Gut microbiota reshapes host energy metabolism to modulate depressive behaviors

Disturbances in energy metabolism are a key pathophysiological feature of major depressive disorder (MDD). The gut microbiota, as a critical regulator of host metabolism, may influence systemic energy homeostasis and contribute to depression. To investigate this, we performed a multi-omics analysis integrating targeted metabolomics and shotgun metagenomics on samples from 100 MDD patients and 68 healthy controls. MDD patients exhibited significant disruptions in central energy pathways (glycolysis, TCA cycle, and ornithine cycle), which correlated with symptom severity and cognitive impairment. We identified 36 bacterial species whose abundances were linked to mitochondrial fatty acid synthesis, ketogenesis, and amino acid metabolism, and were associated with altered levels of core metabolites like lactate and L-glutamic acid. Mediation analysis established a “gut microbiota–energy metabolites–depressive phenotype” axis, where metabolites mediated the effects of specific bacteria (e.g., Dorea_formicigenerans) on symptoms. To validate causality, we used a chronic social defeat stress mouse model with simultaneous autologous fecal microbiota transplantation (FMT). FMT effectively reshaped the gut microbiota, ameliorated depression-like behaviors, and reversed the stress-induced shift toward anaerobic glycolysis in serum and the central nervous system. Critically, FMT restored mitochondrial morphology and structural integrity in the prefrontal cortex and hippocampus, renormalizing the relationship between metabolism and behavior. Our findings elucidate the gut microbiota's role in MDD pathogenesis via host energy metabolism regulation and posit early autologous FMT as a novel strategy to correct central energy imbalances.