Mechanisms of transcutaneous bilateral auricular vagus nerve stimulation in treating functional dyspepsia through promoting M2 macrophage polarization

BACKGROUND: Functional dyspepsia (FD) is characterized by duodenal mucosal barrier dysfunction and chronic low-grade inflammation. Macrophage polarization imbalance, particularly the predominance of pro-inflammatory M1 over anti-inflammatory M2 phenotypes, contributes significantly to FD pathogenesis. Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a promising non-invasive therapeutic approach for gastrointestinal disorders. OBJECTIVE: This study aimed to investigate the therapeutic mechanisms of taVNS in FD treatment, specifically focusing on its effects on M2 macrophage polarization and the roles of metabolic regulator UCP2 and transcription factor GATA3 in this process. METHODS: Male C57BL/6J mice (n = 27) and Gata3∆mac mice (n = 9), totaling 36 mice were used to establish an FD model through multi-factorial stress induction and were divided into four experimental groups. taVNS treatment was administered for 2 weeks. Feeding behavior, duodenal mucosal inflammatory cytokines, inflammatory markers, macrophage polarization markers, and intestinal barrier function were assessed. Gata3∆mac + taVNS mice were used to determine the transcription factor's role in taVNS-mediated effects. RESULTS: TaVNS treatment significantly improved feeding behavior in FD mice. At the duodenal mucosal level, taVNS markedly reduced the elevated IL-1βlevels and restored the suppressed TGF-β1 levels. TaVNS also promoted M2 macrophage polarization, as evidenced by decreased Nos2 expression and increased Arg1 expression. TaVNS partially restored Ucp2 and Gata3 expression relative to FD mice, elevated the expression of tight junction ZO-1 to relieve duodenal tight junction impairment linked to barrier dysfunction, and modulated inflammatory responses (decreased TNF-α, increased IL-10). The therapeutic effects of taVNS were significantly attenuated in Gata3∆mac + taVNS mice, confirming the critical role of GATA3 in mediating taVNS-induced M2 polarization. CONCLUSIONS: taVNS promotes M2 macrophage polarization to treat FD through mechanisms involving both metabolic regulation (UCP2) and transcriptional control (GATA3). These findings provide novel insights into the immunometabolic mechanisms underlying taVNS therapy and support its clinical application for FD management.