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Hypericin alleviates depression via the microbiota-gut-brain Axis: Role of Akkermansia muciniphila and glycerophospholipid metabolism.
BACKGROUND: Depression is one of the most severe mental disorders, affecting approximately 3.8 % of the global population. Chronic stress represents a major contributing factor, with the microbiota-gut-brain (MGB) axis playing a critical role in its pathophysiology. PURPOSE OF THE STUDY: This study aimed to evaluate whether hypericin can ameliorate depression through MGB axis and its underlying mechanism. MATERIALS AND METHODS: To evaluate the antidepressant potential of hypericin, a chronic restraint stress mouse model was established. Behavioral tests were conducted. Fecal 16S rRNA sequencing and serum untargeted metabolomics were performed to investigate alterations in gut microbiota and metabolic profiles, followed by integrative analysis. The glycerophospholipid signaling pathway was further examined in both colon and hippocampus. Finally, microbiota depletion experiments were carried out to validate the essential role of gut microbiota in mediating the antidepressant effects of hypericin. RESULTS: Hypericin ameliorated anxiety- and depression-like behaviors, accompanied by reduced histological damage, inflammation, and dysregulated serotonin metabolism in both the colon and hippocampus. Furthermore, significant alterations in Akkermansia muciniphila (A. muciniphila) abundance and glycerophospholipid metabolites were observed after hypericin treatment, with strong correlations identified among A. muciniphila, differential glycerophospholipid metabolites, and behavioral scores. The sPLA2/LPCATs/LYPLA1 axis was further demonstrated to mediate hypericin's regulatory effects on glycerophospholipid metabolism in both tissues. Finally, microbiota depletion abolished the behavioral improvements induced by hypericin. CONCLUSIONS: Together, our findings offer novel insights into the role of the MGB axis in mediating the antidepressant effects of hypericin, potentially through mechanisms involving the modulation of A. muciniphila and glycerophospholipid metabolism.
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Gut microbiota: Linking nutrition and perinatal depression.
Perinatal depression is a mood disorder that is reported in women during pregnancy (prenatal) and after childbirth (postnatal). The onset of perinatal depression is associated with changes in reproductive hormones, stress hormones and neurosteroids. These chemical compounds can be modulated by the gut microbiota, which may affect maternal mental health during the perinatal period via the gut-brain-axis. Recent studies suggest that nutritional and dietary interventions (vitamin D, ω-3 fatty acids, iron, and fiber) effectively prevent or mitigate maternal depression and anxiety, but their efficacy is confounded by various factors, including the gut microbiota. Probiotics are efficacious in maintaining microbiota homeostasis, and thus, have the potential to modulate the development of perinatal mood disorders, despite no evidence in human. Therefore, clinical trials are warranted to investigate the role of probiotic supplementation in perinatal depression and behavioral changes. This article reviews the interplay between nutrition, gut microbiota and mood and cognition, and the evidence suggesting that probiotics affect the onset and development of perinatal depression.
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Shugan granule contributes to the improvement of depression-like behaviors in chronic restraint stress-stimulated rats by altering gut microbiota.
AIM: The investigation aims to evaluate the potential effect of Shugan Granule (SGKL) on the gut, brain, and behaviors in rats exposed to chronic restraint stress (CRS). METHODS: The fecal microbiota and metabolite changes were studied in rats exposed to CRS and treated with SGKL (0.1 mg/kg/day). Depressive behaviors of these rats were determined through an open-field experiment, forced swimming test, sucrose preference, and weighing. Moreover, LPS-stimulated microglia and CRS-stimulated rats were treated with SGKL to investigate the regulation between SGKL and the PI3K/Akt/pathway, which is inhibited by LY294002, a PI3K inhibitor. RESULTS: (i) SGKL improved the altered behaviors in CRS-stimulated rats; (ii) SGKL ameliorated the CRS-induced neuronal degeneration and tangled nerve fiber and also contributed to the recovery of intestinal barrier injury in these rats; (iii) SGKL inhibited the hippocampus elevations of TNF-α, IL-1β, and IL-6 in response to CRS modeling; (iv) based on the principal coordinates analysis (PCoA), SGKL altered α-diversity indices and shifted β-diversity in CRS-stimulated rats; (v) at the genus level, SGKL decreased the CRS-enhanced abundance of Bacteroides; (vi) Butyricimonas and Candidatus Arthromitus were enriched in SGKL-treated rats; (vii) altered gut microbiota and metabolites were correlated with behaviors, inflammation, and PI3K/Akt/mTOR pathway; (viii) SGKL increased the LPS-decreased phosphorylation of the PI3K/Akt/mTOR pathway in microglia and inhibited the LPS-induced microglial activation; (ix) PI3K/Akt/mTOR pathway inactivation reversed the SGKL effects in CRS rats. CONCLUSION: SGKL targets the PI3K/Akt/mTOR pathway by altering gut microbiota and metabolites, which ameliorates altered behavior and inflammation in the hippocampus.
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Depression and anxiety in patients with active ulcerative colitis: crosstalk of gut microbiota, metabolomics and proteomics.
Patients with ulcerative colitis (UC) have a high prevalence of mental disorders, such as depression and anxiety. Gut microbiota imbalance and disturbed metabolism have been suggested to play an important role in either UC or mental disorders. However, little is known about their detailed multi-omics characteristics in patients with UC and depression/anxiety. In this prospective observational study, 240 Chinese patients were enrolled, including 129 patients with active UC (69 in Phase 1 and 60 in Phase 2; divided into depression/non-depression or anxiety/non-anxiety groups), 49 patients with depression and anxiety (non-UC), and 62 healthy people. The gut microbiota of all subjects was analyzed using 16S rRNA sequencing. The serum metabolome and proteome of patients with UC in Phase 2 were analyzed using liquid chromatography/mass spectrometry. Associations between multi-omics were evaluated by correlation analysis. The prophylactic effect of candidate metabolites on the depressive-like behavior of mice with colitis was investigated. In total, 58% of patients with active UC had depression, while 50% had anxiety. Compared to patients with UC without depression/anxiety, patients with UC and depression/anxiety had lower fecal microbial community richness and diversity, with more Lactobacillales, Sellimonas, Streptococcus, and Enterococcus but less Prevotella_9 and Lachnospira. Most metabolites (e.g., glycochenodeoxycholate) were increased in the serum, while few metabolites, including 2'-deoxy-D-ribose and L-pipecolic acid, were decreased, accompanied by a general reduction in immunoglobulin proteins. These related bacteria, metabolites, and proteins were highly connected. A prophylactic administration of 2'-deoxy-D-ribose and L-pipecolic acid significantly reduced the depressive-like behaviors in mice with colitis and alleviated the inflammatory cytokine levels in their colon, blood and brain. This study has identified a comprehensive multi-omics network related to depression and anxiety in active UC. It is composed of a certain set of gut microbiota, metabolites, and proteins, which are potential targets for clinical intervention for patients with UC and depression/anxiety.
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Exercise-Mediated Molecular Mechanisms of Antidepressant Effects: The Role of the Microbiota-Gut-Brain Axis.
Depression is a prevalent and complex neuropsychiatric disorder that substantially impairs quality of life worldwide. Current pharmacological and psychotherapeutic interventions are often limited by inadequate efficacy and restricted accessibility. Exercise has emerged as a potent non-pharmacological alternative, exhibiting antidepressant effects comparable to conventional treatments, with the microbiota-gut-brain (MGB) axis increasingly recognized as a key mediator. Despite growing interest, existing research articles largely describe associations without mapping the molecular pathways from exercise-altered microbes to neurobiological changes in depression. This review addresses these gaps by comprehensively dissecting the molecular cascades from microbial remodeling to synaptic and systemic adaptations, thereby providing a mechanistic roadmap absent in current syntheses. We first delineate how gut dysbiosis contributes to depression via endocrine, neural, and immune pathways. Subsequently, we highlight the ability of exercise to reverse these pathological states by restoring microbial diversity, reinforcing intestinal barrier function, and modulating the production of microbial metabolites. These exercise-driven changes collectively attenuate systemic and neuroinflammation, enhance brain-derived neurotrophic factor signaling, augment serotonin synthesis, and dampen hypothalamic-pituitary-adrenal axis hyperactivity. By reinstating intestinal homeostasis, exercise acts as a central regulator of the MGB axis and represents a promising therapeutic strategy. This integrative framework offers novel insights into depression pathogenesis and opens avenues for multifaceted intervention.
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Schisandrin C alleviates depressive-like behaviors by modulating the AKT/CREB/BDNF pathway, the serotonin pathway of tryptophan metabolism, and the gut microbiota composition.
BACKGROUND: Schisandrin C (SCC), a bioactive lignan compound derived from Schisandra chinensis (S. chinensis), has been demonstrated to promote intestinal health. However, the antidepressant activity of SCC and its impact on the gut‒brain axis have not been reported. PURPOSE: This study aimed to investigate the antidepressant effects of SCC and elucidate its molecular mechanisms through modulation of the microbiota‒gut‒brain axis. METHODS: Artificial intelligence (AI)-based target protein prediction, network pharmacology analysis, and experimental validation using intestinal cells, Caenorhabditis elegans, and mice models were conducted. Targeted metabolomics, gut microbiota analyses, and molecular biology techniques were employed for mechanistic elucidation. RESULTS: SCC treatment effectively suppressed depressive-like behaviors in mice subjected to chronic unpredictable mild stress (CUMS). SCC upregulated brain-derived neurotrophic factor (BDNF) expression in the brain by regulating the AKT/CREB/BDNF signaling pathway. Additionally, integrated network pharmacology, molecular docking, and metabolomics analyses revealed that SCC significantly increased brain serotonin levels by inhibiting monoamine oxidase (MAO) activity. Furthermore, SCC increased the abundance of Akkermansia and Bifidobacterium, as observed both in the synthetic microbial community in vitro and in the gut microbiota in vivo. Additionally, SCC effectively alleviated intestinal barrier dysfunction and reduced intestinal inflammation in vitro in intestinal cells, in vivo in C. elegans infected with Bacteroides fragilis, and in vivo in the CUMS-induced mice model. CONCLUSION: SCC improves depressive-like behaviors by modulating the microbiota‒gut‒brain axis. These findings underscore the potential of SCC as an effective therapeutic agent for depression.
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Study on the mechanism of gut microbiota in the pathogenetic interaction between depression and Parkinson 's disease.
Depression and Parkinson's disease share pathogenetic characteristics, meaning that they can impact each other and exacerbate their respective progression. From a pathogenetic perspective, depression can develop into Parkinson's disease and is a precursor symptom of Parkinson's disease; Parkinson's disease is also often accompanied by depression. From a pharmacological perspective, the use of antidepressants increases the risk of developing Parkinson's disease, and therapeutic medications for Parkinson's disease can exacerbate symptoms of depression. Therefore, identifying how Parkinson's disease and depression impact each other in their development is key to formulating preventive measures and targeted treatment. One commonality in the pathogenesis of depression and Parkinson's disease are alterations in the gut microbiota, with mechanisms interacting in neural, immune inflammatory, and neuroendocrine pathways. This paper reviews the role of gut microbiota in the pathogenesis of depression and Parkinson's disease; conducts a study of the relationship between both conditions and medication; and suggests that dysregulated gut microbiota may be a key factor in explaining the relationship between Parkinson's disease and depression. Finally, on the basis of these findings, this article hopes to provide suggestions that new ideas for the prevention and treatment of depression and Parkinson's disease.
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[Gut microbiota and depression : Pathophysiology of depression: hypothalamic-pituitary-adrenal axis and microbiota-gut-brain axis].
Depression is a chronic disease with a complex multifactorial and still not fully clarified etiology. Due to new insights after recent investigations of the microbiota-gut-brain (MGB) axis, a relationship between a disrupted gut microbiota composition and the probability to develop a depression can be assumed. This hypothesis is supported by evidence that there is a strong communication between gut microbiota and the central nervous system (CNS) and that this communication is mediated through the MGB axis. Apparently, this bidirectional axis can be modulated by environmental factors, such as stress, pharmaceuticals (in particular antibiotics) and dietary habits. Moreover, modulation of this axis can also result in mood alterations. As the hypothalamic-pituitary-adrenal (HPA) axis is a key element regulating the MGB axis and is also related to the pathophysiology of depression, it is important to understand the relationship between both biological systems. An English language literature search was conducted using the biomedical database PubMed. We used combined terms, such as "gut microbiota", "depression", "hypothalamic-pituitary-adrenal axis" or "microbiota-gut-brain axis". The current literature supports the idea that the MGB axis has an impact on the risk to develop depression and that stress modulation through the HPA axis plays a key role in this context.
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Dose-dependent action of cordycepin on the microbiome-gut-brain-adipose axis in mice exposed to stress.
The high risk for anxiety and depression among individuals with stress has become a growing concern globally. Stress-related mental disorders are often accompanied by symptoms of metabolic dysfunction. Cordycepin is a Chinese herbal medicine commonly used for its metabolism-enhancing effects. We aimed to investigate the dose-dependent effects of cordycepin on psycho-metabolic disorders induced by stress. Our behavioral tests revealed that 12.5 mg/kg cordycepin by oral gavage significantly attenuated the anxiety- and depression-like behaviors induced by stress in mice. At 25 mg/kg, cordycepin restored the reduced weight and cell size of adipose tissues caused by stress. Besides ameliorating the metabolic dysbiosis of gut microbiota due to stress, cordycepin significantly reduced the elevated contents of 5-hydroxyindoleacetic acid in the serum and prefrontal cortex at 12.5 mg/kg and reversed the decrease in adipose induced by stress at 25 mg/kg. Correlation analyses further revealed that 12.5 mg/kg cordycepin reversed stress-induced changes in the intestinal microbiome of NK4A214_group and decreased serum Myristic acid and PC(15:0/18:1(11Z)) and cytokines, such as IFN-γ and IL-1β. 25 mg/kg cordycepin reversed stress-induced changes in the abundances of Prevoteaceae_UCG-001 and Desulfovibrio, increased serum L-alanine level, and decreased serum Inosine-5'-monophosphate level. Cordycepin thereby ameliorated the anxiety- and depression-like behaviors as well as disturbances in the adipose metabolism of mice exposed to stress. Overall, these findings offer evidence indicating that the prominent effects of cordycepin in the brain and adipose tissues are dose dependent, thus highlight the importance of evaluating the precise therapeutic effects of different cordycepin doses on psycho-metabolic diseases.
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Corydalis yanhusuo Polysaccharides Ameliorate Chronic Stress-Induced Depression in Mice through Gut Microbiota-Derived Short-Chain Fatty Acid Activation of 5-Hydroxytryptamine Signaling.
Depression, a prevalent psychiatric disorder, presents a serious health risk to humans. Increasing evidence suggested that the gut microbiota and the 5-hydroxytryptamine (5-HT) pathway both contribute significantly to depression. This research aimed to investigate how Corydalis yanhusuo polysaccharides (CYP) could potentially alleviate depression induced by chronic unpredictable mild stress in mice, as well as its underlying mechanism. The sucrose preference test, tail suspension test, and forced swimming test were employed to evaluate the behavior of mice. Enzyme-linked immunosorbent assay and PCR techniques were utilized to measure depression-related factors (dopamine [DA], 5-HT, norepinephrine [NE], brain-derived neurotrophic factor [BDNF], tryptophan hydroxylase 2 [TPH-2], 5-hydroxytryptophan [5-HTP], and tryptophan hydroxylase [TPH-1] levels). Hematoxylin and eosin staining and Nissl staining were conducted to observe histopathological changes in the hippocampus, the differences in the diversity of gut flora between groups were analyzed using 16S rRNA sequencing, and gas chromatography-mass spectrometry metabolomics was utilized to evaluate short-chain fatty acid (SCFA) concentrations. The findings indicated that CYP treatment increased the sucrose preference index, decreased the immobility time, and improved neuropathological injury. In depressed mice, CYP improved the dysregulation of the gut microbiota, and increased the SCFA levels. In addition, CYP enhanced the DA, 5-HT, NE, BDNF, and TPH-2 levels in the brain and the expression of 5-HTP and TPH-1 in the colon, while SCFAs were positively correlated with these levels. In summary, our study suggested that CYP may mitigate depression by ameliorating gut microbiota dysregulation, promoting the generation of SCFAs, and activation of 5-HT signaling expression.