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Comparative analysis of gut microbiota and fecal metabolome features among multiple depressive animal models.
BACKGROUNDS: Emerging studies reported that gut microbiota and fecal metabolites take part in major depressive disorder (MDD) pathogenesis. However, the conclusions based on a single depressive animal model seem inconsistent or even controversial. METHODS: Multiple depression rat models, including chronic unpredictable mild stress, chronic restraint stress, social defeat, and learned helplessness, were used. Then, the 16S ribosomal RNA gene sequencing and liquid chromatography-mass spectrometry analysis determined the alteration of gut microbiota and fecal metabolites. RESULTS: The results of sucrose preference test and forced swimming test suggested that each model successfully established depression-like behavior. A total of 179 discriminative amplicon sequence variants (ASVs) were identified among four models. The overall discriminative ASVs mainly belonged to the family Lachnospiraceae, Muribaculaceae, and Oscillospiraceae. Moreover, the fecal metabolomic analysis identified 468 differential expressed metabolites. Among all the differential metabolites, 11 specific pathways significantly altered, which were mainly belonged to lipid and amino acid metabolism. Finally, co-occurrence network analysis suggested that target differential metabolites were associated with discriminative ASVs mainly assigned to family taxon Lachnospiraceae, Muribaculaceae, and Oscillospiraceae. LIMITATIONS: The heterogeneity of MDD in humans cannot be totally imitated by animal models. CONCLUSIONS: In multiple depression models, the alterations of family Lachnospiraceae, Muribaculaceae, and Oscillospiraceae with the dysbiosis of lipid and amino acid metabolism were gut microbiota and fecal metabolome features. The findings of our research may help us to have a comprehensive understanding of gut microbiota and fecal metabolome in depression.
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Alterations in Gut Microbiota-Brain Axis in Major Depressive Disorder as Identified by Machine Learning.
Major depressive disorder (MDD) is a complex mental health condition whose causes may extend beyond purely biological explanations and are increasingly understood within wider ecological and social frameworks. Emerging research on the human gut-brain axis with the help of statistical and artificial intelligence tools aims to elucidate the links between the gut microbiota, diet, environment, and MDD. In this study, we analyzed data from the American Gut Project (AGP), including 361 control and 23 MDD samples, to find potential biomarkers associated with MDD. While alpha and beta diversity analyses revealed no significant differences except for age, multiple differential abundance tools and machine learning (ML) models (Random Forest and XGBoost), whose results were analyzed using Shapley Additive Explanations values, consistently detected a decrease in Bifidobacterium adolescentis and increases in Odoribacter, Ruminococcus, and Adlercreutzia among MDD samples. These four organisms influence inflammation, neurotransmitter balance, gut permeability, and other pathways associated with depression and thus can be recognized as potential biomarkers for MDD. This study highlights the promise of ML to decode the gut-brain axis as a first step in biomarker discovery, thus providing new possibilities for a personalized treatment approach and an improvement in diagnostic tools for MDD.
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Exploring role of Bacillus coagulans BCP92™ (MTCC 25460) in modulation of depressive-like behavior: Unraveling microbiome gut-brain axis.
BACKGROUND: Recent findings indicate that gut microbiota can significantly impact cognitive health. In this study, we explored the effects of Bacillus coagulans (Heyndrickxia coagulans) BCP92™ on depression-like behaviors using maternal separation and the chronic unpredictable mild stress model. METHODS: Depression in rats was induced through maternal separation followed by chronic unpredictable mild stress. B. coagulans BCP92™ was administered to the rats at a dose of 2 billion CFU for six weeks. Depression-like behaviors were assessed using the sucrose preference test, forced swim test, elevated plus maze test, and open-field test. After the treatment period, the animals were sacrificed, and brain, intestine, and fecal samples were collected for biochemical, molecular, and histopathological analyses. RESULTS: B coagulans BCP92™ mitigated depressive behaviors as evidenced by improvements in the behavior assessments. The treatment related changes in levels of neurotransmitters such as noradrenaline, dopamine, serotonin, and brain-derived neurotrophic factor while reducing pro-inflammatory markers like C-reactive protein, TNF-α, and IL-1β in the brain. Additionally, B. coagulans BCP92™ administration restored levels of BDNF, doublecortin, GFAP, and zona occludens in the brain, suggesting a neuroprotective effect. An increased ratio of Firmicutes to Bacteroidetes, along with higher levels of short-chain fatty acids in fecal samples, was observed. Histopathological analysis indicated that both brain and intestinal structures were preserved, demonstrating the maintenance of their integrity. CONCLUSION: The findings from this study suggest that B. coagulans BCP92™ exerts antidepressant effects by modulating the gut-brain axis, thereby remodeling gut microbiota and promoting neurobehavioral health.
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Different roles of microbiota and genetics in the prediction of treatment response in major depressive disorder.
The roles of gut microbiota and susceptibility genes in patients with major depression disorder (MDD) are not well understood. Examining the microbiome and host genetics might be helpful for clinical decision-making. Patients with MDD were recruited in this study and subsequently treated for eight weeks. We identified the differences between the population with a response after two weeks and those with a response after eight weeks. The factors that were significantly correlated with efficacy were used to predict the treatment response. The differences in the importance of microbiota and genetics in prediction were analyzed. Our study identified rs58010457 as a potentially key locus affecting the treatment effect. Different microbiota and enriched pathways might play different roles in the response after two and eight weeks. We found that the area under the curve (AUC) value was greater than 0.8 for both random forest models. The contribution of different components to the AUC was evaluated by removing genetic information, microbiota abundance, and pathway data. The gut microbiome was an important predictor of the response after eight weeks, while genetics was an important predictor of the response after two weeks. These results suggested a dynamic effect of interaction among genetics and gut microbes on treatment. Furthermore, these results provide new guidance for clinical decisions: in cases of inadequate treatment effects after two weeks, the composition of the intestinal flora can be improved by diet therapy, which could ultimately affect the efficacy.
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A shift toward proteolytic gut fermentation links systemic inflammation to clinical phenotypes in major depressive disorder.
BACKGROUND: The "Neuro-Immune-Metabolic-Oxidative Stress" (NIMETOX) theory identified systemic dysregulation in Major Depressive Disorder (MDD), yet the precise gut-derived metabolic triggers initiating this cascade remain elusive. This study investigated the interplay between fecal short-chain fatty acids (SCFAs), systemic immune activation, and clinical phenotypes to identify a potential "gut-immune biotype" for MDD. METHODS: Fecal SCFA profiles and serum immune-inflammatory markers were quantified in 102 patients with MDD and 38 matched healthy controls. A multistage statistical approach was employed: binary logistic regression and linear discriminant analysis were utilized to evaluate the joint discriminative performance of the biomarkers, while multivariable regression models were applied to examine associations with clinical phenotypes, including the overall severity of depression (OSOD), physiosomatic symptoms, and recurrence of illness (ROI). RESULTS: MDD patients exhibited a significant depletion of protective straight-chain SCFAs (acetate, propionate, butyrate) and an elevation in branched-chain SCFAs (BSCFAs), indicating a pathological shift from saccharolytic to proteolytic fermentation. This metabolic shift correlated with elevated acute phase inflammatory index (API) and epidermal growth factor (EGF). A multidimensional model combining BSCFAs, acetate, API, and EGF discriminated MDD from controls with adequate accuracy (AUC = 0.871). Furthermore, elevated BSCFAs and decreased protective SCFAs were strongly associated with higher OSOD, more severe physiosomatic symptoms, and increased ROI. Notably, 5-HT1A agent use remained associated with higher BSCFA levels after adjustment for MDD status. CONCLUSION: MDD is characterized by a distinct "gut-immune biotype" tightly linked to toxic proteolytic gut fermentation. This metabolic-immune fingerprint provides a systems biology explanation for MDD and highlights the need for microbiome-targeted interventions in precision psychiatry.
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Modulation of high fat diet-induced microbiome changes, but not behaviour, by minocycline.
An emerging novel therapeutic agent for major depressive disorder, minocycline, has the potential to influence both gut microbiome and inflammatory status. The present study showed that chronic high fat diet feeding led to changes in both behaviour and the gut microbiome in male mice, without an overt inflammatory response. The diet-induced behavioural changes were characterised as increased immobility in the forced swim test and changes in locomotor activities in the open field test. Minocycline significantly altered the gut microbiome, rendering a community distinctly different to both untreated healthy and diet-affected states. In contrast, minocycline did not reverse high fat diet-induced changes in behaviour.
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Supplementation with Lactobacillus helveticus NS8 alleviated behavioral, neural, endocrine, and microbiota abnormalities in an endogenous rat model of depression.
INTRODUCTION: Major depressive disorder is a condition involving microbiota-gut-brain axis dysfunction. Increasing research aims to improve depression through gut microbiota regulation, including interventions such as probiotics, prebiotics, and fecal microbiota transplants. However, most research focuses on exogenous depression induced by chronic stress or drugs, with less attention given to endogenous depression. Additionally, research on gut mycobiota in depression is significantly less than that on gut bacteria. METHODS: In the present study, Wistar-Kyoto rats were used as an endogenous depression and treatment-resistant depression model, while Wistar rats served as controls. Differences between the two rat strains in behavior, gut bacteria, gut mycobiota, nervous system, endocrine system, immune system, and gut barrier were evaluated. Additionally, the effects of Lactobacillus helveticus NS8 supplementation were investigated. RESULTS: Wistar-Kyoto rats demonstrated increased depressive-like behaviors in the forced swimming test, reduced sucrose preference in the sucrose preference test, and decreased locomotor activity in the open field test. They also exhibited abnormal gut bacteria and mycobiota, characterized by higher bacterial α-diversity but lower fungal α-diversity, along with increased butyrate, L-tyrosine, and L-phenylalanine biosynthesis from bacteria. Furthermore, these rats showed dysfunction in the microbiota-gut-brain axis, evidenced by a hypo-serotonergic system, hyper-noradrenergic system, defective hypothalamic-pituitary-adrenal axis, compromised gut barrier integrity, heightened serum inflammation, and diminished gut immunity. A 1-month L. helveticus NS8 intervention increased the fecal abundance of L. helveticus; reduced the abundance of Bilophila and Debaryomycetaceae; decreased immobility time but increased climbing time in the forced swimming test; reduced hippocampal corticotropin-releasing hormone levels; decreased hypothalamic norepinephrine levels; increased hippocampal glucocorticoid receptor, brain-derived neurotrophic factor dopamine, and 5-hydroxyindoleacetic acid content; and improved the gut microbiota, serotonergic, and noradrenergic system. CONCLUSION: The depressive phenotype of Wistar-Kyoto rats is not only attributed to their genetic context but also closely related to their gut microbiota. Abnormal gut microbiota and a dysfunctional microbiota-gut-brain axis play important roles in endogenous depression, just as they do in exogenous depression. Supplementing with probiotics such as L. helveticus NS8 is likely a promising approach to improve endogenous depression and treatment-resistant depression.
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Increased Serum Immunoglobulin Responses to Gut Commensal Gram-Negative Bacteria in Unipolar Major Depression and Bipolar Disorder Type 1, Especially When Melancholia Is Present.
Major depressive disorder (MDD) is accompanied by higher serum IgM/IgA responses to LPS of Gram-negative bacteria, suggesting increased bacterial translocation and gut dysbiosis while the latter may occur in bipolar disorder (BD). There are differences between MDD and BD type 1 (BP1) and 2 (BP2) in nitro-oxidative stress biomarkers associated with leaky gut. This study examines serum IgM/IgA responses directed to LPS of 6 Gram-negative bacteria as well as IgG responses to oxidized LDL (oxLDL) in 29 BP1, 37 BP2, 44 MDD, and 30 healthy individuals. Increased IgM/IgA responses to Pseudomonas aeruginosa significantly discriminated patients with affective disorders (MDD plus BD) from controls. BP1 patients showed higher IgM responses to Morganella morganii as compared with MDD and BP2 patients. Patients with melancholia showed higher IgA responses to Citrobacter koseri as compared to controls and non-melancholic depression. The total score on the Hamilton Depression Rating Scale was significantly associated with IgA responses to C. koseri. IgG to oxLDL was significantly associated with increased bacterial translocation. In conclusion, MDD, BP1, and BP2 are accompanied by an immune response due to the increased load of LPS while these aberrations in the gut-brain axis are most pronounced in BP1 and melancholia. Activated oxidative stress pathways and autoimmune responses to oxidative specific epitopes in mood disorders may be driven by a breakdown in gut paracellular, transcellular, and/or vascular pathways. If replicated, drugs that protect the integrity of the gut barrier may offer novel therapeutic opportunities for BP1 and MDD.
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Bacterial Butyrate in Parkinson's Disease Is Linked to Epigenetic Changes and Depressive Symptoms.
BACKGROUND: The gut microbiome and its metabolites can impact brain health and are altered in Parkinson's disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. OBJECTIVES: Here, we investigate whether the changes in the gut microbiome and associated metabolites are related to PD symptoms and epigenetic markers in leucocytes and neurons. METHODS: Stool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified genome-wide DNA methylation by targeted bisulfite sequencing. RESULTS: We show that lower fecal butyrate and reduced counts of genera Roseburia, Romboutsia, and Prevotella are related to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA regions in PD overlap with those altered in gastrointestinal (GI), autoimmune, and psychiatric diseases. CONCLUSIONS: Decreased levels of bacterially produced butyrate are related to epigenetic changes in leucocytes and neurons from PD patients and to the severity of their depressive symptoms. PD shares common butyrate-dependent epigenetic changes with certain GI and psychiatric disorders, which could be relevant for their epidemiological relation. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Mice lacking Casp1, Ifngr and Nos2 genes exhibit altered depressive- and anxiety-like behaviour, and gut microbiome composition.
Converging evidence supports the involvement of pro-inflammatory pathways and the gut microbiome in major depressive disorder (MDD). Pre-clinical and clinical studies suggest that decreasing pro-inflammatory signaling may provide clinical benefit in MDD. In this study, we used the chronic unpredictable stress (CUS) paradigm to assess whether mice lacking the pro-inflammatory caspase 1, interferon gamma-receptor, and nitric oxide synthase (Casp1, Ifngr, Nos2)-/- present altered depressive- and anxiety-like behaviour at baseline and in response to CUS. In comparison to wild-type (wt) mice, (Casp1, Ifngr, Nos2)-/- mice displayed decreased depressive- and anxiety-like behaviour, and increased hedonic-like behaviour and locomotor activity at baseline, and resistance to developing anhedonic-like behaviour and a heightened emotional state following stress. Plasma levels of ACTH and CORT did not differ between the triple knockout and wt mice following stress. The faecal microbiome of (Casp1, Ifngr, Nos2)-/- mice differed from that of wt mice at baseline and displayed reduced changes in response to chronic stress. Our results demonstrate that simultaneous deficit in multiple pro-inflammatory pathways has antidepressant-like effects at baseline, and confers resilience to stress-induced anhedonic-like behaviour. Moreover, accompanying changes in the gut microbiome composition suggest that CASP1, IFNGR and NOS2 play a role in maintaining microbiome homeostasis.