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Gut microbiota from NLRP3-deficient mice ameliorates depressive-like behaviors by regulating astrocyte dysfunction via circHIPK2.
BACKGROUND: Inflammasomes have been found to interact with the gut microbiota, and this effect is associated with depression, but the mechanisms underlying this interaction have not been elucidated in detail. RESULTS: The locomotor activity of NLRP3 KO mice was significantly greater than that of their WT littermates, while cohousing and transplantation of the NLRP3 KO gut microbiota avoid the effects of NLRP3 KO on the general locomotor activity at baseline. Meanwhile, transplantation of the NLRP3 KO microbiota alleviated the CUS-induced depressive-like behaviors. The compositions of the gut microbiota in NLRP3 KO mice and WT mice were significantly different in terms of the relative abundance of Firmicutes, Proteobacteria, and Bacteroidetes. Fecal microbiota transplantation (FMT) from NLRP3 KO mice significantly ameliorated the depressive-like behavior induced by chronic unpredictable stress (CUS) in recipient mice. Given the correlation between circular RNA HIPK2 (circHIPK2) and depression and the observation that the level of circHIPK2 expression was significantly increased in CUS-treated mice compared with that in the control group, further experiments were performed. FMT significantly ameliorated astrocyte dysfunction in recipient mice treated with CUS via inhibition of circHIPK2 expression. CONCLUSIONS: Our study illustrates the involvement of the gut microbiota-circHIPK2-astrocyte axis in depression, providing translational evidence that transplantation of the gut microbiota from NLRP3 KO mice may serve as a novel therapeutic strategy for depression.
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Intestinal Flora and Depression: Interaction Mechanisms and Therapeutic Prospects.
Depression is a mental disorder characterized by high incidence and relapse rates, and the search for effective treatments has been continuously pursued. To assess the effectiveness of existing studies, recent research advances are summarized with an emphasis on potential pathophysiological mechanisms through specific pathways of intestinal flora affecting depression, including microbial and metabolic activities, neuroendocrine regulation, immune and inflammatory responses, and microbial dysbiosis. This review also presents current therapeutic strategies targeting intestinal flora in depression and provides potential directions for future research.
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Exploratory studies of the antidepressant effect of Cordyceps sinensis polysaccharide and its potential mechanism.
Cordyceps sinensis, a traditionally prized medicinal fungus, contains polysaccharides as one of its main bioactive constituents, known for their significant immunomodulatory properties. In this study, we systematically investigated the composition and structure of Cordyceps sinensis polysaccharide, followed by an evaluation of its therapeutic effect on depression using a chronic restraint stress-induced depression model. The polysaccharide CSWP-2, extracted via hot water, precipitated with ethanol, and purified using DEAE-cellulose column chromatography from Cordyceps sinensis, is primarily composed of glucose, mannose, and galactose, with α-1,4-D-glucan as its major structural component. Behavioral tests, immunological profiling, metabolomics, and gut microbiota analyses indicated a notable ameliorative effect of CSWP-2 on depressive-like symptoms in mice. Furthermore, the action of CSWP-2 may be attributed to the modulation of the gut microbiome's abundance and its metabolic impacts, thereby transmitting signals to the host immune system and exerting immunomodulatory activity, ultimately contributing to its antidepressant effects.
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Potential mechanisms of gut microbiota influence on different types of vertigo: a bidirectional Mendelian randomization and mediation analysis.
BACKGROUND: The relationship between gut microbiota and vertigo, specifically Benign Paroxysmal Vertigo (BPV) and Vertigo of Central (VC), remains underexplored. AIM AND HYPOTHESES: This study aims to investigate the causal relationships between gut microbiota and two types of vertigo, BPV and VC. Additionally, the study seeks to explore the mediation effects of metabolic, inflammatory, and psychological factors on these relationships. We hypothesize that specific taxa of gut microbiota have a causal effect on the risk of developing BPV and VC. The mediation effects of HbA1c, obesity, major depression, and interleukin-18 levels significantly influence the relationships between gut microbiota and vertigo. METHOD: Utilizing a bidirectional two-sample Mendelian randomization approach, this study investigated causal associations between gut microbiota and the two types of vertigo. A network MR assessed mediation effects of HbA1c, major depression, obesity, and interleukin-18 levels, with data sourced from several consortia, including MiBioGen. RESULTS: Distinct gut microbiota displayed varying influences on BPV and VC risks. A total of ten taxa affect BPV. Among these, two taxa have an odds ratio (OR) greater than 1, including one class, one order. Conversely, eight taxa have an OR less than 1, encompassing four families, three genera, and one order. The OR for these taxa ranges from 0.693 to 0.930, with p-values between 0.006 and 0.048. For VC, eight taxa were found to have an impact. Five of these taxa exhibit an OR greater than 1, including four genera and one phylum. The OR for these taxa ranges from 1.229 to 2.179, with p-values from 0.000 to 0.046. The remaining three taxa have an OR less than 1, comprising one family and two genera, with an OR range of 0.445 to 0.792 and p-values ranging from 0.013 to 0.050. The mediation analysis for BPV shows that major depression, obesity, and HbA1c are key mediators between specific taxa and BPV. Major depression mediates 28.77% of the effect of family Rhodospirillaceae on BPV. Obesity mediates 13.90% of the effect of class Lentisphaeria/order Victivallales. HbA1c mediates 11.79% of the effect of genus Bifidobacterium, 11.36% of family Bifidobacteriaceae/order Bifidobacteriales. For VC, interleukin-18 levels and major depression are significant mediators. Interleukin-18 levels mediate 6.56% of the effect of phylum Actinobacteria. Major depression mediates 6.51% of the effect of genus Alloprevotella. CONCLUSION: The study highlights potential causal links between gut microbiota and vertigo, emphasizing metabolic and psychological mediators. These insights underscore the therapeutic potential of targeting gut health in vertigo management.
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Investigations of microbiota composition and neuroactive pathways in association with symptoms of stress and depression in a cohort of healthy women.
BACKGROUND: Despite mounting evidence of gut-brain involvement in psychiatric conditions, functional data remain limited, and analyses of other microbial niches, such as the vaginal microbiota, are lacking in relation to mental health. This aim of this study was to investigate if the connections between the gut microbiome and mental health observed in populations with a clinical diagnosis of mental illness extend to healthy women experiencing stress and depressive symptoms. Additionally, this study examined the functional pathways of the gut microbiota according to the levels of psychological symptoms. Furthermore, the study aimed to explore potential correlations between the vaginal microbiome and mental health parameters in young women without psychiatric diagnoses. METHODS: In this cross-sectional study, 160 healthy Danish women (aged 18-40 years) filled out questionnaires with validated scales measuring symptoms of stress and depression and frequency of dietary intake. Fecal and vaginal microbiota samples were collected at the beginning of the menstrual cycle and vaginal samples were also collected at cycle day 8-12 and 18-22. Shotgun metagenomic profiling of the gut and vaginal microbiome was performed. The Kyoto Encyclopedia of Genes and Genomes (KEGG) was used for functional profiling and 56 Gut Brain Modules were analyzed in the fecal samples. RESULTS: The relative abundance in the gut of the genera Escherichia, Parabacteroides, and Shigella was higher in women with elevated depressive symptoms. Women with high perceived stress showed a tendency of increased abundance of Escherichia, Shigella, and Blautia. Amongst others, the potentially pathogenic genera, Escherichia and Shigella correlate with alterations in the neuroactive pathways such as the glutamatergic, GABAeric, dopaminergic, and Kynurenine pathways. Vaginosis symptoms were more prevalent in women reporting high levels of stress and depressive symptoms. CONCLUSIONS: The findings of this study support the concept of a microbiota-associated effect on the neuroactive pathways even in healthy young women. This suggest, that targeting the gut microbiome could be a promising approach for future psychiatric interventions.
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Shedding light on biological sex differences and microbiota-gut-brain axis: a comprehensive review of its roles in neuropsychiatric disorders.
Women and men are suggested to have differences in vulnerability to neuropsychiatric disorders, including major depressive disorder (MDD), generalized anxiety disorder (GAD), schizophrenia, eating disorders, including anorexia nervosa, and bulimia nervosa, neurodevelopmental disorders, such as autism spectrum disorder (ASD), and neurodegenerative disorders including Alzheimer's disease, Parkinson's disease. Genetic factors and sex hormones are apparently the main mediators of these differences. Recent evidence uncovers that reciprocal interactions between sex-related features (e.g., sex hormones and sex differences in the brain) and gut microbiota could play a role in the development of neuropsychiatric disorders via influencing the gut-brain axis. It is increasingly evident that sex-microbiota-brain interactions take part in the occurrence of neurologic and psychiatric disorders. Accordingly, integrating the existing evidence might help to enlighten the fundamental roles of these interactions in the pathogenesis of neuropsychiatric disorders. In addition, an increased understanding of the biological sex differences on the microbiota-brain may lead to advances in the treatment of neuropsychiatric disorders and increase the potential for precision medicine. This review discusses the effects of sex differences on the brain and gut microbiota and the putative underlying mechanisms of action. Additionally, we discuss the consequences of interactions between sex differences and gut microbiota on the emergence of particular neuropsychiatric disorders.
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The change of gut microbiota in MDD patients under SSRIs treatment.
The alterations in the gut microbiota have been reported to be correlated with the development of depression. The purpose of this study was to investigate the changes of intestinal microbiota in depressed patients after antidepressant treatment. We recruited 30 MDD patients (MDD group) and 30 healthy controls (control group). The MDD group received individualized treatment with escitalopram at a maximum dose of 20 mg/day. After depressive symptoms improved to a HAMD scale score > 50%, a fecal sample was collected again and used as the follow-up group. The differences of gut microbiota between patients and controls, the characteristics of gut microbiota under treatment and the potential differences in metabolic functions were thus investigated. The Firmicutes/Bacteroidetes ratio was significantly different within three groups, and the ratio of follow-up group was significantly lower than those of the other two groups. Alpha diversity was significantly higher in MDD group than those of the other groups, and the alpha diversity was not significantly different between control and follow-up groups. The beta diversity of some patients resembled participants in the control group. The metabolic function of gut microbiota after treatment was still different from that of the control group. This study suggests that the intestinal flora of depressed patients has a tendency to return to normal under escitalopram treatment.
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Network pharmacological analysis and animal experiment verification of SAL inhibiting the IL-17 signaling pathway in the treatment of depression.
Depression is a prevalent and severe mental disorder. Recently, the "Gut-Brain Axis" theory has offered a novel perspective on its pathophysiological mechanisms. As a major bioactive constituent isolated from Rhodiola rosea L., Salidroside (SAL) possesses well-documented anti-stress, antioxidant, and neuroprotective activities. Based on the gut-brain axis hypothesis, the present work evaluated whether SAL exerts antidepressant-like actions in a murine model of chronic unpredictable mild stress (CUMS) and further clarified its potential molecular mechanisms. During the establishment of the CUMS model, mice received intragastric SAL at doses of 25 mg·kg-1 and 50 mg·kg-1 daily for 4 weeks. Behavioral experiments evaluated anxiety and depressive-like behaviors, while gastrointestinal function changes were monitored. Results indicated that SAL significantly alleviated depressive-like behaviors, restored gastrointestinal function and structure, increased serotonin expression in the gut-brain axis, and repaired hippocampal neural damage. RNA sequencing of hippocampal tissue suggested that SAL inhibited abnormal IL-17 signaling pathway activation. Western blot analysis confirmed that SAL reduced IL-17 levels in hippocampal tissue and inhibited excessive phosphorylation of downstream p-MAPK and p-NF-κB. Additionally, SAL intervention restored the disrupted intestinal flora in depressed mice. Spearman correlation analysis showed that changes in bacterial genera such as Rikenella, Oscillibacter, and Barnesiella might be crucial in SAL's regulation of the gut-brain axis and its antidepressant effects. In summary, this study documented the ameliorative effects of SAL on depressive-like behaviors in CUMS model mice, as well as its impact on the gut-brain axis and the IL-17 signaling pathway. These observations may serve as a reference for future research on SAL as a functional food ingredient.
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Associations Between Microbial Depletion and Autonomic Dysregulation in Binge-Eating Disorder.
OBJECTIVE: The interplay between the gut microbiome and autonomic nervous system remains unexplored in binge-eating disorder (BED). We aimed to explore specific microbial alterations in BED and examine their potential association with cardiac vagal tone as a distinct bio-behavioral phenotype. METHOD: Women with BED and co-occurring major depressive disorder (BED+MDD; n = 19) were compared to strictly matched controls with MDD alone (n = 38) to isolate BED-specific effects. We analyzed the gut microbiome via 16S rRNA sequencing and assessed cardiac vagal tone using short-term heart rate variability (specifically normalized high-frequency power, HFnu). Nutritional intake was analyzed to explore diet-microbiome interactions. RESULTS: While global diversity did not differ between groups, differential abundance analysis identified lower relative abundance of several fermentative taxa, including Catenibacterium, Acidaminococcus, Pediococcus, Fusobacterium, Megasphaera, and Prevotella in the BED group. Notably, a cross-system association emerged exclusively in the BED group: the depletion of Pediococcus was strongly correlated with reduced vagal tone (HFnu; p = 0.003) and specific micronutrient patterns. This relationship was absent in the MDD-only controls. DISCUSSION: Our findings demonstrate a BED-specific link between the depletion of the fermentative guild, autonomic instability, and dietary energy intake. This linked state may reflect a physiological response to the acute substrate surges characteristic of binge-eating, potentially compromising gut-brain axis homeostasis. Future research incorporating direct measures of binge behavior and luminal environment is required to validate whether these microbial patterns represent a causal mechanism or a reproducible physiological marker of the disorder.
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Core antibiotic resistance genes mediate gut microbiota to intervene in the treatment of major depressive disorder.
INTRODUCTION: The relationship between depression and gut microbiota remains unclear, but an important role of gut microbiota has been verified. The relationship between gut microbiota and antibiotic resistance genes (ARGs) may be a potential new explanatory pathway. METHODS: We collected samples from 63 depressed patients and 30 healthy controls for metagenomic sequencing. The two groups' microbiota characteristics, functional characteristics, and ARG differences were analyzed. RESULTS: We obtained 30 differential KEGG orthologs (KOs) and their producers in 5 genera and 7 species by HUMAnN3. We found 6 KOs from Weissella_cibaria and Lactobacillus_plantaru are potentially coring functional mechanism of gut microbiota. Different metabolites including sphingolipids, pyrans, prenol lipids, and isoflavonoids also showed significance between MDD and HC. We detected 48 significantly different ARGs: 5 ARGs up-regulated and 43 ARGs down-regulated in MDD compared to HC. Based on Cox model results, Three ARGs significantly affected drug efficacy (ARG29, ARG105, and ARG111). Eggerthella, Weissella, and Lactobacillus were correlated with different core ARGs, which indicated different mechanisms in affecting MDD. LIMITATIONS: The present study needs to be replicated in different ethnic groups. At the same time, a larger Chinese cohort study and detailed experimental verification are also the key to further discussion. CONCLUSION: Our findings suggest that ARGs play a role in the interplay between major depressive disorder and gut microbiota. The role of ARGs should be taken into account when understanding the relationship between depression and gut microbiota.