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Mice lacking Casp1, Ifngr and Nos2 genes exhibit altered depressive- and anxiety-like behaviour, and gut microbiome composition.
Converging evidence supports the involvement of pro-inflammatory pathways and the gut microbiome in major depressive disorder (MDD). Pre-clinical and clinical studies suggest that decreasing pro-inflammatory signaling may provide clinical benefit in MDD. In this study, we used the chronic unpredictable stress (CUS) paradigm to assess whether mice lacking the pro-inflammatory caspase 1, interferon gamma-receptor, and nitric oxide synthase (Casp1, Ifngr, Nos2)-/- present altered depressive- and anxiety-like behaviour at baseline and in response to CUS. In comparison to wild-type (wt) mice, (Casp1, Ifngr, Nos2)-/- mice displayed decreased depressive- and anxiety-like behaviour, and increased hedonic-like behaviour and locomotor activity at baseline, and resistance to developing anhedonic-like behaviour and a heightened emotional state following stress. Plasma levels of ACTH and CORT did not differ between the triple knockout and wt mice following stress. The faecal microbiome of (Casp1, Ifngr, Nos2)-/- mice differed from that of wt mice at baseline and displayed reduced changes in response to chronic stress. Our results demonstrate that simultaneous deficit in multiple pro-inflammatory pathways has antidepressant-like effects at baseline, and confers resilience to stress-induced anhedonic-like behaviour. Moreover, accompanying changes in the gut microbiome composition suggest that CASP1, IFNGR and NOS2 play a role in maintaining microbiome homeostasis.
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Microbiota Alters and Its Correlation with Molecular Regulation Underlying Depression in PCOS Patients.
Depression is one of the complications in patients with polycystic ovary syndrome (PCOS) that leads to considerable mental health. Accumulating evidence suggests that human gut microbiomes are associated with the progression of PCOS and depression. However, whether microbiota influences depression development in PCOS patients is still uncharacterized. In this study, we employed metagenomic sequencing and transcriptome sequencing (RNA-seq) to profile the composition of the fecal microbiota and gene expression of peripheral blood mononuclear cells in depressed women with PCOS (PCOS-DP, n = 27) in comparison to mentally healthy women with PCOS (PCOS, n = 18) and compared with healthy control (HC, n = 27) and patients with major depressive disorder (MDD, n = 29). Gut microbiota assessment revealed distinct patterns in the relative abundance in the PCOS-DP compared to HC, MDD, and PCOS groups. Several gut microbes exhibited uniquely and significantly higher abundance in the PCOS-DP compared to PCOS patients, inducing EC Ruminococcus torques, Coprococcus comes, Megasphaera elsdenii, Acidaminococcus intestini, and Barnesiella viscericola. Bacteroides eggerthii was a potential gut microbial biomarker for the PCOS-DP. RNA-seq profiling identified that 35 and 37 genes were significantly elevated and downregulated in the PCOS-DP, respectively. The enhanced differential expressed genes (DEGs) in the PCOS-DP were enriched in pathways involved in signal transduction and endocrine and metabolic diseases, whereas several lipid metabolism pathways were downregulated. Intriguingly, genes correlated with the gut microbiota were found to be significantly enriched in pathways of neurodegenerative diseases and the immune system, suggesting that changes in the microbiota may have a systemic impact on the expression of neurodegenerative diseases and immune genes. Gut microbe-related DEGs of CREB3L3 and CCDC173 were possible molecular biomarkers and therapeutic targets of women with PCOS-DP. Our multi-omics data indicate shifts in the gut microbiome and host gene regulation in PCOS patients with depression, which is of possible etiological and diagnostic importance.
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Adenosine regulates depressive behavior in mice with chronic social defeat stress through gut microbiota.
Major depressive disorder (MDD) is recognized as the most prevalent affective disorder worldwide. Metagenomic studies increasingly support a critical role for dysbiosis of gut microbiota in the development of depression. Previous studies have demonstrated that adenosine alleviates gut dysbiosis, suggesting that elevating adenosine levels could be a novel intervention for MDD; however, the mechanisms underlying this effect remain unclear. This study utilized 16S rRNA gene sequencing, fecal microbiota transplantation (FMT) and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to test the hypothesis that increased adenosine alleviates depressive behaviors in male mice subjected to chronic social defeat stress (CSDS) through alterations to gut microbiota. The data showed that depression-susceptible (SUS) mice exhibited gut dysbiosis, and FMT from SUS mice increased depression-like behaviors in healthy recipients. In SUS mice, adenosine supplementation ameliorated both depression-like behaviors and abnormalities in gut microbiota, and co-administration of probiotics and adenosine not only mitigated depression-like behaviors but also enhanced gut barrier integrity. By including 83 depressed adolescents and 67 healthy controls, this study found that the level of short-chain fatty acids (SCFAs) in the depression group was reduced, this finding parallels reductions seen in SUS mice and in recipient mice after FMT from SUS donors. Conversely, supplementation with either adenosine or probiotics led increased SCFAs concentrations in the serum of SUS mice. These findings suggest that adenosine may alleviate depression-like behaviors in CSDS mice by modulating the gut microbiota. This effect is likely associated with increased serum SCFAs, metabolites produced by the gut microbiota, following adenosine supplementation. This article is part of the Special Issue on "Personality Disorders".
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The role of gut microbiota and metabolomic pathways in modulating the efficacy of SSRIs for major depressive disorder.
This study aims to explore the mechanism by which gut microbiota influences the antidepressant effects of serotonin reuptake inhibitors (SSRIs) through metabolic pathways. A total of 126 patients were analyzed for their gut microbiota and metabolomics. Patients received SSRI treatment and were categorized into responder and non-responder groups based on changes in their Hamilton Depression Rating Scale (HAMD-17) scores before and after treatment. The association between gut microbiota composition and the efficacy of SSRIs was investigated through 16S rRNA gene sequencing and metabolomic analysis, and a predictive model was developed. As a result, the study found significant differences in gut microbiota composition between the responder and resistant groups. Specific taxa, such as Ruminococcus, Bifidobacterium, and Faecalibacterium, were more abundant in the responder group. Functional analysis revealed upregulation of acetate degradation and neurotransmitter synthesis pathways in the responder group. The machine learning model indicated that gut microbiota and metabolites are potential biomarkers for predicting SSRIs efficacy. In conclusion, gut microbiota influences the antidepressant effects of SSRIs through metabolic pathways. The diversity and function of gut microbiota can serve as biomarkers for predicting the treatment response, providing new insights for personalized treatment.
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Gut microbiota dysbiosis in depressed women: The association of symptom severity and microbiota function.
BACKGROUND: The association between abnormal gut microbiome composition and depression is well established. However, the composition and functional capacity of the gut microbiota regarding depressed women has been poorly addressed. METHODS: Stool samples from 62 female patients with major depressive disorder (MDD) and 46 healthy controls (Con) were analyzed by 16S rRNA gene sequencing; Twenty fecal samples from the patient group and 21 fecal samples from the Con group were further analyzed by shotgun metagenomic sequencing. Psychiatric symptoms and psychological, social, and professional functioning was also assessed. RESULTS: Phylum Bacteroidetes, proteobaeteria, and Fusobacteria were greatly enriched in patients with MDD, while the Firmicutes and Actinobacteria phyla were consistently higher in Con. Notably, 18 microbial markers were identified on a random forest model and achieve an area under the curve of 0.92 between patients with MDD and the Con group. Forty-five species and their associated function were identified with statistically significant differences between patients with MDD and the Con group. LIMITATIONS: The number of recruited samples, especially samples enrolled for shotgun metagenomic sequencing was relatively small, and the stool samples were collected only at baseline, making it difficult to establish a causal association between changes in gut microbiota compositions and disease remission. CONCLUSIONS: This study characterizes the gut microbiota and their related function in female MDD. The gut microbiota-based biomarkers may be helpful in diagnosis and the altered gut microbial metabolites may contribute to the pathogenesis of MDD in women, representing potential microbial targets.
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Complex correlations between mitochondrial DNA variants and gut microbiome in major depressive disorder: a genome-wide association analysis.
BACKGROUND: Gut microbiota disturbances and impaired mitochondrial function are both linked with the development of major depressive disorder (MDD). However, little is known about how they interact in MDD. METHODS: We used shotgun metagenomic sequencing to explore fecal microbiome based on 63 MDD patients and 30 healthy controls (HCs). Then we performed GWAS for the discriminative taxonomic features of gut microbiota to identify genetic associations between gut microbiome and mitochondrial DNA (mtDNA) in MDD. RESULTS: Characteristic gut microbiome-based features, including significant differences in gut microbiota composition and 101 differentially enriched gut microbial species, were found in MDD group vs. HC group. 68 mitochondrial single-nucleotide polymorphisms (mtSNPs) shared between the two groups were identified through GWAS at a Bonferroni-corrected significance level of p < 0.05. The genetic variants and their associated gut microbes were mapped to mitochondrial genome, most of which were located in coding regions, including MT-ND, MT-ND4L, MT-ND5, MT-ND6; MT-CO, MT-CO3; MT-RNR, MT-RNR, and MT-TE. Manhattan plots showed 9 mtSNPs in MDD group and 10 mtSNPs in HC group were associated with 20 gut microbial species at a significance of -log10(p) >20. Furthermore, Sankey diagram was used to visualize the relationships of gut microbiota and mtDNA. 36 mtSNPs (-log10(p) >5) were shown to be associated with 54 gut microbes in crosslinked patterns. CONCLUSIONS: The current findings provide substantial evidence that complex interactions between gut microbiota and mtDNA contribute to MDD, which enables a better understanding of MDD pathogenesis and suggests new leads for future investigations. CLINICAL TRIAL NUMBER: ChiCTR2000029703. Registration Date: Feb. 9th, 2020. Registration Details are available at the website of Chinese Clinical Trial Registry (https://www.chictr.org.cn).
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Adolescent male rats show altered gut microbiota composition associated with depressive-like behavior after chronic unpredictable mild stress: Differences from adult rats.
Accumulating evidence reveals the metabolism and neurotransmitter systems are different in major depressive disorder (MDD) between adolescent and adult patients; however, much is still unknown from the gut microbiome perspective. To minimize confounding factors such as geographical location, ethnicity, diet, and drugs, we investigated the gut microbial differences between adolescent and adult male Sprague-Dawley rats. We exposed the adolescent rats to chronic unpredictable mild stress (CUMS) for 3 weeks and assessed their behavior using the sucrose preference test (SPT), open field test (OFT), and forced swimming test (FST). We collected and sequenced fecal samples after the behavioral tests and compared them with our previous data on adult rats. Both adolescent and adult CUMS rats exhibited reduced sucrose preference in SPT, reduced total distance in OFT, and increased immobility time in FST. Moreover, compared to their respective controls, the adolescent CUMS rats had distinct amplicon sequence variants (ASVs) mainly in the Muribaculaceae family, Bacteroidetes phylum, while the adult CUMS rats had those in the Lachnospiraceae family, Firmicutes phylum. In the adolescent group, the Muribaculaceae negatively correlated with FST and positively correlated with SPT and OFT. In the adult group, the different genera in the Lachnospiraceae showed opposite correlations with FST. Furthermore, the adolescent CUMS rats showed disrupted microbial functions, such as "Xenobiotics biodegradation and metabolism" and "Immune system", while the adult CUMS rats did not. These results confirmed the gut microbiota differences between adolescent and adult rats after CUMS modeling and provided new insight into the age-related influence on depression models.
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Characteristics of gut microbiota and metabolic phenotype in patients with major depressive disorder based on multi-omics analysis.
Depression is a chronic, relapsing mental illness, often accompanied by loss of appetite, increased fatigue, insomnia and poor concentration. Here, we performed serum and urine metabolomics and fecal 16S rDNA sequencing studies on 57 unmedicated patients with major depressive disorder (MDD) and 57 healthy controls to characterize the metabolic and flora profile of MDD patients. We observed significant differences in serum and urinary metabolome between MDD patients and healthy individuals. Specifically, glycerophospholipid metabolism, primary bile acid biosynthesis and linoleic acid metabolism were significantly disordered in serum, and aminoacyl-tRNA biosynthesis, arginine biosynthesis, purine metabolism, phenylalanine metabolism, alanine, aspartate and glutamate metabolism, and pyrimidine metabolism were significantly impaired in urine. On this basis, we identified four potential diagnostic biomarkers for carnitine and four fatty acid classes in serum and urine, respectively. In addition, we observed significant disturbances of the gut microbiota in MDD patients. Spearman correlation analysis showed that imbalances in the gut microbiota were associated with metabolic disturbances, suggesting an important role of the gut microbiota in the pathogenesis of MDD. Our study provides a theoretical basis for further understanding of the pathogenesis of depression and for future clinical diagnosis and screening, as well as a basis for targeting the gut flora to optimize its structure for the prevention and treatment of depression.
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Gut Microbiota, Bacterial Translocation, and Interactions with Diet: Pathophysiological Links between Major Depressive Disorder and Non-Communicable Medical Comorbidities.
BACKGROUND: Persistent low-grade immune-inflammatory processes, oxidative and nitrosative stress (O&NS), and hypothalamic-pituitary-adrenal axis activation are integral to the pathophysiology of major depressive disorder (MDD). The microbiome, intestinal compositional changes, and resultant bacterial translocation add a new element to the bidirectional interactions of the gut-brain axis; new evidence implicates these pathways in the patho-aetiology of MDD. In addition, abnormalities in the gut-brain axis are associated with several chronic non-communicable disorders, which frequently co-occur in individuals with MDD, including but not limited to irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), obesity, and type 2 diabetes mellitus (T2DM). METHODS: We searched the PubMed/MEDLINE database up until May 1, 2016 for studies which investigated intestinal dysbiosis and bacterial translocation (the 'leaky gut') in the pathophysiology of MDD and co-occurring somatic comorbidities with an emphasis on IBS, CFS, obesity, and T2DM. RESULTS: The composition of the gut microbiota is influenced by several genetic and environmental factors (e.g. diet). Several lines of evidence indicate that gut-microbiota-diet interactions play a significant pathophysiological role in MDD and related medical comorbidities. Gut dysbiosis and the leaky gut may influence several pathways implicated in the biology of MDD, including but not limited to immune activation, O&NS, and neuroplasticity cascades. However, methodological inconsistencies and limitations limit comparisons across studies. CONCLUSIONS: Intestinal dysbiosis and the leaky gut may constitute a key pathophysiological link between MDD and its medical comorbidities. This emerging literature opens relevant preventative and therapeutic perspectives.
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Gut proinflammatory bacteria is associated with abnormal functional connectivity of hippocampus in unmedicated patients with major depressive disorder.
Accumulating evidence has revealed the gut bacteria dysbiosis and brain hippocampal functional and structural alterations in major depressive disorder (MDD). However, the potential relationship between the gut microbiota and hippocampal function alterations in patients with MDD is still very limited. Data of resting-state functional magnetic resonance imaging were acquired from 44 unmedicated MDD patients and 42 demographically matched healthy controls (HCs). Severn pairs of hippocampus subregions (the bilateral cornu ammonis [CA1-CA3], dentate gyrus (DG), entorhinal cortex, hippocampal-amygdaloid transition area, and subiculum) were selected as the seeds in the functional connectivity (FC) analysis. Additionally, fecal samples of participants were collected and 16S rDNA amplicon sequencing was used to identify the altered relative abundance of gut microbiota. Then, association analysis was conducted to investigate the potential relationships between the abnormal hippocampal subregions FC and microbiome features. Also, the altered hippocampal subregion FC values and gut microbiota levels were used as features separately or together in the support vector machine models distinguishing the MDD patients and HCs. Compared with HCs, patients with MDD exhibited increased FC between the left hippocampus (CA2, CA3 and DG) and right hippocampus (CA2 and CA3), and decreased FC between the right hippocampal CA3 and bilateral posterior cingulate cortex. In addition, we found that the level of proinflammatory bacteria (i.e., Enterobacteriaceae) was significantly increased, whereas the level of short-chain fatty acids producing-bacteria (i.e., Prevotellaceae, Agathobacter and Clostridium) were significantly decreased in MDD patients. Furthermore, FC values of the left hippocampal CA3- right hippocampus (CA2 and CA3) was positively correlated with the relative abundance of Enterobacteriaceae in patients with MDD. Moreover, altered hippocampal FC patterns and gut microbiota level were considered in combination, the best discrimination was obtained (AUC = 0.92). These findings may provide insights into the potential role of gut microbiota in the underlying neuropathology of MDD patients.