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[Mechanism of Xiangshao Granules in alleviating anxiety and depression in mice based on integrated metabolomics and gut microbiota].
This study aims to investigate the mechanism through which Xiangshao Granules treat anxiety and depression using metabolomics and gut microbiota techniques, combined with animal experiments. Sixty female ICR mice were selected for the experiment and randomly divided into six groups: a control group, a model group, a low-dose Xiangshao Granules group, a medium-dose Xiangshao Granules group, a high-dose Xiangshao Granules group, and an estradiol(positive drug) group. Except for the control group, rats in other groups were induced for anxiety and depression model by ovariectomy(OVX) combined with chronic unpredictable mild stress(CUMS). After successful modeling, the mice received oral administration of Xiangshao Granules or estradiol for three weeks. Anxiety and depression behaviors in mice were evaluated using light-dark box tests, open field tests, and elevated plus-maze tests. The levels of substances closely related to anxiety and depression, such as serotonin(5-HT) and estrogen(E_2), were quantified in plasma and hippocampal tissue using enzyme-linked immunosorbent assay(ELISA). Metabolomics and 16S rDNA amplicon sequencing techniques were employed to analyze the regulatory effects of Xiangshao Granules on plasma metabolites and metabolic pathways in anxiety and depression mice, as well as their impact on the distribution of gut microbiota. Finally, the correlation between plasma metabolites and differential gut microbiota was constructed using the Spearman correlation coefficient method. Behavioral experimental results indicated that, compared to the control group, the model group exhibited significantly decreased dwell time in the light box, reduced total distance in the open field, and diminished dwell time in the open arm. In contrast, high dose of Xiangshao Granules were found to increase the dwell time in the light box and total distance in the open field. ELISA results indicated that the levels of 5-HT, gamma-aminobutyric acid(GABA), E_2 were significantly decreased, luteinizing hormone(LH), adrenocorticotropic hormone(ACTH), and corticosterone(CORT) were significantly elevated in the anxiety and depression mice, and treatment with middle, high dose of Xiangshao Granules reversed the levels of these substances. Additionally, in the anxiety and depression mouse model, the levels of follicle-stimulating hormone(FSH) were significantly increased, whereas middle, high dose of Xiangshao Granules decreased FSH levels. Metabolomics analysis revealed that Xiangshao Granules significantly changed the metabolic profile of the anxiety and depression mice, affecting central carbon metabolism, amino acid biosynthesis, and ABC transporter pathways. The results from 16S rDNA amplicon sequencing showed that Xiangshao Granules improved the relative abundance of genera such as Bacteroidia, Bacilli, Lactobacillales, and Lactobacillus. Spearman correlation analysis indicated a close association between specific differential gut microbiota and plasma differential metabolites. This study suggests that Xiangshao Granules significantly ameliorate anxiety and depression symptoms in mice by altering the levels of substances associated with these conditions, including 5-HT, GABA, E_2, LH, and ACTH. The metabolomics and gut microbiota data suggest that the therapeutic mechanism may be closely related to the regulation of amino acid biosynthesis, central carbon metabolism, and the alteration of key microbial community compositions.
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Total glycosides from stems of Cistanche tubulosa alleviate depression-like behaviors: bidirectional interaction of the phytochemicals and gut microbiota.
BACKGROUND: As the most frequently used kidney-yang tonifying herb in traditional Chinese medicine, dried succulent stems of Cistanche tubulosa (Schenk) Wight (CT) have been shown to be effective in the treatment of depression. However, the antidepressant components and their underlying mechanism remain unclear. PURPOSE: To explore the active components of CT against depression, as well as the potential mechanisms. STUDY DESIGN AND METHODS: Behavioral despair tests were used to assess the antidepressant activities of polysaccharides, oligosaccharides and different glycoside-enriched fractions separated from CT, as well as the typical gut microbiota metabolites including 3-hydroxyphenylpropionic acid (3-HPP) and hydroxytyrosol (HT). Furthermore, the effects of bioactive fractions and metabolites on chronic unpredictable mild stress (CUMS) model were explored with multiple pharmacodynamics and biochemical analyses. Changes in colonic histology and the intestinal barrier were observed by staining and immunohistochemical analysis. Gut microbial features and tryptophan-kynurenine metabolism were explored using 16S rRNA sequencing and western-blotting, respectively. RESULTS: Total glycosides (TG) dramatically alleviated depression-like behaviors compared to different separated fractions, reflecting in the synergistic effects of phenylethanoid and iridoid glycosides on the hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, severe neuro- and peripheral inflammation, and deficiencies in 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor in the hippocampus. Moreover, TG mitigated low-grade inflammation in the colon and intestinal barrier disruption, and the abundances of several bacterial genera highly correlated with the HPA axis and inflammation in CUMS rats. Consistently, the expression of indoleamine 2, 3-dioxygenase 1 (IDO1) in the colon was significantly reduced after TG administration, accompanied by the suppression of tryptophan-kynurenine metabolism. On the other hand, HT also exerted a marked antidepressant effect by ameliorating HPA axis function, pro-inflammatory cytokine release, and tryptophan-kynurenine metabolism, while it was unable to largely adjust the disordered gut microbiota in the same manner as TG. Surprisingly, superior to fluoxetine, TG and HT could further improve dysfunction of the hypothalamic-pituitary-gonadal axis and abnormal cyclic nucleotide metabolism. CONCLUSION: TG are primarily responsible for the antidepressant activity of CT; its effect might be achieved through the bidirectional interaction of the phytochemicals and gut microbiota, and reflect the advantage of CT in the treatment of depression.
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Lactococcus lactis and Bifidobacterium bifidum alleviate postmenopausal symptoms by suppressing NF-κB signaling and microbiota dysbiosis.
To understand the action mechanism of probiotics against postmenopausal symptoms, we examined the effects of Lactococcus lactis P32 (PL) and Bifidobacterium bifidum P45 (PB), which suppressed interleukin (IL)-6 and receptor activator of nuclear factor-κB (RANK) ligand (RNAKL) expression in Gardnerella vaginalis (Gv)-stimulated macrophages, on vaginitis, osteoporosis, and depression/cognitive impairment (DC) in mice with vaginally infected Gv, ovariectomy (Ov), or Ov/Gv (oG). Oral administration of PL or PB decreased Gv-induced DC-like behavior and tumor necrosis factor (TNF)-α, IL-6, RANK, and/or RANKL expression in the vagina, bone, hypothalamus, hippocampus, and colon, while Gv-suppressed bone osteoprotegerin and brain serotonin and brain-derived neurotrophic factor (BDNF) levels increased. They partially shifted vaginal and gut dysbiosis in Gv-infected mice to the gut microbiota composition in normal control mice. In mice with oG, oral administration of PL or PB decreased oG-induced DC-like behavior and TNF-α, IL-6, RANK, and/or RANKL expression in the vagina, bone, brain, and colon, while oG-suppressed bone osteoprotegerin and brain serotonin and BDNF levels increased. They also alleviated oG-induced vaginal and gut dysbiosis: they decreased Proteobacteria population. PL and PB (4:1) mix (PM) suppressed DC-like behavior in mice with Gv, Ov, or oG. PM also suppressed TNF-α, IL-6, RANK, and/or RANKL expression in the vagina, bone, colon, and brain. PM alleviated Gv-induced vaginal and gut dysbiosis: it decreased Proteobacteria population. These findings suggest that PL and PB, singly or together, can alleviate postmenopausal symptoms including vaginitis, colitis, osteoporosis, and DC by suppressing RANK/RANKL-mediated NF-κB activation and alleviating vaginal/gut microbiota dysbiosis.
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From Mind to Milk: The Influence of Psychological Factors on the Composition of Human Breast Milk.
Background/Objectives: Breast milk is a complex fluid crucial for infant development, nutrition, and immunological and neurodevelopmental support. Recent findings suggest that factors regarding mental health, such as stress, anxiety, and postpartum depression (PPD), may influence the composition of breast milk. This review aims to synthesize current knowledge regarding the relationship between a mother's mental state and the biochemical profile of human milk, focusing mainly on nutrients, hormones, immune factors, and microbiota. Methods: A systematic literature search was conducted in PubMed and the Web of Science using predefined keywords related to psychological factors and milk composition. Studies involving validated psychological assessment tools and only human subjects were included, in accordance with PRISMA guidelines. Results: Findings indicated that maternal stress and PPD are associated with alterations in breast milk composition. Elevated cortisol and changes in melatonin and prolactin levels have been observed. Immune components, such as secretory immunoglobulin A and transforming growth factor beta 2, exhibit variable responses depending on stress type and duration. Lower concentrations of docosahexaenoic acid and polyunsaturated fatty acid have been observed among mothers diagnosed with depression. Additionally, maternal psychological distress may influence infants' gut microbiota composition, potentially affecting long-term health outcomes. Conclusions: The maternal psychological state plays an essential role in shaping the composition of human breast milk. Understanding these associations highlights the need for mental health support during the postpartum period to optimize infant development. Future research should focus on the molecular mechanisms underlying these changes and potential interventions to mitigate adverse effects.
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Paroxetine alleviates ulcerative colitis in mice via restoring intestinal microbiota homeostasis and metabolism.
Ulcerative colitis (UC) is an inflammatory bowel disease and psychological factors may be one of its pathogeneses. Selective serotonin reuptake inhibitor drug such as paroxetine with an effective anti-depression ability may be a new option for UC treatment. To evaluate the therapeutic effect of paroxetine on the exacerbation of UC symptoms caused by depression, a dual model of C57BL/6 mice was established using dextran sulphate sodium and chronic unpredictable mild stress (CUMS). Behavioural experiments, H&E staining and the level of 5-hydroxytryptamine (5-HT) in the brain were used to demonstrate successful replication of the CUMS model. The levels of 5-HT, TNF-α and IL-1β in the colon and the activity of MPO in the serum were determined by ELISA kits. The levels of some gut microbiota in the faeces were measured by qPCR and faecal differential metabolites were analysed by 1H NMR. The results indicate that CUMS can exacerbate UC symptoms in mice by exacerbating inflammation, and UC+CUMS can disrupt gut microbiota and fatty acid metabolism. Paroxetine can improve the mental state of mice, reduce serum MPO activity, but increase TNF-α and IL-1β levels in the colon. In addition, paroxetine also can restore the intestinal flora of mice and improve intestinal absorption and metabolic function of amino acids and short-chain fatty acids.
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Sexual dimorphism in neurobehavioural phenotype and gut microbial composition upon long-term exposure to structural analogues of bisphenol-A.
Bisphenol S (BPS) and Bisphenol F (BPF), the analogues of the legacy endocrine disrupting chemical, Bisphenol A (BPA) are ubiquitous in the environment and present in various consumer goods, and potentially neurotoxic. Here, we studied sex-specific responses of bisphenols on behavioural phenotypes, including their association with pro-inflammatory biomarkers and altered neurotransmitters levels, and the key gut microbial abundances. Neurobehavioural changes, using standard test battery, biochemical and molecular estimations for inflammatory cytokines, neurotransmitters, and oxido-nitrosative stress markers, gene expression analysis using qRT-PCR, H&E based histological investigations, gut permeability assays and Oxford Nanopore-based 16S-rRNA metagenomics sequencing for the gut microbial abundance estimations were performed. Bisphenol(s) exposure induces anxiety and depression-like behaviours, particularly in the male mice, with heightened pro-inflammatory cytokines levels and systemic endotoxemia, altered monoamine neurotransmitters levels/turnovers and hippocampal neuronal degeneration and inflammatory responses in the brain. They also increased gut permeability and altered microbial diversity, particularly in males. Present study provides evidence for sex-specific discrepancies in neurobehavioural phenotypes and gut microbiota, which necessitate a nuanced understanding of sex-dependent responses to bisphenols. The study contributes to ongoing discussions on the multifaceted implications of bisphenols exposure and underscores the need for tailored regulatory measures to mitigate potential health risks associated with them.
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Insomnia, OSA, and Mood Disorders: The Gut Connection.
PURPOSE OF REVIEW: With the growing body of research examining the link between sleep disorders, including insomnia and obstructive sleep apnea (OSA), and the gut microbiome, this review seeks to offer a thorough overview of the most significant findings in this emerging field. RECENT FINDINGS: Current evidence suggests a complex association between imbalances in the gut microbiome, insomnia, and OSA, with potential reciprocal interactions that may influence each other. Notably, specific gut microbiome species, whether over- or under-abundant, have been associated with variation in both sleep and mood in patients diagnosed with, e.g., major depressive disorder or bipolar disorder. Further studies are needed to explore the potential of targeting the gut microbiome as a therapeutic approach for insomnia and its possible effects on mood. The variability in current scientific literature highlights the importance of establishing standardized research methodologies.
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A novel antidepressant homogeneous polysaccharide YLP-1 from Millettia pulchra ameliorates tryptophan metabolism and SCFAs through modulating gut microbiota.
The root of Millettia pulchra (YLS) has been traditionally used as a folk medicine for the treatment of depression and insomnia in the Zhuang nationality of China, and its polysaccharides have potential antidepressant effect. In this study, a novel homogeneous polysaccharide (YLP-1) was purified from the crude polysaccharides of YLS, and it is mainly composed of glucose, arabinose and mannose with molar ratio of 87.25%, 10.77%, and 1.98%, respectively. YLP-1 is a novel α-glucan with the backbone of 1,4-Glcp and branched at C6 of 1,4,6-Glcp to combine 1,4-Manp and 1,5-Araf. The microstructure of YLP-1 displayed a uniform ellipsoidal-like chain morphology and dispersed uniformly in solution. YLP-1 effectively ameliorated depression-like ethological behaviors and restored the decreased catecholamine levels in chronic variable stress (CVS)-induced depression rats. Additionally, it significantly improved the disturbance of gut microbiota induced by CVS stimuli, particularly affecting bacteria that produce short-chain fatty acids (SCFAs), such as bacteria species Lactobacillus spp.. In vitro fermentation study further confirmed that YLP-1 intake could promote SCFAs production by Lactobacillus spp. YLP-1 also mitigated the disruption of tryptophan metabolites in urine and serum. These findings provide evidences for the further development of YLP-1 as a macromolecular antidepressant drug.
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Dietary advanced glycation end products induced anxiety- and depression-like behaviors in female C57BL/6 mice and the ameliorative effects of quercetin.
Quercetin is a flavonoid bioactive compound with potential anti-depression effect. Dietary advanced glycation end-products (AGEs) might be critically associated with depression. We aimed to explore whether quercetin ameliorates dietary AGEs-induced anxiety and depression-like behaviors in female mice, with a focus on hypothalamic-pituitary-adrenal (HPA) axis regulation and gut microbiota composition. Mice were divided into three groups: control, dietary AGEs, and AGEs plus quercetin. Dietary AGEs induced anxiety and depression-like behavioral effects, reduced brain-derived neurotrophic factor, P-CREB (phosphorylated cyclic adenosine monophosphate response element-binding protein), post-synaptic density protein-95, doublecortin, and synaptophysin protein expression. Dietary AGEs induced HPA axis overactivation has been confirmed by decreased hippocampal glucocorticoid receptor, phospho-glucocorticoid receptor Ser211, and arginase-1, and elevated FK506 binding protein 51, NOD-like receptor thermal protein domain associated protein 3, caspase-1, and p65 protein expression. Dietary AGEs resulted in gut microbiota disorder and correlation analysis revealed significant associations between Proteobacteria, the [Eubacterium] coprostanoligenes group, Klebsiella and Lachnospiraceae_NK4A136_group with behavioral parameters. Quercetin intervention improved dietary AGEs associated anxiety and depression-like behavioral effects via restoring HPA axis and gut microbiota.
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Lactobacillus plantarum and Bifidobacterium longum Alleviate High-Fat Diet-Induced Obesity and Depression/Cognitive Impairment-like Behavior in Mice by Upregulating AMPK Activation and Downregulating Adipogenesis and Gut Dysbiosis.
Background/Objective: Long-term intake of a high-fat diet (HFD) leads to obesity and gut dysbiosis. AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism. Herein, we investigated the impacts of Lactobacillus (Lactiplantibacillus) plantarum P111 and Bifidobacterium longum P121, which suppressed dexamethasone-induced adipogenesis in 3T3 L1 cells and increased lipopolysaccharide-suppressed AMPK activation in HepG2 cells, on HFD-induced obesity, liver steatosis, gut inflammation and dysbiosis, and depression/cognitive impairment (DCi)-like behavior in mice. Methods: Obesity is induced in mice by feeding with HFD. Biomarker levels were measured using immunoblotting, enzyme-linked immunosorbent assay, and immunofluorescence staining. Results: Orally administered P111, P121, or their mix LpBl decreased HFD-induced body weight gain, epididymal fat pad weight, and triglyceride (TG), total cholesterol (TC), and lipopolysaccharide levels in the blood. Additionally, they downregulated HFD-increased NF-κB activation and TNF-α expression in the liver and colon, while HFD-decreased AMPK activation was upregulated. They also suppressed HFD-induced DCi-like behavior and hippocampal NF-κB activation, NF-κB-positive cell population, and IL-1β and TNF-α levels, while increasing the hippocampal BDNF-positive cell population and BDNF level. The combination of P111 and P122 (LpBl) also improved body weight gain, liver steatosis, and DCi-like behavior. LpBl also mitigated HFD-induced gut dysbiosis: it decreased Desulfovibrionaceae, Helicobacteriaceae, Coriobacteriaceae, and Streptococcaceae populations and lipopolysaccharide production, which were positively correlated with TNF-α expression; and increased Akkermansiaceae, Bifidobacteriaceae, and Prevotellaceae populations, which were positively correlated with the BDNF expression. Conclusions: P111 and/or P121 downregulated adipogenesis, gut dysbiosis, and NF-κB activation and upregulatde AMPK activation, leading to the alleviation of obesity, liver steatosis, and DCi.