Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising therapy for irritable bowel syndrome (IBS). This clinical trial aims 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. This study was a single-center, single-blind, randomized controlled trial executed at the First Affiliated Hospital of USTC, Anhui, China. Individual patients' 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 (NO), anorectal manometry, and heart rate variability (HRV) were assessed both prior to and following the therapy. Fecal samples from each group were assessed to compare the gut microbiota, short-chain fatty acids, and gut microbiota-derived tryptophan metabolites. Between September 2023 and May 2024, 40 participants (n=20 in both taVNS and sham-taVNS group) completed the four-week study by performing an intention-to-treat (ITT) analysis. No differences in all parameters between taVNS and sham-taVNS groups at the baseline was found. The taVNS significantly improved the VAS score (P < 0.001), IBS Severity Scoring System (IBS-SSS) (P < 0.001), weekly frequency of spontaneous bowel movements (SBMs) (P < 0.001), weekly frequency of complete SBMs (CSBMs) (P = 0.004), Bristol Stool Form Scale (BSFS) (P < 0.001), Hamilton Anxiety Scale (HAMA) (P < 0.001), Hamilton Depression Scale (HAMD) (P < 0.001), and IBS-QOL scores (P < 0.001). Furthermore, taVNS improved rectal sensation in IBS-C patients, including improvements in the threshold volume for initial sensation (P = 0.033), the 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 NO (P = 0.016) while also enhancing vagal activity (P < 0.001) as determined by spectral analysis of HRV. Three individuals in the taVNS group and two in the control group had adverse consequences, which were manageable. Additionally, taVNS led to a significant rise in the level of the genus Bifidobacterium (P = 0.038), increased levels of acetic (P = 0.003), butyric (P = 0.011), and propionic acids (P = 0.005). It also decreased tryptophan metabolism content, including 3-hydroxyanthranilic acid (P = 0.007), anthranilic acid (P = 0.026) and L-tryptophan (P = 0.002). The study manifested that non-invasive taVNS effectively improved constipation and abdominal pain symptoms in IBS-C patients. The alleviation of IBS-C symptoms may be attributed to the integrative effects of taVNS on rectal functions, mediated through vagal, cholinergic, and multi-omics mechanisms.
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