Dose–Response Relationship of Transcutaneous Auricular Vagus Nerve Stimulation in a Rat Model of Ulcerative Colitis

Abstract

Objective:

This study aimed to evaluate the therapeutic effects of transcutaneous auricular vagus nerve stimulation (taVNS) at different intensities on ulcerative colitis (UC) and its effects on the IL-6/JAK2/STAT3 signaling pathway.

Methods:

UC was established in rats via ad libitum intake of 5% dextran sulfate sodium (DSS) in drinking water. Beginning on Day 2 of DSS administration, taVNS was administered unilaterally to the right cymba conchae for 20 min daily over 5 days, with ongoing DSS exposure. Parameters included 1, 2, or 3 mA current intensity, 200 μs pulse width, and a 2/15 Hz dense-disperse waveform.

Results:

DSS exposure led to hallmark UC signs: impaired weight gain, elevated disease activity index (DAI), severe colonic injury, and dysregulation of multiple cytokines—including IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-17A, M-CSF, IFN-γ, and TNF-α. A 2 mA taVNS showed maximal efficacy, normalizing weight, arresting DAI rise, reducing injury, and suppressing all 10 cytokines, and a 1 mA taVNS improved weight, DAI, and histology, with reduced M-CSF, IL-10, and TNF-α, showing dose-dependent M-CSF suppression. No benefit occurred with 3 mA taVNS. DSS downregulated occludin and ZO-1, indicating barrier disruption; taVNS restored expression, significantly with 2 and 3 mA. Occludin was highest at 2 mA. The IL-6/JAK2/STAT3 pathway was activated in UC rats and suppressed by 2 mA taVNS, reducing IL-6, p-JAK2, and p-STAT3.

Conclusion:

This study identifies a nonlinear dose–response of taVNS in UC, with 2 mA as the optimal intensity; its superior efficacy is closely linked to IL-6/JAK2/STAT3 pathway suppression, highlighting taVNS as a promising noninvasive therapy.