Multi-omics reveals associations between the microbiota-gut-brain axis and antidepressant effects of vagus nerve stimulation

Background: Major depressive disorder is a severe mental health condition characterized by persistent depressed mood and loss of interest. Current first-line pharmacotherapies often exhibit limited therapeutic performance and adverse side effects. Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising, safe, and noninvasive alternative intervention with demonstrated neuromodulatory efficacy. Nevertheless, its mechanisms remain unclear. This study investigated whether the antidepressant properties of taVNS are associated with the microbiota-gut-brain axis, focusing on the potential crosstalk between differentially expressed hippocampal proteins and the gut microbiota. Methods: A chronic unpredictable mild stress (CUMS) rat model of depression was established, and taVNS was administered for 14 days. Hippocampal proteomic profiling was performed using data-independent acquisition. Fecal metagenomic sequencing was conducted to characterize alterations in gut microbial communities. Key signaling pathways were validated using Western blot, qRT-PCR, HE staining, and transmission electron microscopy, all of which were employed to systematically assess behavioral, proteomic, microbial, and molecular changes. Results: . Ligilactobacillus levels were positively correlated with synaptogyrin-1 (Syngr1), indicating their potential association in enhancing the antidepressant effects mediated by the GluN1/MAPK/BDNF signaling cascade. Conclusion: . The positive correlation between Syngr1 protein level and Ligilactobacillus abundance in the hippocampus suggests that the microbiota-gut-brain axis may play a key role in the antidepressant effects of taVNS.