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Xiaoyaosan against depression through suppressing LPS mediated TLR4/NLRP3 signaling pathway in "microbiota-gut-brain" axis.
ETHNOPHARMACOLOGICAL RELEVANCE: Depression impairs not only central nervous system, but also peripheral systems of the host. Gut microbiota have been proved to be involved in the pathogenesis of depression. Xiaoyaosan (XYS) has a history of over a thousand years in China for treating depression, dramatically alleviating anxiety, cognitive disorders, and especially gastrointestinal dysfunctions. Yet, it still just scratches the surface of the anti-depression mechanisms of XYS. AIM OF THE STUDY: This study aims to elucidate the mechanism of actions of XYS from the perspective of "microbiota-gut-brain" axis. MATERIALS AND METHODS: We firstly evaluated the effects of XYS on the macroscopic behaviors of depressed rats that induced by chronic unpredictable mild stress (CUMS). Secondly, the effects of XYS on intestinal homeostasis of depressed rats were revealed by using dysbacteriosis model. Subsequently, the underlying mechanisms were demonstrated by 16S rRNA gene sequencing technology and molecular biology methods. Finally, correlation analysis and visualization of the anti-depression effects of XYS were performed from the "microbiota - gut - brain" perspective. RESULTS: Our data indicated that XYS ameliorated the depression-like symptoms of CUMS rats, partly depending on the presence of gut microbiota. Furthermore, we illustrated that XYS reversed CUMS-induced gut dysbiosis of depressed rats in terms of decreasing the Bacteroidetes/Firmicutes ratio and the abundances of Bacteroides, and Corynebacterium, while increasing the abundances of Lactobacillus and Adlercreutzia. The significant enrichment of Bacteroides and the level of lipopolysaccharides (LPS) suggested that depression damaged the immune responses and gut barrier. Mechanistically, XYS significantly down-regulated the expression levels of factors that involved in TLR4/NLRP3 signaling pathway in the colon and brain tissues of depressed rats. In addition, XYS significantly increased the levels of claudin 1 and ZO-1, showing that XYS positively maintained the integrity of gut and blood-brain barriers (BBB). CONCLUSION: Our study offers insights into the anti-depression effects of XYS through a lens of "microbiota-TLR4/NLRP3 signaling pathway-barriers", providing a foundation for enhancing clinical efficiency and enriching drug selection, and contributing to our understanding of the mechanisms of traditional Chinese medicines (TCMs) in treating depression.
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Nanocrystalline cellulose-geniposide complex enhances gut-brain axis modulation for depression treatment.
Depression, a major global health issue, is closely associated with imbalances in gut microbiota and altered intestinal functions. This study investigates the antidepressant potential of a composite of Geniposide (GP) and Nanocrystalline Cellulose (NCC), focusing on its effects on the gut-brain axis. Utilizing network pharmacology, GP was identified as a key compound targeting the BCL2 gene in depression management. Experimental approaches, including a chronic unpredictable mild stress (CUMS) model in mice, cellular assays, and fecal microbiota transplantation (FMT), were used to evaluate the composite's effectiveness. Results indicate that GP activates the adenosine monophosphate-activated protein kinase (AMPK) pathway by upregulating BCL2, enhancing intestinal barrier integrity, and balancing gut flora. These mechanisms contribute to its positive effects on hippocampal function and depressive-like behaviors in mice, suggesting that the GP-NCC composite could be a promising avenue for developing depression therapies that target gut health.
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The Gut-Brain Axis in Ganoderma lucidum's Antidepressant Effects in Cancer Comorbidity: A Review.
Depression is a common and serious comorbidity in patients with cancer and is associated with worse clinical outcomes and reduced quality of life. Gut microbiota dysbiosis has been implicated as a pathogenic factor, potentially driving depressive symptoms through metabolic alterations and disruption of the gut-brain axis-mechanisms that may also contribute to cancer progression. The medicinal mushroom Ganoderma lucidum has been investigated primarily for its immunomodulatory effects in patients with cancer, and emerging preclinical evidence suggests that it may possess antidepressant properties, positioning it as a candidate for microbiota-targeted intervention. Preclinical evidence indicates that G. lucidum can act as a gut microbiota modulator and alleviate depressive-like behaviors in animal models, with mechanisms involving the correction of dysbiosis and the normalization of key metabolic pathways, including those related to short-chain fatty acids and tryptophan, thereby improving inflammatory tone and neuroendocrine function. In contrast, human studies have largely focused on its immunomodulatory and quality-of-life effects in patients with cancer, with limited direct assessment of depression-related outcomes. Consequently, current mechanistic insights are derived predominantly from animal studies and require validation in large-scale human trials. This review proposes that gut microbiota modulation represents a plausible and potentially important mechanism through which G. lucidum may exert antidepressant effects in the context of cancer comorbidity, namely that the "G. lucidum-gut microbiota-depression" pathway is an inferred translational framework rather than an established clinical mechanism. Nonetheless, this framework provides a rationale for future efforts to develop G. lucidum and its active components into microbiota-based therapeutics for cancer-related depression.
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Understanding morphine influence on gut health and depression: Evidence from a rat model.
BACKGROUND: Opioid addiction severely impacts mental health, and recent evidence links opioid use to gut microbiota changes and mood disorders. This study examines how morphine influences gut microbiota, inflammatory responses, and depressive behaviors in rats. METHODS: Male Wistar rats received escalating morphine sulfate doses (30 mg/kg) or served as controls. Depressive-like behaviors were assessed via the Forced Swim Test (FST) and Sucrose Preference Test (SPT). Gut microbiota composition was analyzed using qPCR, and pro-inflammatory markers were measured in intestinal tissue. RESULTS: Morphine treatment induced depressive-like behaviors, as evidenced by increased immobility time in the FST (120 s vs. 69.5 s in controls; P<0.01) and reduced sucrose preference (40%vs. 70% in controls; P<0.05). Gut microbiota analysis revealed a significant decrease in beneficial bacteria, including Bifidobacterium longum (P<0.05) and Lactobacillus rhamnosus (P=0.02), and an increase in pathogenic bacteria such as Fusobacterium nucleatum (P<0.001) and Clostridium difficile (P<0.01). Enterococcus faecalis was also significantly increased in the morphine-treated group (P<0.001). Ileal inflammatory marker analysis showed significantly elevated TNF-α (2.15±0.45, P<0.001) and IL-1β (3.81±1.16, P<0.001) mRNA levels, with a trend towards elevated IL-6 (1.72±1.75; P=0.22). CONCLUSION: Morphine treatment significantly alters gut microbiota composition, worsening depressive-like behaviors and inducing intestinal inflammation. These findings highlight the complex link between opioid use, gut health, and mental well-being, suggesting microbiota-targeted therapies may help manage opioid addiction and related psychological disorders. Further research is needed to explore how modulating gut microbiota can lessen the negative effects of opioid therapy.
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Heat-killed Lactobacillus helveticus strain MCC1848 confers resilience to anxiety or depression-like symptoms caused by subchronic social defeat stress in mice.
The gut microbiota is involved in the pathogenesis of stress-related disorders. Probiotics can benefit the central nervous system via the microbiota-gut-brain axis, which raises the possibility that probiotics are effective in managing depression. In the present study, we examined the effects of heat-killed Lactobacillus helveticus strain MCC1848 in subchronic and mild social defeat stress (sCSDS) model mice (a widely used animal model of depression). MCC1848 supplementation significantly enhanced the interaction time in the social interaction test and sucrose preference ratio in the sucrose preference test, suggesting that MCC1848 improved anxiety- or depressive-like behaviors in sCSDS mice. The gene expression profile analysis of the nucleus accumbens, which plays an important role in stress resilience, indicated that MCC1848 ameliorated sCSDS-induced gene expression alterations in signal transduction or nervous system development. These findings suggest that MCC1848 supplementation is useful as a preventive strategy for chronic-stress-induced depression.
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Antidepressant effects of supercritical CO2 extract of Citri Reticulatae Pericarpium through mediating gut microbiota dysbiosis, tryptophan and bile acid metabolisms.
Citri Reticulatae Pericarpium (CRP) is a traditional Chinese medicinal herb with both medicinal and edible properties. The supercritical CO2 extract of Citri Reticulatae Pericarpium (C-CRP) has shown potential antidepressant effects, but the precise mechanisms remain unclear. In this paper, we confirmed that C-CRP alleviated depressive-like behaviors in a chronic unpredictable mild stress (CUMS) depression rat model, as evidenced by increased sucrose preference in the sucrose preference test (SPT), increased total distance traveled in the open field test (OFT), reduced immobility time in both the tail suspension test (TST) and forced swim test (FST), and elevated serum levels of 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE) in CUMS rats. C-CRP reshaped gut microbiota dysbiosis, significantly regulating the abundance of specific bacteria, including Lactobacillus, unclassified_f_Lachnospiraceae, Blautia, Allobaculum, Prevotella, and UCG-005 via 16S rRNA sequencing. Untargeted/targeted metabolomics indicated that C-CRP normalized the dysregulated metabolic profiles in plasma, urine, and feces of depressed rats, and identified tryptophan metabolism and bile acid metabolism as key routes through which C-CRP exerts its effects, which was corroborated by pathway-specific protein and metabolite changes. Through multivariate correlation analysis, Blautia was identified as a crucial gut bacterium associated with the antidepressant efficacy of C-CRP, which was further confirmed in lipopolysaccharide (LPS)-induced depression-like mice by oral administration of Blautia obeum. Thus, the findings demonstrate that C-CRP exerts antidepressant effects by modulating specific gut bacteria-most notably Blautia obeum-and regulating tryptophan and bile acid metabolic pathways, thereby alleviating depression-like behaviors in the CUMS rats.
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Dietary polyphenols as modulators of the microbiota-gut-brain axis in depression and anxiety: a preclinical perspective.
Mood and anxiety disorders are increasingly prevalent conditions, and growing evidence indicates that the gut microbiota plays a central role in their pathophysiology through the microbiota-gut-brain axis. This review summarizes the current preclinical evidence of the effects of dietary polyphenols on this axis and their implications for mood regulation, while also discussing their translational relevance based on human-equivalent dose estimations and available clinical findings. Overall, the literature supports that polyphenols modulate the gut microbial composition and diversity, promote beneficial bacterial groups, and alter microbiota-derived metabolites, particularly short-chain fatty acids, while improving the gut barrier integrity and reducing systemic and neuroinflammatory processes. These microbiota-related changes were often associated with alterations in neurotransmitter systems, neurotrophic factors, and markers of synaptic plasticity, resulting in improvements in depressive- and anxiety-like behaviors and, in some cases, cognitive performance in animal models. Correlation analyses further strengthen the links between specific microbial taxa, metabolites, and neurobehavioral outcomes, reinforcing the relevance of gut microbiota modulation as a determinant pathway. In addition, dose translation analyses reveal substantial variability in dietary feasibility, and clinical studies, although limited, generally support beneficial effects on mood-related outcomes. Collectively, these findings highlight dietary polyphenols as promising modulators of the microbiota-gut-brain axis and emphasize their relevance for future nutritional strategies targeting mood-related disorders.
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Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model.
Accumulating evidence suggests a key role of the gut-microbiota-brain axis in the antidepressant actions of certain compounds. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, showed rapid and sustained antidepressant effects in treatment-resistant depressed patients. In contrast, another NMDAR antagonist, lanicemine, did not exhibit antidepressant effects in such patients. (R)-ketamine, the (R)-enantiomer of ketamine, has rapid-acting and long-lasting antidepressant effects in rodent models of depression. Here we compared the effects of (R)-ketamine and lanicemine on depression-like phenotype and the composition of the gut microbiota in susceptible mice after chronic social defeat stress (CSDS). In behavioral tests, (R)-ketamine showed antidepressant effects in the susceptible mice, whereas lanicemine did not. The 16S ribosomal RNA gene sequencing of feces demonstrated that (R)-ketamine, but not lanicemine, significantly attenuated the altered levels of Bacteroidales, Clostridiales and Ruminococcaceae in the susceptible mice after CSDS. At the genus level, (R)-ketamine significantly attenuated the marked increase of Clostridium in the susceptible mice. In contrast, the effects of lanicemine were less potent than those of (R)-ketamine. This study suggests that the antidepressant effects of (R)-ketamine might be partly mediated by the restoration of altered compositions of the gut microbiota in a CSDS model.
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Post-stroke depression: exploring gut microbiota-mediated barrier dysfunction through immune regulation.
Post-stroke depression (PSD) is one of the most common and devastating neuropsychiatric complications in stroke patients, affecting more than one-third of survivors of ischemic stroke (IS). Despite its high incidence, PSD is often overlooked or undertreated in clinical practice, and effective preventive measures and therapeutic interventions remain limited. Although the exact mechanisms of PSD are not fully understood, emerging evidence suggests that the gut microbiota plays a key role in regulating gut-brain communication. This has sparked great interest in the relationship between the microbiota-gut-brain axis (MGBA) and PSD, especially in the context of cerebral ischemia. In addition to the gut microbiota, another important factor is the gut barrier, which acts as a frontline sensor distinguishing between beneficial and harmful microbes, regulating inflammatory responses and immunomodulation. Based on this, this paper proposes a new approach, the microbiota-immune-barrier axis, which is not only closely related to the pathophysiology of IS but may also play a critical role in the occurrence and progression of PSD. This review aims to systematically analyze how the gut microbiota affects the integrity and function of the barrier after IS through inflammatory responses and immunomodulation, leading to the production or exacerbation of depressive symptoms in the context of cerebral ischemia. In addition, we will explore existing technologies that can assess the MGBA and potential therapeutic strategies for PSD, with the hope of providing new insights for future research and clinical interventions.
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Daidzein alleviates chronic restraint stress-induced depression-like behavior by regulating neuroinflammation and synaptic plasticity via microbiota-gut-brain axis.
BACKGROUND: Depression is one of the most serious psychological disorders worldwide. Growing evidence suggests that the gut-brain axis plays a pivotal role in its pathophysiology. Daidzein, a naturally occurring isoflavone compound, exhibits neuroprotective properties and can be metabolized by gut microbiota into highly bioactive secondary metabolites. PURPOSE: This study aims to evaluate the antidepressant effects of daidzein and to investigate its underlying mechanisms, particularly mediated by the gut microbiome. STUDY DESIGN AND METHODS: We employed the chronic restraint stress (CRS) mice models and classic behavioral tests to investigate the therapeutic effect of daidzein. Furthermore, we used 16S rRNA sequencing and metabolomics methods to explore the regulatory effects of daidzein on key functional bacteria and metabolites after CRS exposure. Intestinal barrier function was evaluated by histopathology and FITC-dextran detection. Neuroinflammatory responses, neuronal morphology, and plasticity were also evaluated using immunofluorescence staining, western blotting, and Nissl staining. Finally, we employed an antibiotic intervention experiment to validate the pivotal role of gut microbiota in the antidepressant effect of daidzein. RESULTS: Our data demonstrate that daidzein administration mitigated the depression-like behaviors in CRS mice, with gut microbiota composition playing a potentially critical mediating role. Specifically, daidzein induced significant modulations in gut microbial communities (Rikenella, Enterococcus, Akkermansia, and Ruminococcus) and associated metabolic profiles, particularly affecting short-chain fatty acid biosynthesis (valeric acid and acetic acid) and bile acid metabolism (cholic acid/allocholic acid, taurine-deoxycholic acid, and 3-dehydrocholic acid). Mechanistic investigations revealed that daidzein exerted protective effects on intestinal barrier integrity while concurrently reducing pro-inflammatory cytokine levels in both serum and hippocampus. At the neurobiological level, daidzein exhibited multifaceted regulatory effects, including attenuation of glial cell activation (microglia and astrocytes), normalization of FXR/NF-κB/NLRP3 inflammasome signaling, and enhancement of BDNF/TrkB neurotrophic pathways. These molecular changes were further associated with improved neuronal morphological complexity and upregulated expression of synaptic plasticity markers (SYP and PSD95) in the hippocampus. CONCLUSION: These data propose a gut-brain axis-mediated mode of action for daidzein's antidepressant-like effects, highlighting its promise as a potential candidate for depression, while further investigations are required to elucidate the specific microbial and metabolic drivers of these effects.