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The Impact of Akkermansia muciniphila on Mouse Models of Depression, Anxiety, and Stress: A Systematic Review and Meta-Analysis.
BACKGROUND: Akkermansia muciniphila (A. muciniphila), a bacterial species within the human gut microbiome, has shown beneficial effects on host health. Emerging research suggests that A. muciniphila also influences neurobehavioral domains through the microbiota-gut-brain axis. This meta-analysis evaluates A. muciniphila's impact on depression, anxiety, and stress in mouse models. METHODS: We conducted a systematic search of PubMed, Science Direct, Embase, and Web of Science databases up to March 2024, identifying 15 eligible studies. RESULTS: Supplementation with A. muciniphila, its outer membrane protein (Amuc_1100), and extracellular vesicles (EVs) alleviated anxiety, depressive-like behaviors, and enhanced memory in mice. Compared to controls, intervention groups exhibited reduced anxiety-like behaviors, including increased travel distance in the open-field test (OFT) and more time spent in the lightbox during the light-dark box (LDB) test and open arms in the elevated plus maze (EPM). Depression-like symptoms were reduced, with lower immobility time in the tail suspension and forced swim tests. Memory function also improved, and learning time was reduced in the Y-maze and Barnes circular maze tests. Serotonin levels increased significantly in the serum and hippocampus, while corticosterone levels decreased, though not significantly. The intervention reduced hippocampal and serum inflammatory markers (TNFα, IL1β, IL6) and altered gut microbiome composition, increasing Akkermansia, Roseburia, Caldicoprobacter, and Lachnospiraceae. CONCLUSION: This meta-analysis provides evidence supporting the health-promoting effects of A. muciniphila, one of the next-generation probiotics, in alleviating neuropsychiatric disorders. Given the high prevalence and clinical significance of depression, anxiety, and stress, further investigation into the therapeutic utility of A. muciniphila is warranted.
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On inflammatory hypothesis of depression: what is the role of IL-6 in the middle of the chaos?
Many patients with major depressive disorder (MDD) are reported to have higher levels of multiple inflammatory cytokines including interleukin 6 (IL-6). Recent studies both pre-clinical and clinical have advocated for the functional role of IL-6 in development of MDD and suggested a great potential for targeting this cytokine to open new avenues in pharmacotherapy of depression. The purpose of the present narrative review was to provide an integrated account of how IL-6 may contribute to development of depression. All peer-reviewed journal articles published before July 2020 for each area discussed were searched by WOS, PubMed, MEDLINE, Scopus, Google Scholar, for original research, review articles, and book chapters. Publications between 1980 and July 2020 were included. Alterations in IL-6 levels, both within the periphery and the brain, most probably contribute to depression symptomatology in numerous ways. As IL-6 acts on multiple differing target tissues throughout the body, dysregulation of this particular cytokine can precipitate a multitude of events relevant to depression and blocking its effects can prevent further escalation of inflammatory responses, and potentially pave the way for opening new avenues in diagnosis, treatment, and prevention of this debilitating disorder.
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Characteristics of the gut microbiota in bipolar depressive disorder patients with distinct weight.
BACKGROUND: Preliminary studies have indicated metabolic dysfunction and gut dysbiosis in patients with bipolar disorder (BD). In this study, we aimed to clarify the impact of the gut microbial composition and function on metabolic dysfunction in BD patients with an acute depressive episode. METHODS: Fresh fecal samples were provided from 58 patients with BD depression, including 29 with normal weight (NW) and 29 with overweight/obesity (OW), and 31 healthy controls (HCs). The hypervariable region of 16 S rRNA gene (V3-V4) sequencing was performed using IonS5TMXL platform to evaluate the bacterial communities. Differences of microbial community and correlation to clinical parameters across different groups were analyzed. RESULTS: Compared to NW and HCs, the OW group showed a decreased tendency in alpha diversity index. Beta diversity was markedly different among these groups (PERMANOVA: R2 = 0.034, p = 0.01) and was higher in patients versus HCs. A total number of 24 taxa displayed significantly different abundance among OW, NW, and HCs. At the family level, the abundance of three taxa was remarkably increased in NW, one in OW, and one in HCs. At the genus level, five taxa were enriched in OW, eight in NW, and two in HCs. The relative abundance of the genera Megamonas was positively associated with BMI, while Eggerthella was negatively correlated with BMI. Functional prediction analysis revealed the metabolism of cofactors and vitamins and amino acid were highly enriched in OW compared to HCs. In addition, microbial functions involved in "lipid metabolism" were depleted while the "fructose and mannose metabolism" was enriched in OW compared to NW group. CONCLUSIONS: Specific bacterial taxa involved in pathways regulating the lipid, energy, and amino acid metabolisms may underlie the weight concerns in depressed BD patients. Potential targeting gut microbial therapy is provided for overweight/obesity patients with BD, which still need further studies in the future.
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Nutritional considerations in major depressive disorder: current evidence and functional testing for clinical practice.
Depression is a multifaceted condition with diverse underlying causes. Several contributing and inter-related factors such as genetic, nutritional, neurological, physiological, gut-brain-axis, metabolic and psychological stress factors play a role in the pathophysiology of depression. This review aims to highlight the role that nutritional factors play in the aetiology of depression. Secondly, we discuss the biomedical and functional pathology tests which measure these factors, and the current evidence supporting their use. Lastly, we make recommendations on how practitioners can incorporate the latest evidence-based research findings into clinical practice. This review highlights that diet and nutrition greatly affect the pathophysiology of depression. Nutrients influence gene expression, with folate and vitamin B12 playing vital roles in methylation reactions and homocysteine regulation. Nutrients are also involved in the tryptophan/kynurenine pathway and the expression of brain-derived neurotrophic factor (BDNF). Additionally, diet influences the hypothalamic-pituitary-adrenal (HPA) response and the composition and diversity of the gut microbiome, both of which have been implicated in depression. A comprehensive dietary assessment, combined with appropriate evaluation of biochemistry and blood pathology, may help uncover contributing factors to depressive symptoms. By employing such an approach, a more targeted and personalised treatment strategy can be devised, ultimately leading to improved patient outcomes.
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Chronic restraint stress affects the diurnal rhythms of gut microbial composition and metabolism in a mouse model of depression.
BACKGROUND: Depression is a common mental disorder accompanied by gut microbiota dysbiosis, which disturbs the metabolism of the host. While diurnal oscillation of the intestinal microbiota is involved in regulating host metabolism, the characteristics of the intestinal microbial circadian rhythm in depression remain unknown. Our aim was to investigate the microbial circadian oscillation signature and related metabolic pathways in a mouse model with depression-like behaviours. METHODS: Chronic restraint stress (CRS) was used to induce depressive-like behaviours in C57BL/6J mice. The open field test (OFT) and forced swimming test (FST) were used to evaluate anxiety- and depressive-like behaviours in the control and CRS groups. Afterwards, faecal samples from the two groups were collected every four hours from ZT2 (9:00 am) to ZT22 (5:00 am). Faecal 16 S rRNA gene sequencing and metabolomics analysis were performed, and the microbial circadian rhythm was analysed via the MetaCycle package in R/RStudio. RESULTS: CRS mice exhibited depressive-like behaviours after 4 weeks of restriction. Alpha- and beta-diversity analyses revealed that the microbial composition in control and CRS mice oscillated throughout the day. The circadian rhythm analyses revealed that at the phylum level, Bacteroidota, Firmicutes, Cyanobacteria and Patescibacteria showed circadian rhythmicity in the CRS group. At the genus level, Dubosiella and Romboutsia showed circadian rhythmicity in the control group, and Dubosiella abundance was correlated with tryptophan and galactose metabolism. In the CRS group, Bacteroides, Parabacteroides, and Rikenellaceae_RC9_gut_group showed circadian rhythmicity; among these genera, Parabacteroides was related to tryptophan metabolism, axon regeneration, phenylalanine metabolism and tyrosine metabolism. CONCLUSION: Our data highlight the importance of observing the diurnal oscillation of the microbiome in host with depressive-like states. Rhythmicity in the microbiome may affect the host by regulating distinct metabolic pathways during the light and dark phases. A better combination of microbiota composition and oscillation would help to offer novel insight into key genera and their potential effects on depression.
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Gut microbiota regulates chronic ethanol exposure-induced depressive-like behavior through hippocampal NLRP3-mediated neuroinflammation.
Chronic ethanol exposure (CEE), which can lead to neuroinflammation, is an increasing risk factor for depression disorder, but the underlying mechanism is not clear. Recent observations have revealed the associations among psychiatric disorders, ethanol exposure and alterations of the gut microbiota. Here, we found that CEE induced depressive-like behavior, which could be alleviated by probiotics and transferred from donor to recipient mice by fecal microbiota transplantation (FMT). Neuroinflammation and the activation of the NLRP3 inflammasome were also observed in recipient mice. The downregulation of NLRP3 in the hippocampus mitigated CEE-induced depressive-like behavior and neuroinflammation but had no significant effect on FMT recipient mice. Moreover, elevated serum inflammatory factors in recipient mice showed a significant mediation effect between the gut microbiota and depressive-like behavior. Together, our study findings indicate that the gut microbiota contributes to both hippocampal NLRP3-mediated neuroinflammation and depressive-like behavior induced by CEE, which may open avenues for potential interventions against CEE-associated psychiatric disorders.
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Neuroimmunomodulation in Major Depressive Disorder: Focus on Caspase 1, Inducible Nitric Oxide Synthase, and Interferon-Gamma.
Major depressive disorder (MDD) is one of the leading causes of disability worldwide, and its incidence is expected to increase. Despite tremendous efforts to understand its underlying biological mechanisms, MDD pathophysiology remains elusive and pharmacotherapy outcomes are still far from ideal. Low-grade chronic inflammation seems to play a key role in mediating the interface between psychological stress, depressive symptomatology, altered intestinal microbiology, and MDD onset. We review the available pre-clinical and clinical evidence of an involvement of pro-inflammatory pathways in the pathogenesis, treatment, and remission of MDD. We focus on caspase 1, inducible nitric oxide synthase, and interferon gamma, three inflammatory systems dysregulated in MDD. Treatment strategies aiming at targeting such pathways alone or in combination with classical therapies could prove valuable in MDD. Further studies are needed to assess the safety and efficacy of immune modulation in MDD and other psychiatric disorders with neuroinflammatory components.
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Prophylactic effects of Tibetan goat kefir on depression-like behaviors in chronic unpredictable stress model through the gut-brain axis.
BACKGROUND: Depression is a common psychological disorder, and traditional therapeutic drugs often result in side effects such as emesis, dry mouth, headache, dysentery and constipation. Probiotics and goat milk have garnered widespread attention for their ability to modulate immune function and regulate the endocrine system, and for their anti-inflammatory effects. In this work, the effects of Tibetan goat kefir on the behavior, immune status, neuroendocrine response and gut microbiological composition of chronic unpredictable mild stress (CUMS) mouse models were evaluated. RESULTS: The results indicated that Tibetan kefir goat milk significantly alleviated behavioral despair in mice. Furthermore, the results demonstrated that Tibetan kefir goat milk mitigated the inflammatory response in the mice and moderated the hyperactivity of the hypothalamic-pituitary-adrenal axis and the expression of brain-derived neurotrophic factor. Meanwhile, chronic stress-induced gut microbial abnormalities were restored. In addition, the correlation between gut microbiota and nervous system was evaluated. CONCLUSION: These results explained the potential mechanism of Tibetan kefir in the antidepressant effect on the CUMS model and enriched diets for depressed patients. © 2024 Society of Chemical Industry.
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Anti-depressive effects of Xiaoyaosan, Shugan and Jianpi herbal treatments: Role on the gut microbiome of CUMS rats.
BACKGROUND: Xiaoyaosan (XYS), a classic traditional Chinese medicine (TCM) prescription that contained eight Chinese herbs, has been used for treating depression for thousands of years. Yet, the underlying mechanisms are still unclear, which need to be investigated from various perspectives. Disassembling a prescription is one of the effective approaches to study the effects and the mechanisms of TCM prescriptions. By disassembling the prescription, we can find effective combinations of individual herbs to simplify the scale of a given prescription. Accordingly, herein, XYS was disassembled into Shugan and Jianpi groups. PURPOSE: This study aimed to explore the anti-depressive effects of XYS and its disassembled groups on the digestive system functions and the cecal microbiota of rats. METHODS: XYS was divided into two efficacy groups, i.e., the Shugan (SG) and the Jianpi (JP) groups. A depression model was applied by using the chronic unpredictable mild stress (CUMS) method. Various classic behavioral tests were performed to assess the anti-depressive effects of the XYS, the SG, and the JP. Afterward, the effects of the three groups on the digestive system functions and the cecum microbiota of depression rats were evaluated. On top of this, correlation analyses between behavioral and digestive system function indexes and cecum microbiota were conducted. RESULTS: The XYS, the SG, and the JP had significant callback effects on depressive behaviors and gastrointestinal dysfunctions of CUMS rats. The compositions of the gut bacterial community were variable among the five groups. The community composition of the SG was the most similar to that of NC, followed by the XYS and the JP. At phylum, family, and genus levels, 31 potential microbial biomarkers associated with CUMS were identified. Twenty biomarkers were significantly reversed by the SG while 16 and 11 biomarkers were reversed by the XYS and the JP, respectively. The results of degrees of regulatory effects showed that the SG had the highest efficacy index (EI) than the XYS and the JP. CONCLUSION: Regarding the regulation of cecal microbiota of depression rats, the SG treatment was better than XYS and JP. Therefore, SG could be used individually for the clinical treatment of depression, especially in patients with gastrointestinal and gut microbiota disorders.
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Feasibility and acceptability of 8-week oral tributyrin supplementation as add on to antidepressant medication in patients with depression: a study protocol paper for a pilot, randomised controlled trial.
BACKGROUND: Major depressive disorder (MDD) is a severe mental health condition that profoundly affects both psychological and physical well-being. Growing evidence indicates that targeting the gut-brain axis could present new therapeutic opportunities for MDD, given the role of gut microbiota and their metabolites in its pathophysiology. One promising approach involves supplementation with butyrate, a short-chain fatty acid that has demonstrated antidepressant potential in preclinical models of depression. However, clinical research exploring the effects of butyrate supplementation in individuals with MDD remains lacking. METHODS: This study is a double-blind, parallel, 1:1 randomised placebo-controlled trial. The primary aim of this pilot study is to assess the feasibility and acceptability of an 8-week oral supplementation with tributyrin, a triglyceride form of butyrate (4 g/day), added to usual treatment with antidepressant medication in 24 patients with mild-to-severe MDD aged 18-65 years. Secondary outcomes include changes in depressive symptoms, assessed weekly throughout the supplementation period and at 16 weeks post-supplementation during follow-up, as well as changes in anhedonia and affect, measured multiple times per day via a smartphone application throughout the supplementation period. Additional outcomes include changes in gastrointestinal symptoms, changes in faecal microbiome, metabolites in blood and faeces, inflammation, epigenetic markers, stress and intestinal permeability. ETHICS AND DISSEMINATION: The study has been approved by the Medical Research Ethics Committee of the Amsterdam University Medical Centre, the Netherlands. DISCUSSION: Should the pilot demonstrate feasibility and acceptability, a larger-scale study will be warranted to evaluate the efficacy of tributyrin supplementation in alleviating depressive symptoms. This pilot will provide valuable insights to guide sample size calculations and refine study design for subsequent trials. Ultimately, this research could lead to novel adjunctive treatments for MDD targeting gut-brain signalling, offering new therapeutic avenues for patients with MDD. TRIAL REGISTRATION NUMBER: This trial has been registered in the International Clinical Trials Registry Platform (registry number: NL-OMON57116).