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

Background: Depressive disorders affect approximately 322 million people globally and are a worldwide threat to mental health. Recently, the role of gut microbiota (GM) dysbiosis in the pathogenesis of depression has received widespread attention; however, the underlying mechanism remains elusive. Results: Corticosterone (CORT)-treated mice showed depression-like behaviors, reduced hippocampal neurogenesis, and altered composition of the GM. Fecal microbial transplantation (FMT) from CORT-treated mice transferred depression-like phenotypes and their dominant GM, especially Bifidobacterium and Lactobacillus, to the recipients. Fecal metabolic profiling showed that the relative abundance of fecal ceramides significantly increased in CORT-treated and recipient mice. Metagenomic sequencing and correlation analysis revealed the co-relationship between ceramides and increased abundance of Bifidobacterium and Lactobacillus. Colonization study exposed that oral gavage with Bifidobacterium_pseudolongum and Lactobacillus_reuteri could induce elevations of gut ceramides. We found that treatment with ceramides via oral gavage was sufficient to recapitulate depressive-like phenotypes in wild-type mice. Finally, ceramides-treated mice showed significant downregulation of oxidative phosphorylation (OXPHOS)-differentially expressed genes (DEGs). Mitochondrial function assay validated hippocampal mitochondrial dysfunction in CORT- or ceramides-treated mice. Conclusion: Our study demonstrated a significant link between chronic exposure to corticosterone (CORT) and its impact on GM composition. This altered composition, in turn, induces ceramides accumulation, ultimately leading to mitochondrial respiratory chain dysfunction in the hippocampus. This cascade of events plays a critical role in reducing adult hippocampal neurogenesis (AHN) and is strongly associated with the development of depression-like behaviors.