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Gastrodin alleviates the deterioration of depressive-like behavior and glucolipid metabolism promoted by chronic stress in type 2 diabetic mice.
The growing burden of psychological stress among diabetes patients has contributed to a rising incidence of depression within this population. It is of significant importance to conduct research on the impact of stress on diabetes patients and to explore potential pharmacological interventions to counteract the stress-induced exacerbation of their condition. Gastrodin is a low molecular weight bioactive compound extracted from the rhizome of Gastrodiae elata Blume, and it may be a preventive strategy for diabetes and a novel treatment for depression symptoms. However, its relevant pharmacological mechanisms for protecting against the impacts of psychological stress in diabetic patients are unclear. In this study, we performed 5 weeks CUMS intervention and simultaneously administered gastrodin (140 mg/kg, once daily) on T2DM mice, to investigate the potential protective effects of gastrodin. The protective effect of gastrodin was evaluated by behavioral tests, biochemical analysis, histopathological examination, RT-qPCR and gut microbiota analysis. We found that the depressive-like behavior and glucolipid metabolism could be deteriorated by chronic stress in type 2 diabetic mice, while gastrodin showed a protective effect against these exacerbations by regulating HPA hormones, activating FXR and Cyp7a1, reducing inflammatory and oxidative stress responses, and regulating ileal gut microbiota abundance. Gastrodin might be a potential therapeutic agent for mitigating the deterioration of diabetes conditions due to chronic stress.
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Effect of gut microbiota on depressive-like behaviors in mice is mediated by the endocannabinoid system.
Depression is the leading cause of disability worldwide. Recent observations have revealed an association between mood disorders and alterations of the intestinal microbiota. Here, using unpredictable chronic mild stress (UCMS) as a mouse model of depression, we show that UCMS mice display phenotypic alterations, which could be transferred from UCMS donors to naïve recipient mice by fecal microbiota transplantation. The cellular and behavioral alterations observed in recipient mice were accompanied by a decrease in the endocannabinoid (eCB) signaling due to lower peripheral levels of fatty acid precursors of eCB ligands. The adverse effects of UCMS-transferred microbiota were alleviated by selectively enhancing the central eCB or by complementation with a strain of the Lactobacilli genus. Our findings provide a mechanistic scenario for how chronic stress, diet and gut microbiota generate a pathological feed-forward loop that contributes to despair behavior via the central eCB system.
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The relationship between "microbiota-gut-brain" axis and depression: Chronic stress-induced inflammation.
This study aims to investigate the pathogenesis of depression in mice using the chronic unpredictable mild stress (CUMS) model, with a particular focus on the changes in inflammatory gene networks and inflammatory factor levels under the condition of gut microbiota dysbiosis. The results indicate that CUMS-induced mice exhibited significant depressive-like behaviors. Specifically, they displayed reduced sucrose intake in the sucrose preference test, decreased central area distance and time in the open field test, and reduced percentage of entries and time spent in the open arm in the elevated plus maze test. Molecular biological analysis indicated that CUMS treatment significantly upregulated the levels of inflammatory factors TNF-α, IL-1β, IL-6, and IFN-γ in the serum and hippocampus of mice. Through high-throughput sequencing and Pearson correlation analysis, it was found that the levels of inflammatory factors were significantly positively correlated with the expression of multiple inflammatory pathway genes, as well as the abundance of beneficial and harmful bacteria. Furthermore, the persistent changes in inflammatory factors ultimately led to neuronal cell death. This study provides strong evidence for the role of disrupted "microbiota-gut-brain" axis homeostasis in the pathogenesis of CUMS-induced depression in mice. This finding offers a new perspective for understanding the pathological mechanisms of depression and provides strategies for future depression treatment.
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Gut microbial trajectory in patients with bipolar depression: A longitudinal study.
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Gut bacteria-driven homovanillic acid alleviates depression by modulating synaptic integrity.
The gut-brain axis is implicated in depression development, yet its underlying mechanism remains unclear. We observed depleted gut bacterial species, including Bifidobacterium longum and Roseburia intestinalis, and the neurotransmitter homovanillic acid (HVA) in individuals with depression and mouse depression models. Although R. intestinalis does not directly produce HVA, it enhances B. longum abundance, leading to HVA generation. This highlights a synergistic interaction among gut microbiota in regulating intestinal neurotransmitter production. Administering HVA, B. longum, or R. intestinalis to mouse models with chronic unpredictable mild stress (CUMS) and corticosterone (CORT)-induced depression significantly improved depressive symptoms. Mechanistically, HVA inhibited synaptic autophagic death by preventing excessive degradation of microtubule-associated protein 1 light chain 3 (LC3) and SQSTM1/p62 proteins, protecting hippocampal neurons' presynaptic membrane. These findings underscore the role of the gut microbial metabolism in modulating synaptic integrity and provide insights into potential novel treatment strategies for depression.
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Anshen Bunao Syrup alleviates depression on CUMS rats by reducing neuroinflammation: Integral insights from transcriptomics, microbiomics, and metabolomics.
BACKGROUND: Anshen Bunao Syrup (ABS), a traditional Chinese medicinal formula, is widely used to treat neurological disorders such as insomnia, dizziness, and neurasthenia. However, its antidepressant effect and underlying mechanisms remain insufficiently characterized. PURPOSE: This study aims to comprehensively evaluate the antidepressant effect of ABS in a rat model, and to elucidate the underlying mechanism. METHODS: Chronic unpredictable mild stress (CUMS) induced depressive rats were used to evaluate the antidepressant effect of ABS. Histopathological alterations in the hippocampus and colonic mucosa were examined using Nissl and H&E staining. Microglial activation was evaluated by Iba-1 immunohistochemical staining. Gut microbiota composition and metabolic profiles were analyzed using 16S rRNA sequencing and untargeted metabolomics. Differential gene expression and pathway regulation were investigated by transcriptomics and confirmed by Western Blot (WB). RESULTS: ABS significantly ameliorated depressive-like behaviors and elevated dopamine and 5-Hydroxytryptamine levels in cortical regions. Furthermore, ABS mitigated hippocampal neuronal damage, suppressed microglial overactivation and reduced oxidative stress in the cortex. 16S rRNA sequencing analysis showed that ABS exerted antidepressant effects via modulation of the "microbiota-gut-brain" axis, particularly by altering intestinal microbiota composition, enhancing gut function, and suppressing HPA axis hyperactivity. Metabolomics revealed that ABS corrected metabolic disturbances, and alleviated inflammation-related metabolic disturbances, while transcriptomics indicated regulation of the Npas4-BDNF-PI3K/AKT signaling pathway, which was further confirmed by WB. CONCLUSION: ABS significantly ameliorated depression in a CUMS rat model, primarily through coordinated regulation of gut microbiota, metabolic homeostasis, and the Npas4-BDNF-PI3K/AKT signaling pathway, providing integrative mechanistic insights into its antidepressant effects.
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Healthy axis: Towards an integrated view of the gut-brain health.
Despite the lack of precise mechanisms of action, a growing number of studies suggests that gut microbiota is involved in a great number of physiological functions of the human organism. In fact, the composition and the relations of intestinal microbial populations play a role, either directly or indirectly, to both the onset and development of various pathologies. In particular, the gastrointestinal tract and nervous system are closely connected by the so-called gut-brain axis, a complex bidirectional system in which the central and enteric nervous system interact with each other, also engaging endocrine, immune and neuronal circuits. This allows us to put forward new working hypotheses on the origin of some multifactorial diseases: from eating to neuropsychiatric disorders (such as autism spectrum disorders and depression) up to diabetes and tumors (such as colorectal cancer). This scenario reinforces the idea that the microbiota and its composition represent a factor, which is no longer negligible, not only in preserving what we call "health" but also in defining and thus determining it. Therefore, we propose to consider the gut-brain axis as the focus of new scientific and clinical investigation as long as the locus of possible systemic therapeutic interventions.
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Gan-Mai-Da-Zao decoction ameliorates depressive-like behaviors in CUMS mice via the microbiota-metabolism-inflammation axis.
BACKGROUND: Gan-Mai-Da-Zao decoction (GMDZ), a traditional Chinese formulation used as both food and medicines, exhibits antidepressant effects. However, its underlying mechanisms, particularly those involving the gut-brain axis, remain unclear. PURPOSE: To integrate gut microbiota profiling, metabolomics, and neuroinflammation to systematically elucidate GMDZ's antidepressant mechanisms. STUDY DESIGN AND METHODS: Mice with depression-like behaviors were induced using a chronic unpredictable mild stress (CUMS) approach. Behavioral tests, multi-omics approaches (metabolomics, 16 s rRNA sequencing), and molecular biology techniques (histopathology, immunofluorescence, ELISA, qPCR, Western blot) were employed to investigate GMDZ's multi-target mechanisms. RESULTS: We identified 108 bioactive components, with 58 detected in plasma and 43 in the cerebral cortex, confirming systemic exposure and cerebral penetration of key constituents. GMDZ significantly ameliorated depressive-like behaviors and attenuated associated neuronal and colonic pathological damage. Mechanistically, GMDZ exerted its antidepressant effects through three novel and interconnected pathways: (1) Modulating gut microbiota composition and altering fecal and plasma metabolite profiles; (2) Reducing peripheral and central pro-inflammatory cytokines levels and suppressing NLRP3 inflammasome pathway activation; and (3) Enhancing blood-brain barrier (BBB) integrity by up-regulating occludin and claudin-5. CONCLUSION: GMDZ exerts antidepressant effects via a novel multi-target regulatory mechanism involving the microbiota-metabolite-inflammation axis. This study significantly advances our understanding of GMDZ's gut-brain axis mechanism and offers a new paradigm for mechanistic investigations of traditional Chinese medicine.
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Emulsified Mulberry Extract Alleviates CUMS-Induced Anxiety- and Depressive-Like Behaviors in Mice in Association with Gut Microbiota and Short-Chain Fatty Acids.
Mulberry, a traditional medicinal and edible plant rich in polysaccharides and flavonoids, has potential in regulating emotional behaviors. This study compared emulsified mulberry extract (EME) and aqueous mulberry extract (AME) on anxiety- and depression-like behaviors in male C57BL/6J mice exposed to chronic unpredictable mild stress (CUMS), and explored the underlying mechanisms of EME. EME alleviated anxiety- and depression-like behaviors more effectively than AME, with superior colloidal stability and dispersion. Metabolomic profiling revealed higher relative abundances of carbohydrates, eicosanoids, and flavonoids in EME. EME remodeled the gut microbiota-short-chain fatty acid (SCFA) axis, enhanced colonic barrier integrity, reduced serum lipopolysaccharide and proinflammatory cytokines, decreased stress hormone levels, elevated 5-hydroxytryptamine, and suppressed hippocampal glial activation while preserving neuronal integrity. Correlation analyses linked gut microbiota, SCFAs, hypothalamic-pituitary-adrenal axis activity, and behavioral phenotypes. These findings indicate that emulsification enhances the bioactivity of whole-component mulberry extracts, supporting their potential as natural food-based interventions for emotional disorders.
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AICAR improves depression-like behaviors and is associated with hippocampal AMPK activation and modulation of neurogenesis and neuroinflammation in a microbiota disruption model.
Gut microbiota alterations are associated with the onset of depression; however, the underlying mechanisms remain unclear. Activation of hippocampal AMP-activated protein kinase (AMPK) in ulcerative colitis mice with disrupted gut microbiota balance produces antidepressant effects. However, the relationship between hippocampal AMPK and antibiotic treatment (ABX)-induced depression-like behavior remains unclear. Therefore, we aimed to investigate whether 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR), an AMPK activator, is associated with the prevention of ABX-induced depression-like behaviors. ABX mice exhibited depression-like behaviors, as evidenced by prolonged immobility and reduced sucrose preference. In the hippocampus of the ABX mice, Iba1 and pro-inflammatory microglial markers were upregulated, whereas brain-derived neurotrophic factor (BDNF), CD206, arginase-1, and interleukin-10 were downregulated. Additionally, levels of AMPK phosphorylation, cAMP response element binding protein (CREB), and tropomyosin-related kinase B (TrkB) were decreased. AICAR administration attenuated these behavioral and molecular alterations. Phosphorylated AMPK was colocalized with the neuronal marker-NeuN-and microglial marker-Iba1. AICAR ameliorated the reduction in hippocampal neuron proliferation and survival and reduced microglial activation-associated morphological changes in the hippocampus. These findings suggest that AICAR administration is associated with antidepressant-like effects, potentially involving enhanced neurogenesis and attenuation of neuroinflammation in the hippocampus of ABX mice. Together, this study highlights the significance of hippocampal AMPK phosphorylation in depression associated with gut microbiota alterations, and suggests a potential target for therapeutic interventions.