Electroacupuncture alleviates comorbid obesity and depression via the gut-brain axis: orchestrating SCFA-producing bacteria and hippocampal synaptic plasticity.

Introduction: Comorbid obesity and depression (COMBD) represents a complex metabolic-neuropsychiatric challenge with limited therapeutic options. While Electroacupuncture (EA) is effective for both metabolic and mood disorders, the systemic mechanisms-particularly the interplay between the gut microbiome and hippocampal plasticity-remain elusive. Methods: We established a COMBD rat model using a high-fat diet combined with chronic unpredictable mild stress (CUMS). An integrated multi-omics approach comprising 16S rDNA sequencing, LC-MS/MS serum metabolomics, and hippocampal transcriptomics was utilized to decipher the therapeutic mechanisms of EA. Results: EA treatment significantly attenuated body weight gain and reversed depressive-like behaviors. Crucially, EA restructured the dysbiotic gut microbiota, specifically increasing the abundance of short-chain fatty acid (SCFA)-producing bacteria. This microbial restoration was strongly correlated with a reprogrammed serum metabolic profile. In the hippocampus, transcriptomic analysis identified Cd74 as a pivotal upstream regulator modulated by EA. Furthermore, EA mitigated hippocampal oxidative stress and restored synaptic plasticity, evidenced by increased dendritic spine density and upregulated synaptic protein expression. Conclusion: Our findings suggest that EA ameliorates COMBD via a coordinated "Microbiota-Metabolism-Brain" axis. Specifically, EA creates a neuroprotective milieu by promoting beneficial SCFA-producing bacteria and regulating metabolic signals, which subsequently targets hippocampal Cd74 to restore synaptic plasticity. This study provides a novel mechanistic basis for the clinical application of EA in treating complex metabolic-mood comorbidities.