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Gut microbiota composition in depressive disorder: a systematic review, meta-analysis, and meta-regression.
Studies investigating gut microbiota composition in depressive disorder have yielded mixed results. The aim of our study was to compare gut microbiome between people with depressive disorder and healthy controls. We did a meta-analysis and meta-regression of studies by searching PubMed, Web of Science, Embase, Scopus, Ovid, Cochrane Library, ProQuest, and PsycINFO for articles published from database inception to March 07, 2022. Search strategies were then re-run on 12 March 2023 for an update. We undertook meta-analyses whenever values of alpha diversity and Firmicutes, Bacteroidetes (relative abundance) were available in two or more studies. A random-effects model with restricted maximum-likelihood estimator was used to synthesize the effect size (assessed by standardized mean difference [SMD]) across studies. We identified 44 studies representing 2091 patients and 2792 controls. Our study found that there were no significant differences in patients with depressive disorder on alpha diversity indices, Firmicutes and Bacteroidetes compared with healthy controls. In subgroup analyses with regional variations(east/west) as a predictor, patients who were in the West had a lower Chao1 level (SMD -0.42[-0.74 to -0.10]). Subgroup meta-analysis showed Firmicutes level was decreased in patients with depressive disorder who were medication-free (SMD -1.54[-2.36 to -0.72]), but Bacteroidetes level was increased (SMD -0.90[0.07 to 1.72]). In the meta-regression analysis, six variables cannot explain the 100% heterogeneity of the studies assessing by Chao1, Shannon index, Firmicutes, and Bacteroidetes. Depleted levels of Butyricicoccus, Coprococcus, Faecalibacterium, Fusicatenibacter, Romboutsia, and enriched levels of Eggerthella, Enterococcus, Flavonifractor, Holdemania, Streptococcus were consistently shared in depressive disorder. This systematic review and meta-analysis found that psychotropic medication and dietary habit may influence microbiota. There is reliable evidence for differences in the phylogenetic relationship in depressive disorder compared with controls, however, method of measurement and method of patient classification (symptom vs diagnosis based) may affect findings. Depressive disorder is characterized by an increase of pro-inflammatory bacteria, while anti-inflammatory butyrate-producing genera are depleted.
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Metformin reprograms tryptophan metabolism via gut microbiome-derived bile acid metabolites to ameliorate depression-Like behaviors in mice.
As an adjunct therapy, metformin enhances the efficacy of conventional antidepressant medications. However, its mode of action remains unclear. Here, metformin was found to ameliorate depression-like behaviors in mice exposed to chronic restraint stress (CRS) by normalizing the dysbiotic gut microbiome. Fecal transplants from metformin-treated mice ameliorated depressive behaviors in stressed mice. Microbiome profiling revealed that Akkermansia muciniphila (A. muciniphila), in particular, was markedly increased in the gut by metformin and that oral administration of this species alone was sufficient to reverse CRS-induced depressive behaviors and normalize aberrant stress-induced 5-hydroxytryptamine (5-HT) metabolism in the brain and gut. Untargeted metabolomic profiling further identified the bile acid metabolites taurocholate and deoxycholic acid as direct A. muciniphila-derived molecules that are, individually, sufficient to rescue the CRS-induced impaired 5-HT metabolism and depression-like behaviors. Thus, we report metformin reprograms 5-HT metabolism via microbiome-brain interactions to mitigate depressive syndromes, providing novel insights into gut microbiota-derived bile acids as potential therapeutic candidates for depressive mood disorders from bench to bedside.
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Alteration of the gut microbiome and correlated metabolism in a rat model of long-term depression.
OBJECTIVE: This study aims to investigate the composition and function of the gut microbiome in long-term depression using an 8-week chronic unpredictable mild stress (CUMS) rat model. MATERIALS AND METHODS: Animals were sacrificed after either 4 weeks or 8 weeks under CUMS to mimic long-term depression in humans. The gut microbiome was analyzed to identify potential depression-related gut microbes, and the fecal metabolome was analyzed to detect their functional metabolites. The correlations between altered gut microbes and metabolites in the long-term depression rats were explored. The crucial metabolic pathways related to long-term depression were uncovered through enrichment analysis based on these gut microbes and metabolites. RESULTS: The microbial composition of long-term depression (8-week CUMS) showed decreased species richness indices and different profiles compared with the control group and the 4-week CUMS group, characterized by disturbance of Alistipes indistinctus, Bacteroides ovatus, and Alistipes senegalensis at the species level. Additionally, long-term depression was associated with disturbances in fecal metabolomics. D-pinitol was the only increased metabolite in the 8-week CUMS group among the top 10 differential metabolites, while the top 3 decreased metabolites in the long-term depression rats included indoxyl sulfate, trimethylaminen-oxide, and 3 alpha,7 alpha-dihydroxy-12-oxocholanoic acid. The disordered fecal metabolomics in the long-term depression rats mainly involved the biosynthesis of pantothenate, CoA, valine, leucine and isoleucine. CONCLUSION: Our findings suggest that the gut microbiome may participate in the long-term development of depression, and the mechanism may be related to the regulation of gut metabolism.
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The role of the microbiota-gut-brain axis in neuropsychiatric disorders.
The microbiota-gut-brain axis is a bidirectional signaling mechanism between the gastrointestinal tract and the central nervous system. The complexity of the intestinal ecosystem is extraordinary; it comprises more than 100 trillion microbial cells that inhabit the small and large intestine, and this interaction between microbiota and intestinal epithelium can cause physiological changes in the brain and influence mood and behavior. Currently, there has been an emphasis on how such interactions affect mental health. Evidence indicates that intestinal microbiota are involved in neurological and psychiatric disorders. This review covers evidence for the influence of gut microbiota on the brain and behavior in Alzheimer disease, dementia, anxiety, autism spectrum disorder, bipolar disorder, major depressive disorder, Parkinson's disease, and schizophrenia. The primary focus is on the pathways involved in intestinal metabolites of microbial origin, including short-chain fatty acids, tryptophan metabolites, and bacterial components that can activate the host's immune system. We also list clinical evidence regarding prebiotics, probiotics, and fecal microbiota transplantation as adjuvant therapies for neuropsychiatric disorders.
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Revealing the impact of gut microbiota-derived metabolites on depression through network pharmacology.
A total of 208 metabolites and 223 targets were initially extracted from the gutMGene v1.0 database. In addition, 1,630 and 1,321 targets were identified using the Similarity Ensemble Approach and Swiss Target Prediction databases, respectively, resulting in 921 overlapping targets. By integrating data from gutMGenev1.0, 13 core targets were finally identified. A microbiota-metabolite-target-signal pathway-disease network was constructed using Cytoscape 3.9.1, revealing 15 metabolites associated with the IL-17, TLR, and PI3K-Akt signalling pathways. Among these, five metabolites exhibited favourable drug similarity and acceptable toxicological profiles. Molecular docking confirmed the stable binding of two key metabolites-succinate and phenylacetylglutamine-to their respective targets. The results showed that succinate and phenylacetylglutamine demonstrated strong binding affinities to IL-1β and GSK3B, both involved in the IL-17, TLR, and PI3K-Akt signalling pathways. IL-17 and TLR4, as important pro-inflammatory cytokines, are closely associated with the development of depression, while the PI3K/AKT signalling pathway plays a key role in its pathogenesis. The present study reveals the potential mechanisms by which gut microbiota influence MDD and provides a scientific basis and a comprehensive research framework for future investigations.
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Microbiota alterations leading to amino acid deficiency contribute to depression in children and adolescents.
BACKGROUND: Major depressive disorder (MDD) in children and adolescents is a growing global public health concern. Metabolic alterations in the microbiota-gut-brain (MGB) axis have been implicated in MDD pathophysiology, but their specific role in pediatric populations remains unclear. RESULTS: We conducted a multi-omics study on 256 MDD patients and 307 healthy controls in children and adolescents, integrating plasma metabolomics, fecal metagenomics, and resting-state functional magnetic resonance imaging (rs-fMRI) of the brain. KEGG enrichment analysis of 360 differential expressed metabolites (DEMs) indicated significant plasma amino acid (AA) metabolism deficiencies (p-value < 0.0001). We identified 58 MDD-enriched and 46 MDD-depleted strains, as well as 6 altered modules in amino acid metabolism in fecal metagenomics. Procrustes analysis revealed the association between the altered gut microbiome and circulating AA metabolism (p-value = 0.001, M2 = 0.932). Causal analyses suggested that plasma AAs might mediate the impact of altered gut microbiota on depressive and anxious symptoms. Additionally, rs-fMRI revealed that connectivity deficits in the frontal lobe are associated with depression and 22 DEMs in AA metabolism. Furthermore, transplantation of fecal microbiota from MDD patients to adolescent rats induced depressive-like behaviors and 14 amino acids deficiency in the prefrontal cortex (PFC). Moreover, the dietary lysine restriction increased depression susceptibility in adolescent rats by reducing the expression of excitatory amino acid transporters in the PFC. CONCLUSIONS: Our findings highlight that gut microbiota alterations contribute to AAs deficiency, particularly lysine, which plays a crucial role in MDD pathogenesis in children and adolescents. Targeting AA metabolism may offer novel therapeutic strategies for pediatric depression. Video Abstract.
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Links between gut microbes and depression strengthened.
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A decade of evidence linking gut microbiome dysbiosis to depression: a computational meta-analysis of mechanistic pathways: 2014-2024.
OBJECTIVES: The gut microbiome-gut-brain axis (MGBA) has been associated in the pathophysiology of depression; however, the expanding literature remains fragmented across metabolic signalling, immune-inflammatory pathways, stress physiology and dysbiosis outcomes. METHODS: Abstracts were retrieved from bibliographic databases (Lens.org, PubMed, DOAJ, Europe PMC) for studies published between 2014 and 2024 investigating associations between the gut microbiome and depression using 16S rRNA sequencing. Following text preprocessing, Latent Dirichlet Allocation (LDA) was applied to identify latent thematic topics. Topic proportions were subsequently embedded using principal component analysis (PCA), t-distributed stochastic neighbour embedding (t-SNE), and uniform manifold approximation and projection (UMAP). RESULTS: Topic modelling revealed distinct interconnected thematic domains within the gut microbiome depression literature, encompassing metabolic and short chain fatty acid pathways, immune inflammatory mechanisms, stress and hypothalamic pituitary adrenal (HPA) axis regulation, probiotic and interventional work, microbial diversity and compositional metrics, neurochemical and neuroplasticity, developmental cohorts, and sequencing- or methodology-focused research. CONCLUSIONS: Computational synthesis indicates that research on the gut microbiome depression axis is structured around multiple convergent mechanistic themes. This thematic landscape highlights dominant areas of mechanistic focus, providing a conceptual framework to guide future experimental design, mechanistic validation and translational research.
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Gut feelings: A randomised, triple-blind, placebo-controlled trial of probiotics for depressive symptoms.
BACKGROUND: Depression is the leading cause of disability worldwide; with evidence suggesting that decreased gut barrier function and inflammation are correlated with depressive symptoms. We conducted a clinical trial to determine the effect of consumption of probiotic supplements (Winclove's Ecologic® Barrier) on depressive symptoms in a sample of participants with mild to severe depression. METHOD: 71 participants were randomly allocated to either probiotic or placebo, which was, consumed daily over eight weeks. Pre- and post-intervention measures of symptoms and vulnerability markers of depression as well as gut microbiota composition were compared. Clinical trial participants were also compared on psychological variables and gut microbiota composition to a non-depressed group (n = 20). RESULTS: All clinical trial participants demonstrated improvement in symptoms, suggesting non-specific therapeutic effects associated with weekly monitoring visits. Participants in the probiotic group demonstrated a significantly greater reduction in cognitive reactivity compared with the placebo group, particularly in the mild/moderate subgroup. Probiotics did not significantly alter the microbiota of depressed individuals, however, a significant correlation was found between Ruminococcus gnavus and one depression metric. LIMITATIONS: There was a high attrition rate, which may be attributed to weekly monitoring visits. Additionally, modulation of the gut microbiota may need more specific testing to distinguish subtle changes. CONCLUSIONS: While microbiota composition was similar between all groups, probiotics did affect a psychological variable associated with susceptibility to depression. Further research is needed to investigate how probiotics can be utilised to modify mental wellbeing, and whether they can act as an adjunct to existing treatments.
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Landscapes of bacterial and metabolic signatures and their interaction in major depressive disorders.
Gut microbiome disturbances have been implicated in major depressive disorder (MDD). However, little is known about how the gut virome, microbiome, and fecal metabolome change, and how they interact in MDD. Here, using whole-genome shotgun metagenomic and untargeted metabolomic methods, we identified 3 bacteriophages, 47 bacterial species, and 50 fecal metabolites showing notable differences in abundance between MDD patients and healthy controls (HCs). Patients with MDD were mainly characterized by increased abundance of the genus Bacteroides and decreased abundance of the genera Blautia and Eubacterium These multilevel omics alterations generated a characteristic MDD coexpression network. Disturbed microbial genes and fecal metabolites were consistently mapped to amino acid (γ-aminobutyrate, phenylalanine, and tryptophan) metabolism. Furthermore, we identified a combinatorial marker panel that robustly discriminated MDD from HC individuals in both the discovery and validation sets. Our findings provide a deep insight into understanding of the roles of disturbed gut ecosystem in MDD.