This study aims to characterize the gut microbiota in depressed patients with bipolar disorder (BD) compared with healthy controls (HCs), to examine the effects of quetiapine treatment on the microbiota, and to explore the potential of microbiota as a biomarker for BD diagnosis and treatment outcome. Analysis of 16S‐ribosomal RNA gene sequences reveals that gut microbial composition and diversity are significantly different between BD patients and HCs. Phylum Bacteroidetes and Firmicutes are the predominant bacterial communities in BD patients and HCs, respectively. Lower levels of butyrate‐producing bacteria are observed in untreated patients. Microbial composition changes following quetiapine treatment in BD patients. Notably, 30 microbial markers are identified on a random forest model and achieve an area under the curve (AUC) of 0.81 between untreated patients and HCs. Ten microbial markers are identified with the AUC of 0.93 between responder and nonresponder patients. This study characterizes the gut microbiota in BD and is the first to evaluate microbial changes following quetiapine monotherapy. Gut microbiota‐based biomarkers may be helpful in BD diagnosis and predicting treatment outcome, which need further validations.
Gut microbiome disturbances have been implicated in major depressive disorder (MDD). However, little is known about how the gut virome, microbiome, and fecal metabolome change, and how they interact in MDD. Here, using whole-genome shotgun metagenomic and untargeted metabolomic methods, we identified 3 bacteriophages, 47 bacterial species, and 50 fecal metabolites showing notable differences in abundance between MDD patients and healthy controls (HCs). Patients with MDD were mainly characterized by increased abundance of the genus Bacteroides and decreased abundance of the genera Blautia and Eubacterium. These multilevel omics alterations generated a characteristic MDD coexpression network. Disturbed microbial genes and fecal metabolites were consistently mapped to amino acid (γ-aminobutyrate, phenylalanine, and tryptophan) metabolism. Furthermore, we identified a combinatorial marker panel that robustly discriminated MDD from HC individuals in both the discovery and validation sets. Our findings provide a deep insight into understanding of the roles of disturbed gut ecosystem in MDD.
The mechanism of bipolar disorder is unclear. Growing evidence indicates that gut microbiota plays a pivotal role in mental disorders. This study aimed to find out changes in the gut microbiota in bipolar depression (BD) subjects following treatment with quetiapine and evaluate their correlations with the brain and immune function. Totally 36 subjects with BD and 27 healthy controls (HCs) were recruited. The severity of depression was evaluated with the Montgomery-Asberg depression rating scale (MADRS). At baseline, fecal samples were collected and analyzed by quantitative polymerase chain reaction (qPCR). T lymphocyte subsets were measured to examine immune function. Near-infrared spectroscopy (NIRS) was used to assess brain function. All BD subjects received quetiapine treatment (300 mg/d) for four weeks, following which the fecal microbiota and immune profiles were reexamined. Here, we first put forward the new concept of brain-gut coefficient of balance (B-GCB), which referred to the ratio of [oxygenated hemoglobin]/(Bifidobacteria to Enterobacteriaceae ratio), to analyze the linkage between the gut microbiota and brain function. At baseline, the CD3+ T cell proportion was positively correlated with log10 Enterobacter spp count, whereas the correlativity between the other bacteria and immune profiles were negative. Log10 B-GCB was positively correlated with CD3+ T cell proportion. In subjects with BD, counts of Faecalibacterium prausnitzii, Bacteroides–Prevotella group, Atopobium Cluster, Enterobacter spp, and Clostridium Cluster IV were higher, whereas the log10 (B/E) were lower than HCs (B/E refers to Bifidobacteria to Enterobacteriaceae ratio and represents microbial colonization resistance). After treatment, MADRS scores were reduced, whereas the levels of Eubacterium rectale, Bifidobacteria, and B/E increased. The composition of the gut microbiota and its relationship to brain function were altered in BD subjects. Quetiapine treatment was effective for depression and influenced the composition of gut microbiota in patients. Clinical Trial Registration: , identifier ChiCTR-COC-17011401, URL: .
The pathophysiology of major depressive disorder (MDD) remains obscure. Recently, the microbiota-gut-brain (MGB) axis’s role in MDD has an increasing attention. However, the specific mechanism of the multi-level effects of gut microbiota on host metabolism, immunity, and brain structure is unclear. Multi-omics approaches based on the analysis of different body fluids and tissues using a variety of analytical platforms have the potential to provide a deeper understanding of MGB axis disorders. Therefore, the data of metagenomics, metabolomic, inflammatory factors, and MRI scanning are collected from the two groups including 24 drug-naïve MDD patients and 26 healthy controls (HCs). Then, the correlation analysis is performed in all omics. The results confirmed that there are many markedly altered differences, such as elevated Actinobacteria abundance, plasma IL-1β concentration, lipid, vitamin, and carbohydrate metabolism disorder, and diminished grey matter volume (GMV) of inferior frontal gyrus (IFG) in the MDD patients. Notably, three kinds of discriminative bacteria, Ruminococcus bromii, Lactococcus chungangensis, and Streptococcus gallolyticus have an extensive correlation with metabolome, immunology, GMV, and clinical symptoms. All three microbiota are closely related to IL-1β and lipids (as an example, phosphoethanolamine (PEA)). Besides, Lactococcus chungangensis is negatively related to the GMV of left IFG. Overall, this study demonstrate that the effects of gut microbiome exert in MDD is multifactorial.
As hypocretin can markedly affect neurophysiological and behavioural processes in mood disorders. However, few studies have measured changes in hypocretin levels in patients with mood disorders. We estimated the hypocretin-1 plasma levels in mood disorder patients and controls (CON) using an enzyme-linked immunosorbent assay. Results: (i) The hypocretin-1 plasma level was significantly higher in major depressive disorder (MDD) patients [59.04 (35.78–80.12) pg/ml, P < 0.001] and bipolar disorder (BD) patients [65.50 (58.46–74.57) pg/ml, P < 0.001] patients than in CON [49.25 (28.51–80.40) pg/ml]. Moreover, the plasma hypocretin-1 levels in the BD group were significantly higher than those in the MDD group (P < 0.001). (ii). In the MDD group, patients with higher suicidal ideation had higher hypocretin-1 levels [62.09 (38.23–80.12) pg/ml] than those with lower suicidal ideation [59.63 (35.79–77.37) pg/ml), P = 0.032]. (iii). Plasma hypocretin-1 levels were increased in both female and male mood disorder patients compared to CON [male: MDD 60.51 (35.79–80.12) pg/ml; BD 65.40 (58.76–74.14) pg/ml; CON 45.63 (28.51–62.05) pg/ml; all P < 0.016; female: MDD 57.37 (34.59–80.40) pg/ml; BD 65.61 (58.46–74.57) pg/ml; CON 52.92 (38.23–78.89) pg/ml; all P < 0.015]. (iv). In CON, we found a significant negative correlation between plasma hypocretin-1 levels and age (rho = −0.251, P = 0.032), while this negative correlation was absent in the MDD and BD groups. Limitations may partly arise from the relatively small sample size and the medication history of patients participating in our research. We concluded that the clear changes found in plasma hypocretin-1 levels might be applied in the diagnosis of depression and the differential diagnosis of MDD and BD. The clear suicidal-ideation-related change found in hypocretin-1 levels in depression might be taken into account in the prevention of suicidal behaviour and further study of hypocretin-targeted therapies.
Background Most of the previous studies have demonstrated the potential antidepressive and anxiolytic role of prebiotic supplement in male subjects, yet few have females enrolled. Herein, we explored whether prebiotics administration during chronic stress prevented depression‐like and anxiety‐like behavior in a sex‐specific manner and the mechanism of behavioral differences caused by sex. Methods Female and male C57 BL/J mice on normal diet were supplemented with or without a combination of fructo‐oligosaccharides (FOS) and galacto‐oligosaccharides (GOS) during 3‐ and 4‐week chronic restraint stress (CRS) treatment, respectively. C57 BL/J mice on normal diet without CRS were used as controls. Behavior consequences, gut microbiota, dysfunction of gut and brain–blood barriers, and inflammatory profiles were measured. Results In the 3rd week, FOS + GOS administration attenuated stress‐induced anxiety‐like behavior in female, but not in male mice, and the anxiolytic effects in males were observed until the 4th week. However, protective effects of prebiotics on CRS‐induced depression were not observed. Changes in the gene expression of tight junction proteins in the distal colon and hippocampus, and decreased number of colon goblet cells following CRS were restored by prebiotics only in females. In both female and male mice, prebiotics alleviated stress‐induced BBB dysfunction and elevation in pro‐inflammatory cytokines levels, and modulated gut microbiota caused by stress. Furthermore, correlation analysis revealed that anxiety‐like behaviors were significantly correlated with levels of pro‐inflammatory cytokines and gene expression of tight junction proteins in the hippocampus of female mice, and the abundance of specific gut microbes was also correlated with anxiety‐like behaviors, pro‐inflammatory cytokines, and gene expression of tight junction proteins in the hippocampus of female mice. Conclusion Female mice were more vulnerable to stress and prebiotics than males. The gut microbiota, gut and blood–brain barrier, and inflammatory response may mediate the protective effects of prebiotics on anxiety‐like behaviors in female mice.
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