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Associations between gut microbiota and Alzheimer's disease, major depressive disorder, and schizophrenia.
BACKGROUND: Growing evidence has shown that alterations in the gut microbiota composition were associated with a variety of neuropsychiatric conditions. However, whether such associations reflect causality remains unknown. We aimed to reveal the causal relationships among gut microbiota, metabolites, and neuropsychiatric disorders including Alzheimer's disease (AD), major depressive disorder (MDD), and schizophrenia (SCZ). METHODS: A two-sample bi-directional Mendelian randomization analysis was performed by using genetic variants from genome-wide association studies as instrumental variables for gut microbiota, metabolites, AD, MDD, and SCZ, respectively. RESULTS: We found suggestive associations of host-genetic-driven increase in Blautia (OR, 0.88; 95%CI, 0.79-0.99; P = 0.028) and elevated γ-aminobutyric acid (GABA) (0.96; 0.92-1.00; P = 0.034), a downstream product of Blautia-dependent arginine metabolism, with a lower risk of AD. Genetically increased Enterobacteriaceae family and Enterobacteriales order were potentially associated with a higher risk of SCZ (1.09; 1.00-1.18; P = 0.048), while Gammaproteobacteria class (0.90; 0.83-0.98; P = 0.011) was related to a lower risk for SCZ. Gut production of serotonin was potentially associated with an increased risk of SCZ (1.07; 1.00-1.15; P = 0.047). Furthermore, genetically increased Bacilli class was related to a higher risk of MDD (1.07; 1.02-1.12; P = 0.010). In the other direction, neuropsychiatric disorders altered gut microbiota composition. CONCLUSIONS: These data for the first time provide evidence of potential causal links between gut microbiome and AD, MDD, and SCZ. GABA and serotonin may play an important role in gut microbiota-host crosstalk in AD and SCZ, respectively. Further investigations in understanding the underlying mechanisms of associations between gut microbiota and AD, MDD, and SCZ are required.
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Shouhui Tongbian capsule is associated with antidepressant-like effects and gut-brain axis-related biological improvements in mouse models of depression.
BACKGROUND: Major depressive disorder (MDD) is a global health challenge with complex etiology. The gut-brain axis, particularly neuroinflammation and synaptic dysfunction, has emerged as a critical therapeutic target. Shouhui Tongbian Capsule (SHTB), a clinically used Chinese patent medicine for constipation, has shown potential in modulating gut microbiota and alleviating comorbid mood symptoms, yet its systemic antidepressant mechanisms remain unexplored. PURPOSE: This study aimed to evaluate the antidepressant-like effects of SHTB in mouse models and characterize accompanying gut- and brain-related biological changes. STUDY DESIGN AND METHODS: Network pharmacology was used to assess whether reported SHTB constituents were relevant to depression-related gene networks. Subsequent in vivo validation was conducted in lipopolysaccharide (LPS)-induced and chronic unpredictable mild stress (CUMS) mouse models of depression. Behavioral phenotypes, neuroinflammation, hippocampal neuronal and synaptic integrity, intestinal barrier function, and mRNA expression of selected predicted targets were evaluated. RESULTS: Exploratory network analysis indicated potential associations between reported SHTB constituents and depression-related gene networks, providing a preliminary rationale for animal experiments. In vivo, SHTB administration was associated with significant improvements in depressive- and anxiety-like behaviors in both LPS and CUMS-induced mouse models of depression. These behavioral effects were accompanied by attenuation of neuroinflammatory responses, preservation of hippocampal neuronal and synaptic features, maintenance of intestinal barrier integrity, and altered hippocampal expression of several neurotransmitter-related genes. CONCLUSION: SHTB showed significant antidepressant-like effects accompanied by gut-brain axis-related biological improvements. This study provides a novel, multi-evidence rationale for repurposing SHTB as a promising multi-target therapeutic agent for MDD, mediated via the gut-brain axis.
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Patient Perceptions of Microbiome-Based Therapies as Novel Treatments for Mood Disorders: A Mixed Methods Study: Perceptions des patients sur les thérapies basées sur le microbiome pour les troubles de l'humeur : une étude à méthodes mixtes.
OBJECTIVE: Medications are critical for treating major depressive disorder (MDD) and bipolar disorder (BD). Unfortunately, 30% to 40% of individuals do not respond well to current pharmacotherapy. Given the compelling growing body of research on the gut-brain axis, this study aims to assess patient perspectives regarding microbiome-based therapies (MBT) such as probiotics, prebiotics, dietary changes, or fecal microbiota transplantation (FMT) in the management of MDD and BD. METHODS: This single-centred observational study used quantitative and qualitative assessments to examine patient perceptions of MBT. Participants diagnosed with MDD or BD completed an anonymous questionnaire obtaining demographics, prior medication history, and symptom burden. Self-assessment questionnaires specific to each diagnosis were also used: Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR), Altman Self-Rating Mania Scale (ASRM), and General Anxiety Disorder Questionnaire (GAD-7). A logistic regression model analysed the association of MBT acceptance with disorder type, QIDS-SR, and GAD-7 scores. A bootstrap method assessed the proportion of MBT acceptance. The qualitative assessment consisted of 30-minute interviews to elicit perceptions and attitudes towards MBT. RESULTS: The qualitative assessment achieved information power with n = 20. Results from the 63-item MBT questionnaire (n = 43) showed probiotics (37.2%) as the top choice, followed by FMT (32.6%), dietary change (25.6%), and prebiotics (4.6%). A majority of participants (72.1%) expressed willingness to try MBT for their mood disorder, however, logistic regression analysis did not identify statistically significant predictors for MBT acceptance among disorder type, QIDS-SR, and GAD-7. CONCLUSION: There is an increased focus on the gut microbiota's role in mood disorders' etiology and treatment. Promising research and patient interest underscore the necessity for exploring and educating on patient perspectives and the factors influencing attitudes towards MBT.
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Antidepressant-like effects of the leaf extract of Mallotus oppositifolius (Geiseler) Müll. Arg. (Euphorbiaceae) in the chronic unpredictable mild stress model: A role of the gut-brain axis.
The gut microbiota has been posited as a target for the treatment of major depressive disorder. Herein, we investigated the effect of the hydroethanolic leaf extract of Mallotus oppositifolius (MOE) on the gut microbiota of mice and how this contributes to its known antidepressant-like effect. A 6-week chronic unpredictable mild stress (CUMS) procedure was employed in 7 groups of mice to induce depression. From the third week, oral MOE treatments (10, 30, 100 mg/kg) and two reference drugs, fluoxetine (12 mg/kg) and minocycline (40 mg/kg), known to affect the gut microbiota, were administered. The sixth and seventh groups were the vehicle stressed (VEH-S) and non-stressed groups (VEH-NS). Changes in depressive-like behaviors were assessed using sucrose preference test while the forced swimming test (FST) was used to assess sustained antidepressant-effect after treatment discontinuation. Moreover, changes in prefrontal cortex (PFC) and hippocampal serotonin (5-HT) levels were evaluated using enzyme-linked immunosorbent assay (ELISA). The effect of treatment on the profile of the gut microbiota of the groups was elucidated using 16S rRNA Oxford Nanopore sequencing. MOE and reference drugs reversed the depression-associated reduction in sucrose preference when compared to VEH-S. MOE (with peak effect at 30 mg/kg) reduced immobility while increasing swimming and climbing behaviors. MOE reversed CUMS-induced reduction of 5-HT concentration in PFC and hippocampus. The behavioral effects of MOE were associated with shifts in the gut microbiota of CUMS-exposed mice. The study has provided seminal evidence that MOE ameliorates CUMS-induced depressive symptoms by modulating gut microbiota and increasing brain 5-HT levels.
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Longitudinal gut microbiota composition during the perinatal period in women with different intensities of depressive symptoms.
OBJECTIVE: Depressive symptoms during the perinatal period significantly impact mothers and infants. Emerging evidence suggests a connection between gut microbiota and mood regulation. This study investigated whether depressive symptoms are associated with changes in the gut microbiota of women during the perinatal period. METHODS: Thirty-four pregnant women were screened for depression using the Edinburgh Postnatal Depression Scale (EPDS) and categorized based on symptom severity. Stool samples were collected during the third trimester and at two postpartum timepoints. All samples underwent 16S rRNA gene sequencing and quantification of short-chain fatty acids (SCFA) by gas chromatography-mass spectrometry (GC-MS). RESULTS: No differences in SCFA concentrations were observed between groups (p > 0.05). However, postpartum women with moderate to severe symptoms (MS group) had a significant increase in Enterobacteriaceae abundance compared to women with mild or absent symptoms (AM group) (p < 0.05). The Bifidobacterium genus increased significantly in both groups over time (p < 0.05). The MS group showed a reduction in depressive symptoms during psychiatric treatment (p < 0.05). CONCLUSION: These findings suggest a link between gut microbiota and perinatal depressive symptoms. Further research using microbiome-targeted approaches is needed to understand the broader implications for maternal health.
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Intermingling of gut microbiota with brain: Exploring the role of probiotics in battle against depressive disorders.
Depression is a debilitating psychiatric ailment which exerts disastrous effects on one's mental and physical health. Depression is accountable for augmentation of various life-threatening maladies such as neurodegenerative anomalies, cardiovascular diseases and diabetes. Depressive episodes are recurrent, pose a negative impact on life quality, decline life expectancy and enhance suicidal tendencies. Anti-depression chemotherapy displays marked adverse effects and frequent relapses. Thus, newer therapeutic interventions to prevent or combat depression are desperately required. Discovery of gut microbes as our mutualistic partner was made a long time ago and it is surprising that their functions still continue to expand and as of yet many are still to be uncovered. Experimental studies have revealed astonishing role of gut commensals in gut-brain signaling, immune homeostasis and hormonal regulation. Now, it is a well-established fact that gut microbes can alleviate stress or depression associated symptoms by modulating brain functions. Here in, we provide an overview of physiological alleyways involved in cross-talk between gut and brain, part played by probiotics in regulation of these pathways and use of probiotic bacteria as psychobiotics in various mental or depressive disorders.
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Prophylactic effects of supplementation of a combination of Lactobacillus lactis WHH2078 and saffron on depressive-like behaviors in mice exposed to chronic stress.
Depression is one of the most common psychiatric conditions worldwide, with an annual escalation in prevalence. The serotonin (5-Hydroxytryptamine [5-HT]) metabolism through the gut-brain axis has been revealed to be related to the development of depression. Our previous study demonstrated that Lactococcus lactis WHH2078 alleviated depression in mice by shaping the gut microbiome composition and 5-HT metabolism. However, little research has explored the synergistic effects of probiotics and natural mental health-improving products. In this study, three natural products (saffron, l-theanine, and phosphatidylserine), either individually or in combination, were orally administrated for 4 weeks in chronic restraint stress (CRS)-induced mice, and their depressive behaviors, hippocampal 5-HT, and serum corticosterone were assessed. Saffron demonstrated improvement of the depressive-like behaviors via multiple behavioral tests and reversed the declined concentration of 5-HT and increased concentration of corticosterone. Following an initial screening, saffron was chosen to be combined with WHH2078, referred to as WHHMOOD™. Furthermore, the effects of WHHMOOD were evaluated in mice with depressive-like behaviors. WHHMOOD reduced immobility time in the forced swimming test and tail suspension test, increased the time spent in the central area in open field test, and reduced the serum corticosterone level. Besides, WHHMOOD improved the CRS-induced gut microbial dysbiosis by reversing gut microbial diversity and the abundances of Ligilactobacillus, Candidatus Arthromitus, and Erysipelatoclostridium. Compared to WHH2078, WHHMOOD treatment significantly increased the travel distance and hippocampal 5-HT level in mice. In conclusion, WHHMOOD exhibited prophylactic effects on depressive-like in CRS mice, which may act as a promising agent for improving the symptoms of depression.
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Metabolomic signature of exposure and response to citalopram/escitalopram in depressed outpatients.
Metabolomics provides valuable tools for the study of drug effects, unraveling the mechanism of action and variation in response due to treatment. In this study we used electrochemistry-based targeted metabolomics to gain insights into the mechanisms of action of escitalopram/citalopram focusing on a set of 31 metabolites from neurotransmitter-related pathways. Overall, 290 unipolar patients with major depressive disorder were profiled at baseline, after 4 and 8 weeks of drug treatment. The 17-item Hamilton Depression Rating Scale (HRSD17) scores gauged depressive symptom severity. More significant metabolic changes were found after 8 weeks than 4 weeks post baseline. Within the tryptophan pathway, we noted significant reductions in serotonin (5HT) and increases in indoles that are known to be influenced by human gut microbial cometabolism. 5HT, 5-hydroxyindoleacetate (5HIAA), and the ratio of 5HIAA/5HT showed significant correlations to temporal changes in HRSD17 scores. In the tyrosine pathway, changes were observed in the end products of the catecholamines, 3-methoxy-4-hydroxyphenylethyleneglycol and vinylmandelic acid. Furthermore, two phenolic acids, 4-hydroxyphenylacetic acid and 4-hydroxybenzoic acid, produced through noncanconical pathways, were increased with drug exposure. In the purine pathway, significant reductions in hypoxanthine and xanthine levels were observed. Examination of metabolite interactions through differential partial correlation networks revealed changes in guanosine-homogentisic acid and methionine-tyrosine interactions associated with HRSD17. Genetic association studies using the ratios of these interacting pairs of metabolites highlighted two genetic loci harboring genes previously linked to depression, neurotransmission, or neurodegeneration. Overall, exposure to escitalopram/citalopram results in shifts in metabolism through noncanonical pathways, which suggest possible roles for the gut microbiome, oxidative stress, and inflammation-related mechanisms.
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Nicotinamide riboside alleviates alcohol-induced depression-like behaviours in C57BL/6J mice by altering the intestinal microbiota associated with microglial activation and BDNF expression.
The gut microbiota play an important role in many central nervous system diseases through the gut microbiota-brain axis. Recent studies suggest that nicotinamide riboside (NR) has neuroprotective properties. However, it is unknown whether NR can prevent or protect against alcohol-induced depression. Furthermore, it is unclear whether its therapeutic action involves changes in the composition of the gut microbiome. Here, we investigated the effects of NR in the mouse model of alcohol-induced depression. Treatment with NR improved the alcohol-induced depressive behaviour in mice. In addition, NR decreased the number of activated microglia in the hippocampus, and it reduced the levels of pro-inflammatory (IL-1β, IL-6, and TNF-α) and anti-inflammatory (IL-10 and TGF-β) cytokines in the brain of mice with alcohol-induced depression. Furthermore, NR significantly upregulated BDNF and diminished the inhibition of the AKT/GSK3β/β-catenin signalling pathway in the hippocampus of these mice. 16S rRNA sequencing revealed that, compared with control and NR-treated mice, the gut microbiome richness and composition were significantly altered in the depressed mice. Spearman's correlation analysis showed that differential gut bacterial genera correlated with the levels of inflammation-related cytokines and BDNF in the brain. After faecal microbiota transplantation, cognitive behaviours, microglial activity, levels of cytokines and BDNF, and activation state of the AKT/GSK3β/β-catenin signalling pathway (which is downstream of the BDNF receptor, TrkB) in recipient mice were similar to those in donor mice. Collectively, our findings show that NR dietary supplementation protects against alcohol-induced depression-like behaviours, possibly by altering the composition of the gut microbiota.
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Fluoxetine ameliorates dysbiosis in a depression model induced by chronic unpredicted mild stress in mice.
Background: Accumulating evidence has shown that neuropsychiatric disorders are associated with gut microbiota through the gut-brain axis. However, the effects of antidepressant treatment on gut microbiota are rarely studied. Here, we investigated whether stress led to gut microbiota changes and whether fluoxetine plays a role in microbiota alteration. Methods: We investigated changes in gut microbiota in a depression model induced by chronic unpredicted mild stress (CUMS) and a restoration model by applying the classic antidepressant drug fluoxetine. Results: We found that stress led to low bacterial diversity, simpler bacterial network, and increased abundance of pathogens, such as Escherichia/Shigella, and conditional pathogens, such as Enterococcus, Vagococcus, and Aerococcus. However, these changes were attenuated by fluoxetine directly and indirectly. Furthermore, the correlation analysis indicated strong correlations between gut microbiota and anxiety- and depression-like behaviors. Conclusions: This study revealed that fluoxetine led to restoration of dysbiosis induced by stress stimulation, which may imply a possible pathway through which one CNS target drug plays its role in reshaping the gut microbiota.