Abstract
INTRODUCTION: Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising therapy for irritable bowel syndrome (IBS). The aims of this clinical trial were to evaluate the influence of taVNS on autonomic functions, rectal sensation, and acetylcholine (Ach) levels and to explore potential mechanisms involving gut microbiota and metabolic profiles. METHODS: This study was a single-center, single-blind, randomized controlled trial executed at the First Affiliated Hospital of USTC, Anhui, China. Individual patients' constipation-predominant IBS (IBS-C)-related symptoms and mental health were assessed and scored using questionnaires at baseline and at week 4. Levels of serum Ach and nitric oxide, anorectal manometry, and heart rate variability were assessed both before and after the therapy. Fecal samples from each group were assessed to compare the gut microbiota, short-chain fatty acids, and gut microbiota-derived tryptophan metabolites. RESULTS: Between September 2023 and May 2024, 40 patients (n = 20 in both taVNS and sham-taVNS groups) completed the 4-week study by performing an intention-to-treat analysis. No differences in all parameters between taVNS and sham-taVNS groups at the baseline were found. The taVNS significantly improved the visual analog scale score ( P < 0.001), IBS Severity Scoring System score ( P < 0.001), weekly frequency of spontaneous bowel movements ( P < 0.001), weekly frequency of complete spontaneous bowel movements ( P = 0.004), Bristol Stool Form Scale score ( P < 0.001), Hamilton Anxiety Scale score ( P < 0.001), Hamilton Depression Scale score ( P < 0.001), and IBS Quality of Life score ( P < 0.001). Furthermore, taVNS improved rectal sensation in patients with IBS-C, including improvements in the threshold volume for initial sensation ( P = 0.033), urge to defecate ( P = 0.022), and rectoanal inhibitory reflex ( P = 0.002). Moreover, taVNS elevated serum levels of Ach ( P = 0.005) and reduced nitric oxide ( P = 0.016) while also enhancing vagal activity ( P < 0.001) as determined by spectral analysis of heart rate variability. Three patients in the taVNS group and 2 in the control group had adverse consequences, which were manageable. In addition, taVNS led to a significant rise in the level of the genus Bifidobacterium ( P = 0.038) and increased levels of acetic ( P = 0.003), butyric ( P = 0.011), and propionic ( P = 0.005) acids. It also decreased tryptophan metabolism content, including 3-hydroxyanthranilic acid ( P = 0.007), anthranilic acid ( P = 0.026), and L-tryptophan ( P = 0.002). DISCUSSION: The study manifested that noninvasive taVNS effectively improved constipation and abdominal pain symptoms in patients with IBS-C. The alleviation of IBS-C symptoms may be attributed to the integrative effects of taVNS on rectal functions, mediated through vagal, cholinergic, and multiomics mechanisms.