: Bifidobacterium and Lactobacillus in the gut have been suggested to have a beneficial effect on stress response and depressive disorder. We examined whether these bacterial counts are reduced in patients with major depressive disorder (MDD) than in healthy controls. METHOD: Bifidobacterium and Lactobacillus counts in fecal samples were estimated in 43 patients and 57 controls using bacterial rRNA-targeted reverse transcription-quantitative polymerase chain reaction RESULTS: The patients had significantly lower Bifidobacterium counts (P=0.012) and tended to have lower Lactobacillus counts (P=0.067) than the controls. Individuals whose bacterial counts below the optimal cut-off point (9.53 and 6.49log10 cells/g for Bifidobacterium and Lactobacillus, respectively) were significantly more common in the patients than in the controls for both bacteria (Bifidobacterium: odds ratio 3.23, 95% confidence interval [CI] 1.38-7.54, P=0.010; Lactobacillus: 2.57, 95% CI 1.14-5.78, P=0.027). Using the same cut-off points, we observed an association between the bacterial counts and Irritable bowel syndrome. Frequency of fermented milk consumption was associated with higher Bifidobacterium counts in the patients. LIMITATIONS: The findings should be interpreted with caution since effects of gender and diet were not fully taken into account in the analysis. CONCLUSION: Our results provide direct evidence, for the first time, that individuals with lower Bifidobacterium and/or Lactobacillus counts are more common in patients with MDD compared to controls. Our findings provide new insight into the pathophysiology of MDD and will enhance future research on the use of pro- and prebiotics in the treatment of MDD.
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An immunometabolic signature of major depressive disorder in systemic lupus erythematosus.
OBJECTIVES: Systemic lupus erythematosus (SLE) frequently affects the central nervous system, leading to neuropsychiatric SLE (NPSLE). Major depressive disorder in SLE (SLEMDD) is the most frequent manifestation of NPSLE and is believed to arise from an immune-mediated process. However, biomarkers for SLEMDD remain lacking. The aim of this study was to identify candidate immunometabolic biomarkers associated with SLEMDD. METHODS: We analysed deep flow cytometry immune phenotyping, gut microbiota profiling, and targeted mass spectrometry-based metabolomics from 99 patients from the LUPIL-2 study (NCT02955615). Biological signatures were identified using unsupervised principal component analysis and supervised decision tree classification. They were then validated in an independent cohort from the TRANSIMMUNOM study (NCT02466217). RESULTS: SLEMDD patients exhibited a distinct immune profile with decreased naïve CD4⁺ T cells and naïve regulatory T cells (Tregs), alongside increased ICOS⁺ effector memory Tregs (94% classification accuracy). Gut microbiota diversity was reduced with depletion of Akkermansia muciniphila and enrichment of Faecalibacterium prausnitzii. Metabolomic analyses revealed disruptions in kynurenine and short-chain fatty acid pathways, including decreased butyrate levels. Integrative analyses demonstrated coordinated alterations linking Treg activation, microbial metabolites, and immune pathways, distinguishing SLEMDD from SLEnon-MDD with up to 85% accuracy. CONCLUSIONS: SLEMDD is associated with an immunometabolic signature involving alterations in Treg phenotype, gut microbiota composition, and metabolic pathways. These findings provide a rationale for future immunoregulatory or microbiota-targeted therapeutic strategies in SLEMDD.
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The gut microbiota in post-stroke depression: A systematic review of microbial mechanisms and therapeutic targeting of neuroinflammation.
Post-stroke depression (PSD), a frequent and debilitating complication after stroke, severely hinders rehabilitation. Emerging evidence underscores the role of neuroinflammation and the gut microbiota in PSD pathogenesis. This review systematically elaborates the mechanisms by which gut dysbiosis contributes to PSD-related neuroinflammation via immune cell regulation (e.g., Treg/Th17 balance), microbial metabolites (e.g., SCFAs, tryptophan derivatives), and neural pathways (vagus nerve, HPA axis). A key focus is the comparative analysis of the gut microbiota in PSD against major depressive disorder (MDD) and Alzheimer's disease (AD), revealing a unique, stroke-induced microbial signature characterized by a loss of protective symbionts and a bloom of pro-inflammatory taxa. We further discuss the translational potential of microbiota-targeted interventions (e.g., probiotics, prebiotics) for PSD. By integrating clinical microbial ecology with mechanistic insights, this review synthesizes evidence suggesting that the gut microbiome may represent a promising diagnostic and therapeutic target for PSD, offering a distinct perspective from previous literature.