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The Role of Gut Bacteria and Plasma Metabolites in Predicting Post-Stroke Depression in Patients with Acute Ischemic Stroke.
INTRODUCTION: Early diagnosis of Post-Stroke Depression (PSD) is challenging. This study aimed to identify possible biomarkers in gut microbiota and plasma metabolites within 72 hours after Acute Ischemic Stroke (AIS) to predict PSD occurring 2 weeks later. METHOD: In this study, 86 patients with AIS were observed within 3 days of stroke onset and followed up for 2 weeks. We collected the feces and plasma within 72 hours of AIS onset for 16S rRNA sequencing and liquid chromatography-mass spectrometry analysis, respectively. RESULTS: At the genus level, PSD patients at 2 weeks following a stroke had a higher relative abundance of Blautia, Eubacterium_hallii_group, Tyzzerella, and a lower abundance of Ellin6067, Massilia, Luedemannella, and Gemmataceae_others within 3 days of AIS onset. Meanwhile, when all metabolites in plasma collected within 72 hours after AIS onset were used to predict 2-week PSD, 31 altered metabolites were identified, of which 28 metabolites increased and 3 decreased, belonging predominantly to steroid and steroid derivatives, glycerophospholipids, fatty acyls, and prenol lipids. The Area Under the Curve (AUC) values for the clinical data, metabolic profiles, gut microbiota, and combined dataset were 0.664 (0.549,0.779), 0.739 (0.621, 0.857), 0.870 (0.781,0.960), and 0.955 (0.888,1), respectively. DISCUSSION: Our study identified potential biomarkers from clinical data, gut bacteria, and plasma metabolites that contribute to PSD. Within 72 hours after AIS, combining these biomarkers from all three sources showed preliminary ability to predict PSD at 2 weeks. Metabolites had the highest contribution, followed by gut bacteria and clinical data. CONCLUSION: A biomarker panel including metabolites, gut microbiota, and clinical data within 72 hours after AIS onset could preliminarily predict PSD 2 weeks later.
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Hypericin: A potential gut microbiota-based therapeutic for postpartum depression via modulating bile acid metabolism.
BACKGROUND: Postpartum depression (PPD) is a mental disorder that occurs in a special period of time, but its pathophysiological mechanism is still unclear. Although hypericin has been shown to have therapeutic effects in previous studies, the underlying mechanisms of its treatment of PPD, especially its interaction with the gut-brain axis, remain to be explored. The aim of this study was to investigate the mechanism of hypericin in the treatment of PPD. METHODS: The PPD rat model was established by ovariectomy and hormone withdrawal after simulating pregnancy. Postpartum depression-like behavior was assessed by sucrose preference test and open field test. We integrated 16S rRNA sequencing, targeted plasma bile acid metabolomics, brain tissue transcriptomics, histopathology and molecular biology to explain the mechanism. RESULTS: Hypericin intervention significantly improved the postpartum depression-like behavior of PPD model rats. This effect was abolished by depletion of the microbiota induced by antibiotic sweeps, thus establishing that the involvement of the gut microbiota is required for the efficacy of hypericin. Hypericin can reverse the abnormal changes of gut microbiota, bile acid metabolism and inflammatory response observed in PPD model, so as to play a role in the treatment of PPD. CONCLUSION: Hypericin plays an antidepressant role in PPD model, mainly by restoring gut microbiota homeostasis, thereby correcting bile acid metabolism disorders. In this study, the "gut microbiota-bile acid" axis is the key pathological feature and therapeutic target of PPD, and hypericin is expected to become a therapeutic candidate based on the gut microbiota.
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Gut-brain axis modulation by sudachi peel extract enhances resilience to chronic social defeat stress in mice.
BACKGROUND: Sudachitin, an anti-inflammatory compound from Citrus sudachi peel, may influence stress resilience. We examined whether sudachi peel extract affects depression-like behaviors and gut microbiota dysbiosis in mice subjected to chronic social defeat stress (CSDS). METHODS: First, we examined the effect of sudachitin on depression-like behavior and plasma interleukin-6 (IL-6) levels following lipopolysaccharide (LPS, 0.5 mg/kg) administration. Next, we investigated whether supplementation with sudachi peel extract could modulate the gut microbiota dysbiosis induced by CSDS. RESULTS: Sudachitin prevented LPS-induced depression-like behavior and the rise in plasma IL-6. In control mice, CSDS increased IL-6, induced splenomegaly, and caused anhedonia-like behavior. These changes were absent in the sudachi peel extract group. Although alpha-diversity of the gut microbiota remained abnormal under CSDS, beta-diversity was significantly altered by sudachi peel extract. Moreover, plasma IL-6 levels and Iba1 expression in the prefrontal cortex correlated with the relative abundance of certain gut bacteria. LIMITATIONS: The exact mechanisms behind the resilience-promoting effects of sudachi peel extract remain unclear. CONCLUSION: Sudachi peel extract supplementation enhances resilience to CSDS by preventing anhedonia, reducing plasma IL-6 levels and splenomegaly, and modulating gut microbiota composition. Further research is needed to clarify these anti-inflammatory pathways and the roles of additional pro-inflammatory cytokines.
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Melatonin alleviates airway inflammation and anxiety-depression in asthma via gut microbiota-SCFA axis-mediated inhibition of microglial activation.
BACKGROUND: Asthma frequently co-occurs with anxiety and depression, yet the mechanisms underlying this lung-brain comorbidity remain elusive. The gut-lung-brain axis has emerged as a potential key mediator. METHODS: Using an ovalbumin (OVA)-induced murine asthma model, we administered melatonin or sodium butyrate via drinking water. We assessed airway inflammation, lung function, anxiety- and depression-like behaviors, gut microbiota composition, short-chain fatty acid (SCFA) levels, and the MAPK/P65/NLRP3 signaling pathway in the hippocampus and BV2 microglial cells. Fecal microbiota transplantation (FMT) and antibiotic depletion experiments were conducted to establish causality. RESULTS: Both melatonin and sodium butyrate significantly alleviated airway inflammation, improved lung function, and ameliorated anxiety- and depression-like behaviors in asthmatic mice. Melatonin increased gut-derived butyrate levels and restored gut microbiota balance. FMT from melatonin-treated donors replicated the therapeutic benefits, whereas antibiotic-mediated microbiota depletion abrogated the effects of melatonin. Mechanistically, both treatments inhibited the activation of the MAPK/P65/NLRP3 pathway in hippocampal microglia and LPS-stimulated BV2 cells. CONCLUSION: Our findings demonstrate that melatonin mitigates asthma-related airway inflammation and neuropsychiatric comorbidity by modulating the gut microbiota-SCFA axis and suppressing microglial activation via the MAPK/P65/NLRP3 pathway. This study highlights a novel systemic mechanism and potential therapeutic strategy for asthma and its comorbidities.
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Direct evidence for the involvement of intestinal reactive oxygen species in the progress of depression via the gut-brain axis.
Depression is a serious global social problem. Various therapeutic drugs have been developed based on the monoamine hypothesis; however, treatment-resistant depression is a common clinical issue. Recently, the gut-brain axis, which is associated with the hypothesis that the intestinal environment affects the brain, has garnered significant interest, and several studies have attempted to treat brain disorders based on this axis. These attempts include fecal transplantation, probiotics and prebiotics. In this study, we focused on intestinal reactive oxygen species (ROS) because excessive ROS levels disturb the intestinal environment. To elucidate the impact of scavenging intestinal ROS on depression treatment via the gut-brain axis, a novel polymer-based antioxidant (siSMAPoTN), which was distributed only in the intestine and did not diffuse into the whole body after oral administration, was used. siSMAPoTN selectively scavenged intestinal ROS and protected the intestinal environment from damage caused by chronic restraint stress (CRS). In addition, siSMAPoTN suppressed physiological and behavioral depression-related symptoms in the CRS mouse model.
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Chinese medicine formula Kai-Xin-San ameliorates depression-like behaviours in chronic unpredictable mild stressed mice by regulating gut microbiota-inflammation-stress system.
ETHNOPHARMACOLOGICAL RELEVANCE: Kai-Xin-San (KXS) has been prescribed by TCM doctors for treating psychiatric diseases with the core symptoms of anhedonia, amnesia, and dizziness. According to the symptoms of patients, KXS series formulae are created by varying the compatible ratio of herbs. Today, these formulae are still used in the clinic to treat major depressive disorders. AIM OF THE STUDY: We hoped to evaluate the antidepressant-like effect of Kai-Xin-San via regulation of the gut-brain axis. MATERIALS AND METHODS: Standardized extracts of three representative compatible ratios of KXS had been prepared, and quality control of the extracts was performed by HPLC-MS/MS. Chronic unpredictable mild stress (CUMS)-induced depression-like mice were used as the depression animal model. After KXS treatment, the antidepressant-like effects of KXS were assessed by behavioural tests. The gut microbiota compositions in the faeces were determined by 16S rRNA sequencing technology. The levels of LPS, pro-inflammatory cytokines and HPA-axis-related hormones were measured by ELISA kits, and the expression of barrier proteins in the small intestines and prefrontal cortex were determined by Western blot analysis. Furthermore, antibiotics were used to determine the correlation between KXS exerting an antidepressant-like effect and regulating the gut-brain axis. RESULTS: KXS alleviated depression-like behaviours in CUMS-exposed mice. Furthermore, these parameters were also found to be changed after KXS treatment. Alteration of the gut microbiota composition were found in the small intestines. A decrease in the LPS and the pro-inflammatory cytokines were found in both the small intestine and brain. An increase in the tight junction proteins was found in the gut epithelium barrier and the blood-brain barrier. A decrease in the stress-related hormones was found in the central nervous system. Furthermore, antibiotic treatment attenuated the antidepressant-like effect of KXS in CUMS-exposed mice. CONCLUSIONS: KXS exerted an antidepressant-like effect regulating the gut-brain axis, which included gut micro-environment modification, suppression of neuronal inflammation in the brain and inhibition of HPA axis activation in CUMS-induced depression-like mice.
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Arecoline Alleviates Depression via Gut-Brain Axis Modulation, Neurotransmitter Balance, Neuroplasticity Enhancement, and Inflammation Reduction in CUMS Mice.
This study evaluated the antidepressant effects of arecoline, a bioactive alkaloid derived from areca nuts, using a mouse model of depression induced by chronic unpredictable mild stress. Arecoline treatment significantly alleviated depression-like behaviors, including anxiety, anhedonia, and despair, as evidenced by behavioral tests. Mechanistically, arecoline restored serotonin and norepinephrine levels in the brain and serum, reduced pro-inflammatory markers such as IL-1β and LPS in both serum and colon, and enhanced hippocampal neuroplasticity through increased BDNF and PSD-95 expression. Moreover, arecoline modulated gut microbiota composition, particularly enriching beneficial species like Bifidobacterium pseudolongum and Ligilactobacillus murinus, and regulated serum metabolites associated with tryptophan metabolism, neurotransmitter synthesis, and oxidative stress. These findings demonstrate that arecoline exerts its antidepressant effects via a multitargeted approach involving the gut-brain axis, neurotransmitter modulation, and neuroplasticity enhancement. This study highlights arecoline as a promising therapeutic candidate for depression, emphasizing its potential to address both central and peripheral mechanisms.
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Puerarin ameliorates depression-like behaviors of with chronic unpredictable mild stress mice by remodeling their gut microbiota.
BACKGROUND: Puerarin is an isoflavone derivative isolated from the traditional Chinese medicine Pueraria Lobelia, which has proven to relieve depression-like behavior. However, its underlying antidepressant mechanisms have been poorly characterized. Herein, we explored whether Puerarin's antidepressant effect is associated with changes in the gut microbiota (GM). METHODS: The model of depression in mice featuring chronic unpredictable mild stress (CUMS) was eastablished, and its antidepressant effect was estimated by sugar water preference and forced swimming test. Genomic DNA extracted from fecal samples was employed to sequence the 16S rRNA gene for gut microbiota identification. RESULTS: Puerarin (100 mg/kg) treatment was found to alleviate the CUMS-induced depression-like behaviors. Furthermore, chronic stress led to pathological microbial flora, which was principally marked by the increased abundance of pathogenic bacteria (Proteobacteria, Flexispira, Desulfovibrio) and the decreased abundance of beneficial bacteria (Firmicutes, Bacillales, Lactobacillus). Intriguingly, puerarin treatment reversed these changes. LIMITATIONS: The specific role and anti-depression mechanism of characteristic gut microflora were not confirmed. CONCLUSION: Puerarin can remedy stress-induced disruptions of normal gut microflora. It is suggested that the antidepressant mechanism of puerarin may closely interact with restoring beneficial microflora.
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Structural characteristics and potential antidepressant mechanism of a water-insoluble β-1,3-glucan from an edible fungus Wolfiporia cocos.
A water-insoluble β-1,3-glucan (Wβ) with a molecular weight of 8.12 × 104 Da was extracted from an edible fungus Wolfiporia cocos. Its backbone was composed of 1,3-β-linked Glcp branched at the C-2, C-4, and C-6 positions, connecting more 1,3-β-linked Glcp with a triple helical structure. Wβ effectively ameliorated depressive symptoms, abnormality of neurotransmitters and inflammatory factors in chronic unpredictable mild stress (CUMS)-induced rats. Wβ also altered the composition of gut microbiota, especially Romboutsia, norank_f_Muribaculaceae and Ruminococcus. Integration of untargeted and targeted metabolomics and Western blotting analysis suggested that the short-chain fatty acids (SCFAs) and tryptophan metabolites were the most important metabolites involved in Wβ mediation. Wβ significantly modulated the levels of 7 SCFAs and 7 tryptophan metabolites, as well as the protein expression of two related enzymes (indoleamine-2,3-dioxygenase: IDO; kynurenine-3-monooxygenase: KMO). Our results suggest that Wβ exerts its antidepressant effect by influencing neurotransmitters and inflammatory factors through interactions between the gut microbiota, SCFA and tryptophan metabolites. The findings offer new insights into water-insoluble polysaccharides, especially β-glucan in structure analysis and utilization, and provide evidence that Wβ, a novel glucan from the often-discarded water-insoluble part of Wolfiporia cocos, has potential application in antidepressant health products.
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Gut Microbiota-Induced Changes in β-Hydroxybutyrate Metabolism Are Linked to Altered Sociability and Depression in Alcohol Use Disorder.
Patients with alcohol use disorder (AUD) present with important emotional, cognitive, and social impairments. The gut microbiota has been recently shown to regulate brain functions and behavior but convincing evidence of its role in AUD is lacking. Here, we show that gut dysbiosis is associated with metabolic alterations that affect behavioral (depression, sociability) and neurobiological (myelination, neurotransmission, inflammation) processes involved in alcohol addiction. By transplanting the gut microbiota from AUD patients to mice, we point out that the production of ethanol by specific bacterial genera and the reduction of lipolysis are associated with a lower hepatic synthesis of β-hydroxybutyrate (BHB), which thereby prevents the neuroprotective effect of BHB. We confirm these results in detoxified AUD patients, in which we observe a persisting ethanol production in the feces as well as correlations among low plasma BHB levels and social impairments, depression, or brain white matter alterations.