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Dietary Polyphenols as Prospective Natural-Compound Depression Treatment from the Perspective of Intestinal Microbiota Regulation.
The broad beneficial effects of dietary polyphenols on human health have been confirmed. Current studies have shown that dietary polyphenols are important for maintaining the homeostasis of the intestinal microenvironment. Moreover, the corresponding metabolites of dietary polyphenols can effectively regulate intestinal micro-ecology and promote human health. Although the pathogenesis of depression has not been fully studied, it has been demonstrated that dysfunction of the microbiota-gut-brain axis may be its main pathological basis. This review discusses the interaction between dietary polyphenols and intestinal microbiota to allow us to better assess the potential preventive effects of dietary polyphenols on depression by modulating the host gut microbiota.
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Modified Xiaoyaosan rescues depression-like behavior via remodeling gut microbiota and leucine metabolism.
BACKGROUND: Social avoidance is a hallmark symptom of depression. Although Modified Xiaoyaosan (MXYS) has been reported to attenuate this behavior, the underlying mechanisms remain poorly understood. PURPOSE: This study aimed to investigate the mechanisms by which MXYS alleviates social avoidance, with particular emphasis on gut microbiota composition and leucine metabolism. METHODS: A chronic social defeat stress (CSDS) mouse model was established to evaluate the antidepressant effects of MXYS. Fecal samples were subjected to LC-MS-based untargeted metabolomics and 16S rRNA sequencing to characterize alterations in gut microbiota and metabolites. Fecal microbiota transplantation (FMT) was conducted to verify the contribution of gut microbes to MXYS's antidepressant effects. Furthermore, targeted GC-MS, LC-MS/MS, and Western blotting analyses were employed to elucidate the mechanisms underlying leucine reduction. Finally, exogenous leucine supplementation was administered to determine its potential antidepressant efficacy. RESULTS: MXYS treatment significantly ameliorated CSDS-induced social avoidance and other depression-like behaviors. Integrated metabolomic and 16S rRNA analyses identified leucine metabolism as a potential therapeutic target. MXYS modulated gut microbial composition and functional pathways, particularly those involved in leucine metabolism. FMT experiments confirmed the essential role of gut microbiota in mediating the antidepressant effects of MXYS. Targeted metabolic profiling and protein expression analyses revealed that enhanced microbial degradation of leucine contributed to its systemic reduction. Moreover, leucine supplementation robustly reversed depressive-like behaviors and attenuated hippocampal oxidative stress. CONCLUSION: MXYS alleviates social avoidance in CSDS mice by modulating gut microbiota-mediated leucine degradation, thereby restoring systemic leucine levels and improving hippocampal oxidative stress.
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Early-Life Milk αS1-Casein Allergy Induces the Activation of Astrocytes in Mice and Leads to Stress Vulnerability in Adulthood.
In recent years, the incidence of food allergies in children has been increasing annually, significantly affecting the quality of life for patients and their families. It has long been suspected that childhood allergies might potentially lead to behavioral and psychological issues in adulthood, but the specific connection remains unclear. In this study, we established a model of young mice allergic to milk αS1-casein, conducted behavioral tests, and employed transcriptomics, immunohistochemistry, Golgi staining, and fecal microbiota transplantation to explore the link between early life allergies and adult psychological problems. The results showed that early life milk protein allergy significantly increased intestinal epithelial permeability in mice, leading to the translocation of gut microbiota metabolites. This process subsequently activated astrocyte lysosomes via SLC15a3, making astrocytes more susceptible. This susceptibility caused mice with early life milk protein allergy to have more activated astrocytes and excessive dendritic spine phagocytosis (normal group: 5.4 ± 1.26 spines/10 μm, allergy group: 3.2 ± 0.92 spines/10 μm) under acute stress in adulthood, leading to anxiety and depressive behaviors.
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Treatment response of venlafaxine induced alterations of gut microbiota and metabolites in a mouse model of depression.
Antidepressants remain the first-line treatment for depression. However, the factors influencing medication response are still unclear. Accumulating evidence implicates an association between alterations in gut microbiota and antidepressant response. Therefore, the aim of this study is to investigate the role of the gut microbiota-brain axis in the treatment response of venlafaxine. After chronic social defeat stress and venlafaxine treatment, mice were divided into responders and non-responders groups. We compared the composition of gut microbiota using 16 S ribosomal RNA sequencing. Meanwhile, we quantified metabolomic alterations in serum and hippocampus, as well as hippocampal neurotransmitter levels using liquid chromatography-mass spectrometry. We found that the abundances of 29 amplicon sequence variants (ASVs) were significantly altered between the responders and non-responders groups. These ASVs belonged to 8 different families, particularly Muribaculaceae. Additionally, we identified 38 and 39 differential metabolites in serum and hippocampus between the responders and non-responders groups, respectively. Lipid, amino acid, and purine metabolisms were enriched in both serum and hippocampus. In hippocampus, the concentrations of tryptophan, phenylalanine, gamma-aminobutyric acid, glutamic acid, and glutamine were increased, while the level of succinic acid was decreased in the responders group, compared with the non-responders group. Our findings suggest that the gut microbiota may play a role in the antidepressant effect of venlafaxine by modulating metabolic processes in the central and peripheral tissues. This provides a novel microbial and metabolic framework for understanding the impact of the gut microbiota-brain axis on antidepressant response.
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Prebiotic inulin alleviates anxiety and depression-like behavior in alcohol withdrawal mice by modulating the gut microbiota and 5-HT metabolism.
BACKGROUND: Alcohol dependence (AD) is a common psychiatric disorder, often accompanied by anxiety and depression. These comorbidities are linked to disturbances in serotonin (5-HT) metabolism and gut microbiota dysbiosis. Clinical studies suggest that inulin, a prebiotic, can alleviate anxiety and depression in AD patients by affecting the gut microbiota, although the mechanisms remain unclear. PURPOSE: The purpose of this study is to investigate the potential mechanisms by which inulin, a prebiotic, improves anxiety and depression-like behaviors in AD withdrawal mice. This research is based on the drug and food homology and intestinal treatment of encephalopathy, with the goal of developing new clinical strategies for AD treatment. STUDY DESIGN: For this purpose, fecal samples from AD patients were analyzed to identify microorganisms associated with AD. An AD withdrawal mouse model was created, with inulin as the intervention and fluvoxamine maleate as the control. Techniques such as 16S microbiome sequencing and UPLC-TQMS-targeted metabolomics were used to assess gut microbiota, short-chain fatty acids (SCFAs) levels, and 5-HT metabolism. METHODS: The AD withdrawal model was built using the "Drinking-in-the-dark" protocol over 6 weeks. Inulin (2 g/kg/day) and fluvoxamine maleate (30 mg/kg/day) were administered for 4 weeks. The open field test, forced swim test, and tail suspension test were used to evaluate anxiety and depression-like behaviors in mice. ELISA and qRT-PCR assessed 5-HT metabolism in the colon, blood, and prefrontal cortex, while 16S microbiome sequencing analyzed changes in gut microbiota and UPLC-TQMS examined SCFAs levels. Immunohistochemistry was used to study intestinal barrier integrity. RESULTS: AD patients showed reduced SCFA-producing bacteria such as Faecalibacterium and Roseburia. In mice, AD withdrawal led to anxiety and depression-like behaviors, disrupted 5-HT metabolism, and gut microbiota dysbiosis. Inulin supplementation alleviated these behaviors, increased 5-HT and 5-hydroxytryptophan (5-HTP) levels, upregulated colonic tryptophan hydroxylase 1 (TPH1) expression, and promoted the growth of beneficial bacteria such as Faecalibacterium and Roseburia, while also increasing SCFAs levels. CONCLUSION: Inulin increases the abundance of Faecalibacterium and Roseburia, enhances SCFAs production, and regulates 5-HT metabolism, improving anxiety and depression-like behaviors in AD withdrawal mice. These findings suggest that inulin may serve as a nutritional intervention for mental health in AD patients by targeting the microbiome-gut-brain axis.
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Gastrodia elata Blume water extract modulates neurotransmitters and alters the gut microbiota in a mild social defeat stress-induced depression mouse model.
Gastrodia elata Blume has multiple bioactive functions, such as antioxidant and antidepressant activities, immune modulation, neuroplasticity, and neuroprotection. We previously found that the water extract of G. elata exerts antidepressant-like effects in unpredictable chronic mild stress models and animals exposed to the forced swimming test. We aimed to investigate the mechanisms by which the water extract of G. elata protects against subchronic- and mild-social defeat-stress-induced dysbiosis. After a 10-day subchronic and mild-social-defeat-stress program, oral treatment with the water extract of G. elata (500 mg/kg bw) resulted in reversal of depression-like behavior. In addition, monoamine analyses showed that the water extract of G. elata normalized the 5-hydroxyindoleacetic acid:5-HT ratio in the prefrontal cortex and colon and reduced the defeat-stress-induced kynurenine:tryptophan ratio in the colon. After the 10-day subchronic and mild social-defeat-stress program, the water extract of G. elata altered the intestinal microbiome by increasing Actinobacteria levels, modulating intestinal inflammation, and shifting the relative abundances of multiple bacterial groups in the gut. Our results suggest that the water extract of G. elata exhibits a potent antidepressant-like effect via the regulation of monoaminergic neurotransmission and alteration of gut microbiota composition and function, and that it may be an effective prevention for depression.
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Gut Microbiota in Alzheimer's Disease, Depression, and Type 2 Diabetes Mellitus: The Role of Oxidative Stress.
Gut microbiota consists of over 100 trillion microorganisms including at least 1000 different species of bacteria and is crucially involved in physiological and pathophysiological processes occurring in the host. An imbalanced gastrointestinal ecosystem (dysbiosis) seems to be a contributor to the development and maintenance of several diseases, such as Alzheimer's disease, depression, and type 2 diabetes mellitus. Interestingly, the three disorders are frequently associated as demonstrated by the high comorbidity rates. In this review, we introduce gut microbiota and its role in both normal and pathological processes; then, we discuss the importance of the gut-brain axis as well as the role of oxidative stress and inflammation as mediators of the pathological processes in which dysbiosis is involved. Specific sections pertain the role of the altered gut microbiota in the pathogenesis of Alzheimer's disease, depression, and type 2 diabetes mellitus. The therapeutic implications of microbiota manipulation are briefly discussed. Finally, a conclusion comments on the possible role of dysbiosis as a common pathogenetic contributor (via oxidative stress and inflammation) shared by the three disorders.
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Bifidobacterium adolescentis as a key member of the human gut microbiota in the production of GABA.
Gamma aminobutyric acid (GABA) is the principal inhibitory neurotransmitter playing a key role in anxiety and depression disorders in mammals. Recent studies revealed that members of the gut microbiota are able to produce GABA modulating the gut-brain axis response. Among members of the human gut microbiota, bifidobacteria are well known to establish many metabolic and physiologic interactions with the host. In this study, we performed genome analyses of more than 1,000 bifidobacterial strains publicly available revealing that Bifidobacterium adolescentis taxon might represent a model GABA producer in human gastrointestinal tract. Moreover, the in silico screening of human/animal metagenomic datasets showed an intriguing association/correlation between B. adolescentis load and mental disorders such as depression and anxiety. Interestingly, in vitro screening of 82 B. adolescentis strains allowed identifying two high GABA producers, i.e. B. adolescentis PRL2019 and B. adolescentis HD17T2H, which were employed in an in vivo trial in rats. Feeding Groningen rats with a supplementation of B. adolescentis strains, confirmed the ability of these microorganisms to stimulate the in vivo production of GABA highlighting their potential implication in gut-brain axis interactions.
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Review of research progress on intestinal microbiota based on metabolism and inflammation for depression.
Depression is a prevalent mental illness, affecting a significant portion of the global population. Recent research has highlighted the crucial role of the gut microbiota in both metabolic and central nervous health. By reviewing literature from various databases, including Pubmed, Science Direct, Web of Science, and Scopus, spanning the years 2005-2023, a comprehensive search was conducted using keywords such as "Depression" and "Gut Microbiota". The gut microbiota acts as a "second brain" in humans and can communicate bidirectionally with the brain through the Brain-gut-microbiota axis pathway. This communication involves the immune and nervous systems. However, there are challenges in detecting and treating depression effectively. To address these limitations, researchers have been exploring the relationship between gut microbiota and depression. Studies have shown that gut microbial metabolites, such as lipopolysaccharides and short-chain fatty acids, can induce pro-inflammatory cytokines that contribute to neuroinflammation and increase the risk of depression. The kynurenine pathway, triggered by gut microbial metabolites, has also been associated with neuroinflammation. Thus, investigating these microbial metabolites can provide insights into depression treatment. This review focuses on analyzing the connection between gut microbial metabolites, inflammation, and depression. It explores novel mechanisms contributing to depression, specifically focusing on the mediation of inflammation through the release of pro-inflammatory cytokines. The objective is to provide valuable insights into the mechanisms underlying depression and to propose potential treatments.
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Gut microbiota drives dietary lignans to improve perimenopausal depression via activating hippocampal ERβ/GluN2A/PSD95 pathway.
Dietary lignans (Diet-LIG) are a class of estrogenic plant polyphenols whose improve potential for perimenopausal depression (PMD), a condition driven by estrogen deficiency, remains unexplored. This study aims to investigate whether Diet-LIG intake can alleviate perimenopausal depressive symptoms and to explore the underlying mechanisms. The randomized controlled trial conducted in the study revealed that one-month supplementation significantly alleviated depressive and anxiety symptoms and elevated serum estradiol in perimenopausal women. This clinical benefit was associated with increased fecal levels of gut bacterial metabolites (enterolactone and enterodiol) the enzyme β-glucuronidase, and the enrichment of specific bacteria, notably Bacteroides ovatus. Animal studies showed that Diet-LIG upregulated ERβ protein expression in the hippocampal tissue of PMD mice. KEGG analysis of hippocampal proteomics showed that differentially expressed proteins between the Diet-LIG intervention and PMD groups were primarily enriched in the glutamatergic synapse pathway. Golgi staining and Western blot analysis confirmed that Diet-LIG supplementation improved neuronal plasticity, with significantly increased expression of GluN2A and PSD95 proteins. Humanized fecal microbiota transplantation experiments and in vitro cell interventions with Bacteroides ovatus monoculture medium revealed that the antidepressant effects of Diet-LIG are not directly mediated solely by the modulated gut microbiota, but instead rely on the bioactivity of metabolites produced through gut microbiota-driven conversion. In vitro validation experiments, the knockdown of ERβ in HT22 cells significantly suppressed GluN2A and PSD95 expression and blocked their induction by Diet-LIG metabolites. In conclusion, gut microbiota drives Diet-LIG to activate hippocampal ERβ, which regulates the GluN2A/PSD95 pathway and enhances hippocampal neuronal plasticity, thereby ameliorating perimenopausal depressive symptoms. (Chinese Clinical Trial Registry [ChiCTR], ID Number: ChiCTR2400082537.).