Characterization of gut microbiome in mice model of depression with divergent response to escitalopram treatment.
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ABSTRACT:
SUBMITTER: Duan J
PROVIDER: S-EPMC8138009 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Geriatric depression with subjective memory complaints increases the risk for Alzheimer's Disease. Memantine, a neuroprotective drug, can improve depression and help prevent cognitive decline. In our 6-months clinical trial, escitalopram/memantine (ESC/MEM) improved mood and cognition compared to escitalopram/placebo treatment (ESC/PBO; NCT01902004). In this report, we investigated whether baseline brain white matter integrity in fronto-limbic-striatal tracts can predict clinical outcomes using fractional anisotropy (FA). Methods: Thirty-eight older depressed adults (mean age = 70.6, SD = 7.2) were randomized to ESC/MEM or ESC/PBO and underwent diffusion-weighted imaging (DWI) at 3 Tesla at baseline. Mood was assessed using the Hamilton Depression Rating Scale (HAMD), apathy using the Apathy Evaluation Scale (AES) and anxiety using the Hamilton Anxiety Scale (HAMA) at baseline and 6-months follow-up. FA was extracted from seven tracts of interest (six in each hemisphere and one commissural tract) associated with geriatric depression. Non-parametric General Linear Models were used to examine group differences in the association between FA and symptom improvement, controlling for age, sex, baseline symptom scores and scanner model, correcting for false discovery rate (FDR). Post-hoc tests further investigated group differences in axial, mean and radial diffusivity (AD, MD, and RD, respectively). Lastly, we performed an exploratory whole-brain model to test whether FA might be related to treatment response with memantine. Results: There were no differences in remission rates or HAMD change between groups. In bilateral anterior and posterior internal capsule tracts and bilateral inferior and right superior fronto-occipital (IFO and SFO) fasciculus, higher FA was associated with larger improvements in depressive symptoms for ESC/MEM, but not ESC/PBO, correcting for FDR. Lower MD in the left IFO and RD in the right anterior internal capsule were associated with improved treatment responses. We found no significant associations in the whole-brain analysis. Limitations: Included small sample size and high dropout. Conclusions: Higher baseline FA and lower RD and MD in hypothesized fronto-limbic-striatal tracts predicted greater improvement in mood and anxiety with ESC/MEM compared to ESC/PBO in geriatric depression. FA as a biomarker for white matter integrity may serve as a predictor of treatment response but requires confirmation in larger future studies.
| S-EPMC7718009 | biostudies-literature
Project description:To improve our understanding of the stability of mammalian intestinal communities, we characterized the responses of both bacterial and viral communities in murine fecal samples to dietary changes between high- and low-fat (LF) diets. Targeted DNA extraction methods for bacteria, virus-like particles and induced prophages were used to generate bacterial and viral metagenomes as well as 16S ribosomal RNA amplicons. Gut microbiome communities from two cohorts of C57BL/6 mice were characterized in a 6-week diet perturbation study in response to high fiber, LF and high-refined sugar, milkfat (MF) diets. The resulting metagenomes from induced bacterial prophages and extracellular viruses showed significant overlap, supporting a largely temperate viral lifestyle within these gut microbiomes. The resistance of baseline communities to dietary disturbances was evaluated, and we observed contrasting responses of baseline LF and MF bacterial and viral communities. In contrast to baseline LF viral communities and bacterial communities in both diet treatments, baseline MF viral communities were sensitive to dietary disturbances as reflected in their non-recovery during the washout period. The contrasting responses of bacterial and viral communities suggest that these communities can respond to perturbations independently of each other and highlight the potentially unique role of viruses in gut health.
| S-EPMC5029215 | biostudies-literature
Project description:Neuroimaging biomarkers of treatment efficacy can be used to guide personalized treatment in major depressive disorder (MDD). Escitalopram is recommended as first-line therapy for MDD and severe depression. An interesting hypothesis suggests that the reconfiguration of dynamic brain networks might provide important insights into antidepressant mechanisms. The present study assesses whether the spatiotemporal modulation across functional brain networks could serve as a predictor of effective antidepressant treatment with escitalopram. A total of 106 first-episode, drug-naïve patients and 109 healthy controls from three different multicenters underwent resting-state functional magnetic resonance imaging. Patients were considered as responders if they had a reduction of at least 50% in Hamilton Rating Scale for Depression scores at endpoint (>2 weeks). Multilayer modularity framework was applied on the whole brain to construct features in relation to network dynamic characters that were used for multivariate pattern analysis. Linear soft-threshold support vector machine models were used to separate responders from nonresponders. The permutation tests demonstrated the robustness of discrimination performances. The discriminative regions formed a spatially distributed pattern with anterior cingulate cortex (ACC) as the hub in the default mode subnetwork. Interestingly, a significantly larger module allegiance of ACC was also found in treatment responders compared to nonresponders, suggesting high interactivities of ACC to other regions may be beneficial for the recovery after treatment. Consistent results across multicenters confirmed that ACC could serve as a predictor of escitalopram monotherapy treatment outcome, implying strong likelihood of replication in the future.
| S-EPMC7268019 | biostudies-literature
Project description:Up to 10% of women use selective serotonin reuptake inhibitor (SSRI) antidepressants during pregnancy and postpartum. Recent evidence suggests that SSRIs are capable of altering the gut microbiota. However, the interaction between maternal depression and SSRI use on bacterial community composition and the availability of microbiota-derived metabolites during pregnancy and lactation is not clear. We studied this using a rat model relevant to depression, where adult females with a genetic vulnerability and stressed as pups show depressive-like behaviors. Throughout pregnancy and lactation, females received the SSRI fluoxetine or vehicle. High-resolution 16S ribosomal RNA marker gene sequencing and targeted metabolomic analysis were used to assess the fecal microbiome and metabolite availability, respectively. Not surprisingly, we found that pregnancy and lactation segregate in terms of fecal microbiome diversity and composition, accompanied by changes in metabolite availability. However, we also showed that fluoxetine treatment altered important features of this transition from pregnancy to lactation most clearly in previously stressed dams, with lower fecal amino acid concentrations. Amino acid concentrations, in turn, correlated negatively with the relative abundance of bacterial taxa such as Prevotella and Bacteroides. Our study demonstrates an important relationship between antidepressant use during the perinatal period and maternal fecal metabolite availability in a rat model relevant to depression, possibly through parallel changes in the gut microbiome. Since microbial metabolites contribute to homeostasis and development, insults to the maternal microbiome by SSRIs might have health consequences for mother and offspring.
| S-EPMC7524305 | biostudies-literature
Project description:The gut microbiota are involved in adaptations of the maternal immune response to pregnancy. We therefore hypothesized that inducing gut dysbiosis during pregnancy alters the maternal immune response. Thus, pregnant mice received antibiotics from day 9 to day 16 to disturb the maternal gut microbiome. Feces were collected before, during and after antibiotic treatment, and microbiota were measured using 16S RNA sequencing. Mice were sacrificed at day 18 of pregnancy and intestinal (Peyer's patches (PP) and mesenteric lymph nodes (MLN)) and peripheral immune responses (blood and spleen) were measured using flow cytometry. Antibiotic treatment decreased fetal and placental weight. The bacterial count and the Shannon index were significantly decreased (Friedman, followed by Dunn's test, p < 0.05) and the bacterial genera abundance was significantly changed (Permanova, p < 0.05) following antibiotics treatment as compared with before treatment. Splenic Th1 cells and activated blood monocytes were increased, while Th2, Th17 and FoxP3/RoRgT double-positive cells in the PP and MLNs were decreased in pregnant antibiotics-treated mice as compared with untreated pregnant mice. In addition, intestinal dendritic cell subsets were affected by antibiotics. Correlation of immune cells with bacterial genera showed various correlations between immune cells in the PP, MLN and peripheral circulation (blood and spleen). We conclude the disturbed gut microbiota after antibiotics treatment disturbed the maternal immune response. This disturbed maternal immune response may affect fetal and placental weight.
| S-EPMC10300872 | biostudies-literature
Project description:The impact of gut microbiota in eliciting innate and adaptive immune responses beneficial for the host in the context of effective therapies against cancer has been highlighted recently. Chemotherapeutic agents, by compromising, to some extent, the intestinal integrity, increase the gut permeability and selective translocation of Gram-positive bacteria in secondary lymphoid organs. There, anticommensal pathogenic Th17 T-cell responses are primed, facilitating the accumulation of Th1 helper T cells in tumor beds after chemotherapy as well as tumor regression. Importantly, the redox equilibrium of myeloid cells contained in the tumor microenvironment is also influenced by the intestinal microbiota. Hence, the anticancer efficacy of alkylating agents (such as cyclophosphamide) and platinum salts (oxaliplatin, cis-platin) is compromised in germ-free mice or animals treated with antibiotics. These findings represent a paradigm shift in our understanding of the mode of action of many compounds having an impact on the host-microbe mutualism.
| S-EPMC4291500 | biostudies-other
Project description:OBJECTIVE:Cytochrome P450 (CYP) enzymatic activity, which is influenced by CYP genetic polymorphism, is known to affect the inter-individual variation in the efficacy and tolerability of antidepressants in major depressive disorder (MDD). Escitalopram is metabolized by CYP2D6, and recent studies have reported a correlation between clinical outcomes and CYP2D6 genetic polymorphism. The purpose of this study was to determine the relationship between the CYP2D6 P34S polymorphism (C188T, rs1065852) and the efficacy of escitalopram treatment in Korean patients with MDD. METHODS:A total of 94 patients diagnosed with MDD were recruited for the study and their symptoms were evaluated using the 21-item Hamilton Depression Rating scale (HAMD-21). The association between the CYP2D6 P34S polymorphism and the clinical outcomes (remission and response) was investigated after 1, 2, 4, 8, and 12 weeks of escitalopram treatment using multiple logistic regression analysis and ?(2) test. RESULTS:The proportion of P allele carriers (PP, PS) in remission status was greater than that of S allele homozygotes (SS) after 8 and 12 weeks of escitalopram treatment. Similarly, P allele carriers exhibited a greater treatment response after 8 and 12 weeks of escitalopram treatment than S allele homozygotes. CONCLUSION:Our results suggest that the P allele of the CYP2D6 P34S polymorphism is a favorable factor in escitalopram treatment for MDD, and that the CYP2D6 P34S polymorphism may be a good genetic marker for predicting escitalopram treatment outcomes.
| S-EPMC3843022 | biostudies-literature
Project description:BackgroundPsilocybin Therapy (PT) is being increasingly studied as a psychiatric intervention. Personality relates to mental health and can be used to probe the nature of PT's therapeutic action.MethodsIn a phase 2, double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, over a core 6-week trial period. Five-Factor model personality domains, Big Five Aspect Scale Openness aspects, Absorption, and Impulsivity were measured at Baseline, Week 6, and Month 6 follow-up.ResultsPT was associated with decreases in neuroticism (B = -0.63), introversion (B = -0.38), disagreeableness (B = -0.47), impulsivity (B = -0.40), and increases in absorption (B = 0.32), conscientiousness (B = 0.30), and openness (B = 0.23) at week 6, with neuroticism (B = -0.47) and disagreeableness (B = -0.41) remaining decreased at month 6. Escitalopram Treatment (ET) was associated with decreases in neuroticism (B = -0.38), disagreeableness (B = -0.26), impulsivity (B = -0.35), and increases in openness (B = 0.28) at week 6, with neuroticism (B = -0.46) remaining decreased at month 6. No significant between-condition differences were observed.ConclusionsPersonality changes across both conditions were in a direction consistent with improved mental health. With the possible exception of trait absorption, there were no compelling between-condition differences warranting conclusions regarding a selective action of PT (v. ET) on personality; however, post-ET changes in personality were significantly moderated by pre-trial positive expectancy for escitalopram, whereas expectancy did not moderate response to PT.
| S-EPMC10692311 | biostudies-literature
Project description:ObjectiveThis study aims to investigate the composition and function of the gut microbiome in long-term depression using an 8-week chronic unpredictable mild stress (CUMS) rat model.Materials and methodsAnimals were sacrificed after either 4 weeks or 8 weeks under CUMS to mimic long-term depression in humans. The gut microbiome was analyzed to identify potential depression-related gut microbes, and the fecal metabolome was analyzed to detect their functional metabolites. The correlations between altered gut microbes and metabolites in the long-term depression rats were explored. The crucial metabolic pathways related to long-term depression were uncovered through enrichment analysis based on these gut microbes and metabolites.ResultsThe microbial composition of long-term depression (8-week CUMS) showed decreased species richness indices and different profiles compared with the control group and the 4-week CUMS group, characterized by disturbance of Alistipes indistinctus, Bacteroides ovatus, and Alistipes senegalensis at the species level. Additionally, long-term depression was associated with disturbances in fecal metabolomics. D-pinitol was the only increased metabolite in the 8-week CUMS group among the top 10 differential metabolites, while the top 3 decreased metabolites in the long-term depression rats included indoxyl sulfate, trimethylaminen-oxide, and 3 alpha,7 alpha-dihydroxy-12-oxocholanoic acid. The disordered fecal metabolomics in the long-term depression rats mainly involved the biosynthesis of pantothenate, CoA, valine, leucine and isoleucine.ConclusionOur findings suggest that the gut microbiome may participate in the long-term development of depression, and the mechanism may be related to the regulation of gut metabolism.
| S-EPMC10084793 | biostudies-literature
Project description:Clostridium difficile infection (CDI) may not respond to initial therapy and frequently recurs, but predictors of response and recurrence are inconsistent. The impact of specific alterations in the gut microbiota determining treatment response and recurrence in patients with CDI is unknown.To assess microbial signatures as predictors of treatment response and recurrence in CDI.Pre-treatment stool samples and clinical metadata including outcomes were collected prospectively from patients with their first CDI episode. Next generation 16s rRNA sequencing using MiSeq Illumina platform was performed and changes in microbial community structure were correlated with CDI outcomes.Eighty-eight patients (median age 52.7 years, 60.2% female) were included. Treatment failure occurred in 12.5% and recurrence after response in 28.5%. Patients who responded to treatment had an increase in Ruminococcaceae, Rikenellaceae, Clostridiaceae, Bacteroides, Faecalibacterium and Rothia compared to nonresponders. A risk-index built from this panel of microbes differentiated responders (mean 0.07 ± 0.24) from nonresponders (0.52 ± 0.42; P = 0.0002). Receiver operating characteristic (ROC) curve demonstrated that risk-index was a strong predictor of treatment response with an area under the curve (AUC) of 0.85. Among clinical parameters tested, only proton pump inhibitor use predicted recurrent CDI (OR 3.75, 95% CI 1.27-11.1, P = 0.01). Patients with recurrent CDI had statistically significant increases in Veillonella, Enterobacteriaceae, Streptococci, Parabacteroides and Lachnospiraceae compared to patients without recurrence and a risk index was able to predict recurrence (AUC = 0.78).Gut microbiota signatures predict treatment response and recurrence potentially, allowing identification of patients with Clostridium difficile infection that may benefit from early institution of alternate therapies.
| S-EPMC5012905 | biostudies-literature