Gut Microbiota Dysbiosis Induces Depression-like Behaviors via Impairing Mitochondrial Function in Astrocytes

Gut microbiota dysbiosis is implicated in depression, yet the underlying central mechanisms remain unclear. Astrocytes, key regulators of brain energy metabolism, are potential targets for peripheral signals from the gut. This study investigated whether gut microbiota dysbiosis contributes to depression by impairing astrocytic mitochondrial function, focusing on the ATP5O (ATP synthase subunit O, mitochondrial). Antibiotic-induced gut microbiota dysbiosis in mice triggered depression-like behaviors, intestinal barrier damage (elevated serum LPS, zonulin, FABP2), and hippocampal astrocyte dysfunction with mitochondrial impairment, including oxidative phosphorylation (OXPHOS) suppression. Fecal microbiota transplantation reversed all deficits, confirming gut microbial causality. In vitro, LPS induced similar astrocytic and mitochondrial dysfunction. Transcriptomics identified OXPHOS as the primary disrupted pathway, with ATP5O as a central node. Overexpression of ATP5O rescued LPS-induced astrocytic dysfunction, mitochondrial failure, and OXPHOS suppression. Our findings define a "gut-astrocyte" axis wherein microbiota dysbiosis elevates circulating LPS, impairs astrocytic mitochondrial OXPHOS via ATP5O downregulation, and promotes depressive-like behaviors, highlighting astrocytic bioenergetics and ATP5O as potential therapeutic targets.