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Gut microbiota dysbiosis-mediated ceramides elevation contributes to corticosterone-induced depression by impairing mitochondrial function

ABSTRACT: Background: As a worldwide threat to mental health, depression affects about 322 million people globally. Recently, the role of gut microbiota dysbiosis on the pathogenesis of depression has received widespread attention, but the underlying mechanism remains elusive.Results: Corticosterone (CORT)-treated mice showed depressive-like behaviors, a reduction in hippocampal neurogenesis, and an altered composition of gut microbiota (GM). Fecal microbial transplantation (FMT) from CORT-treated mice transferred depressive-like phenotypes and their dominant GM, especially bifidobacterium and lactobacillus, to the recipients. Fecal metabolic profiling showed that the relative abundances of fecal ceramides were significantly increased in CORT-treated and the recipient mice. Metagenomic sequencing exposed that bifidobacterium and lactobacillus might be responsible for gut ceramides production in CORT-treated mice. We then found that treatment with ceramides via oral gavage was sufficient to recapitulate the depressive-like phenotypes in wild -type mice. Finally, RNA-sequencing data exposed that most of the differentially expressed genes (DEGs) between ceramides-treated mice and the control group were enriched in oxidative phosphorylation (OXPHOS) pathway. Conclusion: We conclude that chronic exposure to CORT leads to an altered GM composition and consequent ceramides production, thus leading to subtle mitochondrial OXPHOS dysfunction in hippocampus, which may contribute to the development of depressive disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE229237 | GEO | 2024/04/01

REPOSITORIES: GEO

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Project description:Major depressive disorder (MDD) is the psychiatric disorder with the highest prevalence in the world. Pharmacological antidepressant treatment (AD), such as selective serotonin reuptake inhibitors [SSRI, i.e. fluoxetine (Flx)] is the first line of treatment for MDD. Despite its efficacy, lack of AD response occurs in numerous patients characterizing Difficult-to-treat Depression. ElectroConvulsive Therapy (ECT) is a highly effective treatment inducing rapid improvement in depressive symptoms and high remission rates of ~50–63% in patients with pharmaco-resistant depression. Nevertheless, the need to develop reliable treatment response predictors to guide personalized AD strategies and supplement clinical observation is becoming a pressing clinical objective. Here, we propose to establish a proteomic peripheral biomarkers signature of ECT response in an anxio/depressive animal model of non-response to AD. Using an emotionality score based on the analysis complementary behavioral tests of anxiety/depression (Elevated Plus Maze, Novelty Suppressed Feeding, Splash Test), we showed that a 4-week corticosterone treatment (35 μg/ml, Cort model) in C57BL/6JRj male mice induced an anxiety/depressive-like behavior. A 28-days chronic fluoxetine treatment (Flx, 18 mg/kg/day) reduced corticosterone-induced increase in emotional behavior. A 50% decrease in emotionality score threshold before and after Flx, was used to separate Flx-responding mice (Flx-R, n=18), or Flx non-responder mice (Flx-NR, n=7). Then, Flx-NR mice received 7 sessions of electroconvulsive seizure (ECS, equivalent to ECT in humans) and blood was collected before and after ECS treatment. Chronic ECS normalized the elevated emotionality observed in Flx-NR mice. Then, proteins were extracted from peripheral blood mononuclear cells (PBMCs) and isolated for proteomic analysis using a high-resolution MS Orbitrap. The proteomic analysis revealed a signature of 33 peripheral proteins associated with response to ECS (7 down- and 26 upregulated). These proteins were previously associated with mental disorders and involved in regulating pathways which participate to the depressive disorder etiology. remark for sample name : ECTR=Flx-NR-ES, C=cort/Veh, CFNR= Flx-NR

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Gut microbiota dysbiosis-mediated ceramides elevation contributes to corticosterone-induced depression by impairing mitochondrial function

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