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Page 45 of 320-
Exploring the CDCA-Scd1 Axis: Molecular Mechanisms Linking the Colitis Microbiome to Neurological Deficits.
Inflammatory bowel disease is a risk factor for brain dysfunction; however, the underlying mechanisms remain largely unknown. In this study, we aimed to explore the potential molecular mechanisms through which intestinal inflammation affects brain function and to verify these mechanisms. Mice were treated with multiple cycles of 1% w/v dextran sulfate sodium (DSS) in drinking water to establish a chronic colitis model. Behavioral tests were conducted using the open field test (OFT), tail suspension test (TST), forced swimming test (FST), and Morris water maze test (MWM). Brain metabolomics, transcriptomics, and proteomics analyses were performed, and key target proteins were verified using qPCR and immunofluorescence. Four cycles of DSS administration induced colitis, anxiety, depression, and spatial memory impairment. The integrated multi-omics characterization of colitis revealed decreased brain chenodeoxycholic acid (CDCA) levels as well as reduced stearoyl-CoA desaturase (Scd1) gene and protein expression. Transplantation of the colitis microbiome resulted in anxiety, depression, impaired spatial memory, reduced CDCA content, decreased Scd1 gene and protein expression, and lower concentrations of monounsaturated fatty acids (MUFAs), palmitoleate (C16:1), and oleate (C18:1) in the brain. In addition, CDCA supplementation improved DSS-induced colitis, alleviated depression and spatial memory impairment, and increased Scd1 gene and protein expression as well as MUFA levels in the brain. The gut microbiome induced by colitis contributes to neurological dysfunction, possibly through the CDCA-Scd1 signaling axis. CDCA supplementation alleviates colitis and depressive behavior, likely by increasing Scd1 expression in the brain.
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The Antidepressant- and Anxiolytic-Like Effects of the Phosphodiesterase Type-5 Inhibitor Tadalafil are Associated with the Modulation of the Gut-Brain Axis During CNS Autoimmunity.
Multiple Sclerosis (MS) is a debilitating disease that severely affects the central nervous system (CNS). Apart from neurological symptoms, it is also characterized by neuropsychiatric comorbidities, such as anxiety and depression. Phosphodiesterase-5 inhibitors (PDE5Is) such as Sildenafil and Tadalafil have been shown to possess antidepressant-like effects, but the mechanisms underpinning such effects are not fully characterized. To address this question, we used the EAE model of MS, behavioral tests, immunofluorescence, immunohistochemistry, western blot, and 16 S rRNA sequencing. Here, we showed that depressive-like behavior in Experimental Autoimmune Encephalomyelitis (EAE) mice is due to neuroinflammation, reduced synaptic plasticity, dysfunction in glutamatergic neurotransmission, glucocorticoid receptor (GR) resistance, increased blood-brain barrier (BBB) permeability, and immune cell infiltration to the CNS, as well as inflammation, increased intestinal permeability, and immune cell infiltration in the distal colon. Furthermore, 16 S rRNA sequencing revealed that behavioral dysfunction in EAE mice is associated with changes in the gut microbiota, such as an increased abundance of Firmicutes and Saccharibacteria and a reduction in Proteobacteria, Parabacteroides, and Desulfovibrio. Moreover, we detected an increased abundance of Erysipelotrichaceae and Desulfovibrionaceae and a reduced abundance of Lactobacillus johnsonii. Surprisingly, we showed that Tadalafil likely exerts antidepressant-like effects by targeting all aforementioned disease aspects. In conclusion, our work demonstrated that anxiety- and depressive-like behavior in EAE is associated with a plethora of neuroimmune and gut microbiota-mediated mechanisms and that Tadalafil exerts antidepressant-like effects probably by targeting these mechanisms. Harnessing the knowledge of these mechanisms of action of Tadalafil is important to pave the way for future clinical trials with depressed patients.
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Dysbiosis of the Gut Microbiota and Kynurenine (Kyn) Pathway Activity as Potential Biomarkers in Patients with Major Depressive Disorder.
With increasing attention paid to the concept of the microbiota-gut-brain axis, mounting evidence reveals that the gut microbiota is involved in a variety of neurological and psychiatric diseases. However, gut microbiota changes in major depressive disorder (MDD) patients and their association with disease mechanisms remain undefined. Fifty MDD patients and sixty healthy controls were recruited from the Shanghai Healthy Mental Center, China. Fecal samples were collected, and the compositional characteristics of the intestinal flora were determined in MDD patients by MiSeq sequencing. Venous blood was collected for the detection of plasma indoleamine-2,3-dioxygenase (Ido), kynurenine (Kyn) and tryptophan (Trp) levels. Stool samples of bacterial 16S sequencing was carried out. A total of 2,705,809 optimized sequences were obtained, with an average of 54,116 per sample. More unique OTUs were observed at the family, genus and species levels in the control group compared with the MDD cases. Further analysis showed significant changes in the α- and β-diversities and relative abundance levels of gut microbial entities in MDD patients, as well as elevated amounts of Ido and Kyn indicating Kyn pathway activation, KEGG bacterial 16S function prediction analysis shows a variety of amino acids and metabolic (including Ido, Trp and Kyn) changes in the body of patients with MDD. These may result in increased neurotoxic metabolites and reduced generation of serotonin in the disease process. These changed factors may potentially be utilized as biomarkers for MDD in the future, playing more important roles in the disease course.
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Integrative Analysis of the Impact of Prenatal Depression on the Newborn Intestinal Microbiota.
BACKGROUND: More than 15% of women develop symptoms of depression during pregnancy, which often affects the mental and physical development of the newborn by altering its intestinal microbiota. Previous studies revealed that the gut microbiota plays a crucial role in the maturation of systems involved in the gut-brain axis, including the gastrointestinal system, the immune system, and the hypothalamic-pituitary-adrenal system axis. METHODS: This study aims to explore the cross-talk between the prenatal depression process and neonatal intestinal microbiota diversity. A total of 100 differentially expressed genes (DEGs) associated with prenatal depression were collected from various scientific publications and databases. Bioinformatics tools were used to analyze these DEGs. The STRING database. ToppGene database and DICE were employed for this integrative analysis. RESULTS: The network generated by the STRING database identified six pivotal genes: TNF, BDNF, IL-6, NR3C1, IGF2, and POMC. These genes regulate response to endogenous hormones, particularly cortisol secretion in newborns, as well as inhibiting serotonin secretion. Moreover, these genes are linked to major depressive disorder and other mental diseases, contributing to maternal and neonatal gut microbiota dysbiosis. Analysis using ToppGene and DICE's further validated the biological processes identified by String, including the regulation of cellular cortisol secretion, metabolic processes, and serotonin inhibition. CONCLUSION: The bioinformatics tools employed in this study allowed us to identify pivotal genes involved in prenatal depression, their associated signaling pathways, and their roles in modulating maternal and neonatal gut microbiota.
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The Car1 Knockout Mice Exhibit Antidepressant-like Behaviors Accompanied with Gut Microbiota Disturbance.
Major depressive disorder (MDD) is a severe mental disorder with largely unknown mechanisms. Carbonic anhydrases convert CO2 to carbonates and protons, playing roles in various brain functions. Carbonic anhydrase 1 (Car1) is particularly abundant and may be linked to microbiota at interstitial sites. We developed Car1-deficient mice to explore the relationship between depression-like behaviors and gut microbiota. Behavioral tests confirmed depression-like behavior in Car1-/- mice. Fecal samples from Car1-/- and WT mice were collected, and 16S rRNA gene sequencing identified distinct microbiota components between the groups. Car1-/- mice exhibited significantly increased immobility in the tail suspension test (TST) compared to WT mice. The gut microbiota composition differed at the phylum level in p_Bacteroidetes, p_Verrucomicrobia, p_Firmicutes, and p_Tenericutes. At the family level, Car1-/- mice had significantly different abundances in eight microbiota groups compared to WT mice. Car1 deficiency is associated with depressive-like behavior and gut microbiota dysbiosis, potentially linked to depressive-like phenotypes.
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Chronic paradoxical sleep deprivation-induced depression-like behavior, energy metabolism and microbial changes in rats.
AIMS: Given the lasting impact of chronic paradoxical sleep deprivation (PSD) on behavior and organism metabolic alternations, along with the role of the microbiome in neurobehavioral development and metabolism, we sought to examine the relationship between the microbiota and chronic PSD-induced behavioral and metabolic changes. MATERIALS AND METHODS: Psychological status of 7-day PSD (7d-PSD) male rats was tested by behavioral method, serum inflammatory cytokines and hypothalamic-pituitary-adrenal (HPA) axis-related hormones. In addition, GC-MS based urine metabolomics and 16S rRNA gene sequencing approaches were applied to estimate the influences of chronic PSD on host metabolism and gut-microbiota. Furtherly, microbial functional prediction and Spearman's correlation analysis were implemented to manifest the relations between the differential urinary metabolites and gut microbiota. KEY FINDINGS: 7d-PSD rats displayed depression-like behavior, metabolic and microbial changes. By integrating differential gut bacteria with indicators of depression and differential metabolites, we found that the alterations of Akkermansia, Oscillospira, Ruminococcus, Parabacteroides, Aggregatibacter and Phascolarctobacterium were closely related to abnormalities of depression symptoms and inflammatory cytokines. These bacteria also had close connections with host energy metabolism concerning arginine and proline metabolism, glycine, serine and threonine metabolism, and glyoxylate and dicarboxylate metabolism, pyruvate metabolism, which overlapped with the results of 16S rRNA gene function annotation. SIGNIFICANCE: These data suggest that a specific situation of circadian disturbance, chronic PSD-induced alterations in gut microbiota and related host changes in metabolism may be the pathogenesis of depression.
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Probiotics supplementation in prophylaxis and treatment of depressive and anxiety disorders - a review of current research.
In recent years increased interest in the connection of intestinal microflora and the state of human health resulted in a great deal of research on the influence of intestinal microflora in particular on mental health, including works on affective functions of the central nervous system (CNS). Previous studies on animals have revealed the existence of a bi-directional communication system between the gastrointestinal microbiota and the central nervous system, the so-called .gut-brain axis' which modulates functioning of CNS through immunological, endocrine and neuronal mechanisms. Clinical studies have shown a connection between supplementation of probiotics containing specific species and strains of bacteria and the regulation of the body's response to stress and with the exacerbation of depressive and anxiety symptoms in humans. Studies have also demonstrated differences in the composition of the intestinal microflora of patients with a diagnosis of major depressive disorder in comparison with the healthy population. The aim of this article is to present the current state of knowledge on the relationship between composition of intestinal microflora and affective functions of CNS and on effects of supplementation of probiotics on depressive and anxiety symptoms in humans. Previous studies on the use of probiotics in the prophylaxis and treatment of depressive and anxiety disorders included too small groups of persons, especially in groups of patients diagnosed with depression, to be able to clearly determine the effectiveness of probiotics in prevention and, in particular, treatment of these disorders in humans.
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Biogeography of intestinal mucus-associated microbiome: Depletion of genus Pseudomonas is associated with depressive-like behaviors in female cynomolgus macaques.
INTRODUCTION: Depression is a debilitating and poorly understood mental disorder. There is an urgency to explore new potential biological mechanisms of depression and the gut microbiota is a promising research area. OBJECTIVES: Our study was aim to understand regional heterogeneity and potential molecular mechanisms underlying depression induced by dysbiosis of mucus-associated microbiota. METHODS: Here, we only selected female macaques because they are more likely to form a natural social hierarchy in a harem-like environment. Because high-ranking macaques rarely displayed depressive-like behaviors, we selected seven monkeys from high-ranking individuals as control group (HC) and the same number of low-ranking ones as depressive-like group (DL), which displayed significant depressive-like behaviors. Then, we collected mucus from the duodenum, jejunum, ileum, cecum and colon of DL and HC monkeys for shotgun metagenomic sequencing, to profile the biogeography of mucus-associated microbiota along duodenum to colon. RESULTS: Compared with HC, DL macaques displayed noticeable depressive-like behaviors such as longer duration of huddle and sit alone behaviors (negative emotion behaviors), and fewer duration of locomotion, amicable and ingestion activities (positive emotion behaviors). Moreover, the alpha diversity index (Chao) could predict aforementioned depressive-like behaviors along duodenum to colon. Further, we identified that genus Pseudomonas was consistently decreased in DL group throughout the entire intestinal tract except for the jejunum. Specifically, there were 10, 18 and 28 decreased Pseudomonas spp. identified in ileum, cecum and colon, respectively. Moreover, a bacterial module mainly composed of Pseudomonas spp. was positively associated with three positive emotion behaviors. Functionally, Pseudomonaswas mainly involved in microbiota derived lipid metabolisms such as PPAR signaling pathway, cholesterol metabolism, and fat digestion and absorption. CONCLUSION: Different regions of intestinal mucus-associated microbiota revealed that depletion of genus Pseudomonas is associated with depressive-like behaviors in female macaques, which might induce depressive phenotypes through regulating lipid metabolism.
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Exploration of microbiota targets for major depressive disorder and mood related traits.
Growing evidence suggests the link between gut microbiota and mood regulation. The current study aimed to identify microbiota targets for major depressive disorder (MDD) and mood-related traits in Taiwanese samples, while taking into account the influence of dietary patterns. We recruited 36 MDD patients and 37 healthy controls for 16S rRNA gene sequencing. We assessed nutrient content using food frequency questionnaire, and mood related phenotypes, including depressive severity, anxiety, and perceived stress. Analysis of composition of microbiomes (ANCOM) models were performed to evaluate microbiota compositions between patients and controls, while adjusted for fat intake% and sequencing platforms. We found 23 taxa (4 phyla, 7 families and 12 genera) to be associated with depression and beta diversity was differed between groups. Phylum Actinobacteria and Firmicutes were overrepresented in MDD patients. At genus level, Bifidobacterium (7%) and Blautia (8%) had relatively high abundance among MDD patients, while Prevotella (16%) had high abundance in controls. Holdemania exhibited moderate correlation with anxiety (r = 0.65) and perceived stress level (r = 0.49) mainly in MDD patients but not controls. Pathway analyses revealed that pentose phosphate and starch and sucrose metabolism processes were important pathways for depression via microbiota functions. In conclusion, our results revealed microbiota targets for depression that are independent of fat intake. It is worthwhile to conduct further studies to replicate the current findings and to integrate with biochemistry and metabolomics data to better understand the functions of identified targets.
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Comparative metaproteomics analysis shows altered fecal microbiota signatures in patients with major depressive disorder.
Major depressive disorder (MDD) is a highly prevalent and debilitating mental illness, which is associated with disorder of gut microbiota. However, few studies focusing on detection of the signatures of bacteria in feces of MDD patients using proteomics approach have been carried out. Here, a comparative metaproteomics analysis on the basis of an isobaric tag for relative and absolute quantification coupled with tandem mass spectrometry was carried out to explore the signature of gut microbiota in patients with MDD. Ten patients (age: 18-56 years, five women) who had MDD and a score over 20 on the Hamilton's Depression Scale and 10 healthy controls (age: 24-65 years, five women) group matched for sex, age, and BMI were enrolled. As a result, 279 significantly differentiated bacterial proteins (P<0.05) were detected and used for further bioinformatic analysis. According to phylogenetic analysis, statistically significant differences were observed for four phyla: Bacteroidetes, Proteobacteria, Firmicutes, Actinobacteria (P<0.05, for each). Abundances of 16 bacterial families were significantly different between the MDD and healthy controls (P<0.05). Furthermore, Cluster of Orthologous Groups analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that disordered metabolic pathways of bacterial proteins were mainly involved in glucose metabolism and amino acid metabolism. In conclusion, fecal microbiota signatures were altered significantly in MDD patients. Our findings provide a novel insight into the potential connection between gut microbiota and depression.