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Flavonoids from Seabuckthorn (Hippophae rhamnoides L.) restore CUMS-induced depressive disorder and regulate the gut microbiota in mice.
Seabuckthorn (Hippophae rhamnoides L.), which is enriched with flavonoids, including isorhamnetin, quercetin and kaempferol, is a representative example of "medicine food homology" targeting several diseases. Major depressive disorders seriously threaten mental health worldwide and may even lead to death. Chronic unpredictable mild stress (CUMS)-induced depressive-like symptoms in mice are usually considered as the highest similarity to the situation in humans. Herein, we determined the potential functions of the flavonoid-enriched fraction from Seabuckthorn, which was named SBF, in treating major depressive disorder in mice. In the CUMS-induced mouse model, the intake of SBF reversed their depressive behaviors and relieved the CUMS-disturbed levels of neurotrophins, neurotransmitters, stress-related hormones, and inflammation-related cytokines. Additionally, the treatment of depressive mice with SBF showed ability to regulate the gut microbiota, especially in decreasing the abundance of Lactobacillaceae, while increasing the abundance of Lachnospiraceae at the family level. The results suggest the beneficial effects of Seabuckthorn flavonoids in functioning as a health food supplement to treat major depressive disorders.
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Poricoic acid A alleviates depressive-like behaviors by targeting the gut microbiota-immune axis.
BACKGROUND/OBJECTIVES: Poricoic acid A (PAA) is a bioactive triterpenoid from the fungus Poria cocos. Nevertheless, whether it exerts antidepressant-like effects and whether the gut microbiota and immune regulation are involved remain unknown. METHODS: Male C57BL/6 J mice were subjected to chronic unpredictable stress (CUS) and treated with PAA treatment. Behavioral tests were performed, and hippocampal damage was evaluated by H&E and TUNEL staining. Gut microbiota composition was analyzed using 16S rRNA sequencing, and hippocampal transcriptomic profiling was performed using RNA-seq, followed by immune cell infiltration, correlation, and functional enrichment analyses. RESULTS: PAA treatment eased CUS-induced depression- and anxiety-like behaviors. It also cut down hippocampal neuron damage and cell death. Besides, PAA fixed gut bacteria balance by lowering harmful germs like L. murinus and boosting good germs like A. muciniphila and L. reuteri. Hippocampal transcriptomic analysis revealed that PAA modulated immune cell infiltration by reducing M1 macrophages and restoring M2 macrophages, with significant correlations between gut microbial taxa and hippocampal immune-related gene expression. Functional enrichment analyses indicated that PAA regulates pathways related to synaptic plasticity, neuroinflammation, and neuronal development. qPCR and western blotting confirmed that PAA restored the hippocampal expression of key molecules involved in neuroinflammation (HSP90B1), synaptic plasticity (RPS6KB2 and IGF2BP2), and blood-brain barrier integrity (COL4A5). CONCLUSIONS: PAA alleviates depression-like Behaviors in CUS mice by remodeling the gut microbiota and modulating the hippocampal M1/M2 macrophage balance via the gut-brain axis. These findings support the potential of PAA as a prebiotic-like nutritional agent for major depressive disorder.
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Blood microbiota and metabolomic signature of major depression before and after antidepressant treatment: a prospective case-control study.
BACKGROUND: The microbiota interacts with the brain through the gut-brain axis, and a distinct dysbiosis may lead to major depressive episodes. Bacteria can pass through the gut barrier and be found in the blood. Using a multiomic approach, we investigated whether a distinct blood microbiome and metabolome was associated with major depressive episodes, and how it was modulated by treatment. METHODS: In this case-control multiomic study, we analyzed the blood microbiome composition, inferred bacterial functions and metabolomic profile of 56 patients experiencing a current major depressive episode and 56 matched healthy controls, before and after treatment, using 16S rDNA sequencing and liquid chromatography coupled to tandem mass spectrometry. RESULTS: The baseline blood microbiome in patients with a major depressive episode was distinct from that of healthy controls (patients with a major depressive episode had a higher proportion of Janthinobacterium and lower levels of Neisseria) and changed after antidepressant treatment. Predicted microbiome functions confirmed by metabolomic profiling showed that patients who were experiencing a major depressive episode had alterations in the cyanoamino acid pathway at baseline. High baseline levels of Firmicutes and low proportions of Bosea and Tetrasphaera were associated with response to antidepressant treatment. Based on inferred baseline metagenomic profiles, bacterial pathways that were significantly associated with treatment response were related to xenobiotics, amino acids, and lipid and carbohydrate metabolism, including tryptophan and drug metabolism. Metabolomic analyses showed that plasma tryptophan levels are independently associated with response to antidepressant treatment. LIMITATIONS: Our study has some limitations, including a lack of information on blood microbiome origin and the lack of a validation cohort to confirm our results. CONCLUSION: Patients with depression have a distinct blood microbiome and metabolomic signature that changes after treatment. Dysbiosis could be a new therapeutic target and prognostic tool for the treatment of patients who are experiencing a major depressive episode.
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A new perspective on cognitive impairment in major depressive disorder: Changes in gut microbiota and their inflammatory regulatory mechanisms.
BACKGROUND: Cognitive impairments in major depressive disorder (MDD) affect patients' social functioning, with underlying mechanisms involving gut microbiota and inflammatory factors remaining unclear. METHODS: The study analyzed cognitive function, gut microbiota changes, and inflammatory factor levels in 39 unmedicated MDD patients and 41 healthy controls, employing correlation and moderation effect analysis. RESULTS: MDD patients scored lower than controls in cognitive functions like information processing speed, attention/vigilance, verbal learning, visual learning and social cognition. They showed reduced gut microbiota diversity and increased levels of inflammatory markers (TNF-α, IL-1, IL-6, IL-17, IL-27, IL-33). Sellimonas abundance correlated negatively with attention/vigilance, moderated by TNF-α, IL-27, and IL-33. This relationship was stronger at lower inflammation levels. CONCLUSIONS: MDD patients exhibit multi-domain cognitive dysfunction alongside pro-inflammatory states and disrupted gut microbiota. The abundance of Sellimonas significantly predicts attention/vigilance deficits. Inflammatory factors modulate the impact of gut microbiota on cognitive function, suggesting chronic low-grade inflammation as a key risk factor for cognitive impairment in MDD.
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A next-generation probiotic: Akkermansia muciniphila ameliorates chronic stress-induced depressive-like behavior in mice by regulating gut microbiota and metabolites.
Major depressive disorder (MDD) is a neurasthenic disease, which is the second-largest burden of disease globally. Increasing studies have revealed that depression is associated with abnormalities in gut microbiota and metabolites. Several species of bacteria have been classified as psychobiotics, which confer mental health benefits through interactions with commensal gut microbiota. Therefore, it is essential to identify new psychobiotics and elucidate their mechanisms in the treatment of depression. This study aims to evaluate the antidepressant effect of Akkermansia muciniphila (AKK) in a mouse model of depression induced by chronic restraint stress (CRS). C57BL/6 male mice were divided into three groups: mice subjected to CRS, mice not subjected to CRS, and mice treated with AKK for 3 weeks. Behavioral tests were performed, and hormone, neurotransmitter, and brain-derived neurotrophic factor (BDNF) levels were measured. Cecal microbiota was analyzed using 16S rRNA gene sequencing, and serum metabolites were detected using untargeted metabolomics. In addition, correlations between altered gut microbiota and metabolites with significant variations in serum associated with AKK ameliorating depression were analyzed using Pearson's correlation coefficient. The results revealed that AKK significantly ameliorated depressive-like behavior and restored abnormal variations in depression-related molecular (corticosterone, dopamine, and BDNF). Moreover, AKK altered chronic stress-induced gut microbial abnormalities. Untargeted metabolomics analysis revealed 23 potential biomarkers in serum that could be associated with the mechanisms underlying CRS-induced depression and the therapeutic effects of AKK. Pearson's correlation coefficient analysis revealed that AKK predominantly upregulated β-alanyl-3-methyl-L-histidine and edaravone to relieve depression. Furthermore, β-alanyl-3-methyl-L-histidine and edaravone exhibited the antidepressant phenotype in mice subjected to CRS. In conclusion, the study demonstrated that AKK ameliorates chronic stress-induced depressive symptoms in mice by regulating gut microbiota and metabolites. KEY POINTS: • AKK reduces depressive-like behaviors induced by chronic stress. • AKK regulates the gut microbial structure and metabolomics of serum under the chronic stress. • Antidepressant effect of AKK correlates with the increase of β-alanyl-3-methyl-l-histidine and edaravone.
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Sex differences in fecal metabolic profiles of major depressive disorder: unveiling sex-specific metabolomic panel.
BACKGROUND: Major depressive disorder (MDD) disproportionately affects women, who exhibit a higher prevalence and greater symptom severity than men. However, sex-specific pathophysiological mechanisms remain poorly understood. Emerging evidence implicates gut microbiota-derived metabolites in MDD, but many prior studies have failed to consider sex differences, potentially obscuring critical biomarkers. This study aims to address this gap by characterizing sex-specific fecal metabolite profiles in MDD. METHODS: Untargeted metabolomics was used to examine fecal metabolic profiles in 279 participants (117 with MDD and 162 healthy controls). The cohort was stratified by biological sex to identify sex-specific metabolic alterations associated with depressive symptoms through statistical analyses. A machine learning approach incorporating feature selection was employed to identify potential discriminative biomarkers, with a particular focus on female metabolic characteristics. RESULTS: Sex-stratified analysis revealed significant metabolic divergence in female MDD patients compared to healthy controls. Twenty-four differentially abundant metabolites were identified in females, with heptylamine and phenaceturic acid being unique to this group; no significant differences were observed in males. Correlation analyses showed that phenaceturic acid and 1-monoheptadecanoyl glyceride were significantly negatively correlated with depressive symptom severity in females. Besides, a sex-specific diagnostic panel based on five key fecal metabolites demonstrated promising performance in distinguishing female MDD patients from healthy controls. CONCLUSION: By systematically revealing sex-dependent metabolic alterations, this study identified potential biomarkers for sex-specific diagnostic and therapeutic strategies. These findings highlight the importance of integrating sex-specific perspectives in gut-brain axis research to advance precision medicine in MDD, rather than relying solely on generalized approaches. TRIAL REGISTRATION: Human Research and Ethics Committee of Beijing Anding Hospital, Capital Medical University, China (Approval No. 2017-24), registered on 2018.07.24.
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Bifidobacterium longum CECT 30763 improves depressive- and anxiety-like behavior in a social defeat mouse model through the immune and dopaminergic systems.
Adolescence is a crucial period marked by profound changes in the brain. Exposure to psychological stressors such as bullying, abuse or maltreatment during this developmental period may increase the risk of developing depression, anxiety and comorbid cardiometabolic conditions. Chronic psychological stress is associated with behavioral changes and disruption of the hypothalamic-pituitary-adrenal axis, leading to corticosterone overproduction in rodents and changes in both the immune system and the gut microbiome. Here, we demonstrate the ability of Bifidobacterium longum CECT 30763 (B. longum) to ameliorate adolescent depressive and anxiety-like behaviors in a chronic social defeat (CSD) mouse model. The mechanisms underlying this beneficial effect are related to the ability of B. longum to attenuate the inflammation and immune cell changes induced by CSD after the initial stress exposure through the induction of T regulatory cells with enduring effects that may prevent and mitigate the adverse consequences of repeated stress exposure on mental and cardiometabolic health. B. longum administration also normalized dopamine release, metabolism and signaling at the end of the intervention, which may secondarily contribute to the reversal of behavioral changes. The anti-inflammatory effects of B. longum could also explain its cardioprotective effects, which were reflected in an amelioration of the oxidative stress-induced damage in the heart and improved lipid metabolism in the liver. Overall, our findings suggest that B. longum regulates the links between the immune and dopaminergic systems from the gut to the brain, potentially underpinning its beneficial psychobiotic and physiological effects in CSD.
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Scaffold hopping of agomelatine leads to enhanced antidepressant effects by modulation of gut microbiota and host immune responses.
The mechanisms underlying the pathophysiology of depression remain elusive, and the development of novel, effective antidepressant drugs remains necessary. A dihydroquinoline analog of agomelatine (AGO), N-(2-(7-methoxy-3,4-dihydroisoquinolin-1-yl)ethyl)acetamide hydrochloride (NMDEA), was synthesized by employing a scaffold-hopping strategy in our previous study. In this study, NMDEA was demonstrated to attenuate depression-related behaviors in mice models of chronic unpredictable mild stress (CUMS), using a sucrose preference test, a forced swimming test, and a tail suspension test. However, the antidepressant mechanism of NMDEA appears to differ from that for AGO. Based on the analysis of fecal microbiota from mice, stress can alter the richness of the gut bacterial community, increasing the expression of immune-modulating microbiota, such as Clostridia, and decreasing the expression of probiotic bacteria, such as Lactobacillus. Treatment with NMDEA was able to recover the richness and to regulate the dysbiosis among bacterial species. Several studies have demonstrated that the gut microbiota population can induce inflammatory processes. To explore the effects of NMDEA on the suppression of pro-inflammatory factors, we used Western blotting to analyze the levels of interleukin 1 beta (IL-1β), interleukin 6 (IL-6), p65, and inducible nitric oxide synthase (iNOS). NMDEA suppressed the activation of IL-1β and IL-6, in the hippocampus, and IL-1β, IL-6, p65, and iNOS, in lipopolysaccharide (LPS)-induced BV-2 cells. These results suggested that NMDEA may affect the microbiota-inflammasome-brain axis, regulating relevant neuro-inflammatory markers and gut microbiota. Our data also suggested that using small molecules to modify the gut microbiota population or alter inflammasome signaling may represent a new therapeutic opportunity for the mitigation of depression.
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Shotgun metagenomics reveals both taxonomic and tryptophan pathway differences of gut microbiota in bipolar disorder with current major depressive episode patients.
BACKGROUND: The microbiome-gut-brain axis, especially the microbial tryptophan biosynthesis and metabolism pathway (MiTBamp), is closely connected to bipolar disorder with current major depressive episode (BPD). METHODS: We performed shotgun metagenomics sequencing (SMS) of faecal samples from 25 BPD patients and 28 healthy controls (HCs). Except for the microbiota taxa and MiTBamp analyses, we also built a classification model using the Random Forests (RF) and Boruta algorithm to find the microbial biomarkers for BPD. RESULTS: Compared to HCs, the phylum Bacteroidetes abundance was significantly reduced, whereas that of the Actinobacteria and Firmicutes were significantly increased in BPD patients. We also identified 38 species increased and 6 species decreased significantly in the BPD group. In the MiTBamp, we identified that two Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologies (KOs) (K00658 and K00837) were significantly lower in the BPD, and five KOs (K01696, K00382, K00626, K01667, and K03781) were significantly higher in the BPD group. We also identified significant genera and species which were closely related to these KOs. Finally, RF classification based on gut microbiota at the genus level can achieve an area under the receiver operating characteristic curve of 0.997. LIMITATIONS: The features of cross-sectional design, limited sample size, the heterogeneity of bipolar disorders, and a lack of serum/plasma tryptophan concentration measurements. CONCLUSIONS: The present findings enable a better understanding of changes in gastrointestinal microbiome and MiTBamp in BPD. Alterations of microbes may have potential as biomarkers for distinguishing the BPD patients form HCs.
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A pilot study of daily blueberry intake modulates the gut microbiota enzyme commissions in older, sedentary adults with mild depressive symptoms.
BACKGROUND: Fiber and anthocyanins in blueberries have potential to modify the gut microbiome and metabolites that are relevant to depression in older adults. OBJECTIVE: Our objective was to preliminarily determine the effect of blueberry consumption on the gut microbiome, metabolites, and depressive symptoms. DESIGN: Sedentary, older adults (≥65y) with mild depressive symptoms were enrolled in a randomized, double-blind, parallel-arm, placebo-controlled pilot study. Participants consumed 48 g/day of blueberry powder (∼2 cups of fresh berries) or placebo for 3 months. Metagenomic sequencing measured the abundance of fecal bacterial species and genes, liquid chromatography/mass spectrometry evaluated gut-derived fecal short chain fatty acids (SCFA), and validated questionnaires evaluated depressive symptoms before and after the intervention. PARTICIPANTS: Eighteen participants who were predominantly female and white completed the intervention (Placebo Group, n = 8, mean age: 75 ± 6; Blueberry Group, n = 10, mean age: 71 ± 4). RESULTS: Measures of species abundance, MetaCyc pathways, and metabolites did not change. There were statistically significant in the gene abundance of several Enzyme Commissions (EC) of the gut microbiome within the Blueberry Group-including EC 3.6.3.31 Polyamine Transporting ATPase, which is involved in the production of the neurotransmitter, gamma-aminobutyric acid (GABA). CONCLUSION: While there were no statistically significant differences in changes in depressive symptoms between groups, the magnitude of reduction in depressive symptom severity appeared greater, with smaller variability in the Blueberry Group, which was paired with minor changes in the gut microbial ECs. Our data are preliminary and warrant additional studies to investigate the link between blueberries, the gut-microbiome, and mood in older adults.