Transcutaneous auricular vagus nerve stimulation improves depressive-like behaviors in CUMS rats through regulation of gut microbiome, serum metabolites, and immune factors.

BACKGROUNDDepression is associated with microbiota-gut-brain (MGB) axis dysregulation. Transcutaneous auricular vagus nerve stimulation (taVNS) has shown antidepressant effects and modulated gut microbiota, but its potential to alleviate depression specifically via modulation of the MGB axis remains largely unexplored.

METHODSRats subjected to chronic unpredictable mild stress (CUMS) received taVNS for 3 weeks. We assessed depressive-like behaviors, gut microbiota, plasma metabolism, and inflammatory marker levels. Pearson correlation analyses examined relationships among these factors.

RESULTStaVNS significantly improved depressive behaviors in CUMS rats. It shifted gut microbiota composition, enriching beneficial Lactobacillus murinus, Bifidobacterium animalis, and Prevotellaceae while reducing harmful Bacteroidales and Romboutsia. Metabolomics revealed taVNS modulated plasma metabolism, especially metabolism of cofactor/vitamin, sphingolipid metabolism, amino and organic acid metabolism, increasing the levels of indole-3-lactic acid (ILA), riboflavin, sphingosine-1-phosphate (S1P), sphinganine-1-phosphate (Sa1P) and sphingosine (SP), and creatine. taVNS also reduced blood, hippocampus and prefrontal cortex inflammation. Pearson correlation analysis showed that alleviation of depressive behaviors positively correlated with Lactobacillus murinus, Bifidobacterium animalis, and plasma ILA, riboflavin, S1P, Sa1P, SP, and creatine and all these parameters inversely associated with pro-inflammatory factors.

CONCLUSIONThese findings indicate that taVNS may alleviate depression by enriching Lactobacillus murinus and Bifidobacterium animalis to enhance biosynthesis of microbiota-derived metabolites (ILA, riboflavin) and modulate host plasma metabolites (S1P, Sa1P, SP, creatine), thereby attenuating systemic and neuroinflammatory processes.