Imbalanced autonomic function, characterized by reduced vagal activity and sympathetic dominance, is increasingly recognized in various gastrointestinal (GI) disorders. The vagus nerve, a key component of the parasympathetic nervous system, plays a critical role in regulating upper GI motility, inflammation, and pain perception. Transcutaneous vagal nerve stimulation (tVNS) offers a non-invasive method to modulate vagal activity, presenting a promising therapeutic approach for GI conditions. This review synthesizes evidence from clinical trials on the efficacy of tVNS—including transcutaneous auricular (taVNS), cervical (tcVNS), and percutaneous electrical nerve field stimulation (PENFS)—in managing abdominal pain, improving GI symptoms, and enhancing motility in disorders such as functional dyspepsia (FD), gastroparesis, irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD). tVNS demonstrates significant potential in alleviating symptoms and restoring autonomic balance through anti-inflammatory, anti-nociceptive, and prokinetic mechanisms. However, larger, standardized trials are needed to optimize stimulation parameters and confirm clinical efficacy.
Introduction
The vagus nerve is the longest cranial nerve, innervating thoracic and abdominal organs and facilitating bidirectional communication between the brain and the gut via afferent (80%) and efferent (20%) fibers. It regulates essential GI functions—motility, secretion, satiety, and inflammation—through the dorsal vagal complex in the brainstem. Autonomic imbalance, marked by reduced vagal tone, is implicated in various GI disorders, including FD, gastroparesis, IBS, and IBD. Traditional invasive VNS, while effective, is limited by its cost, surgical risks, and side effects. Non-invasive tVNS methods—taVNS, tcVNS, and PENFS—offer safer, patient-friendly alternatives by stimulating superficial vagal branches through the skin or ear. This review evaluates the clinical effects and mechanisms of tVNS in GI disorders, drawing on evidence from randomized trials and preclinical studies.
Non-invasive VNS for Abdominal Pain in DGBIs
Chronic abdominal pain is a hallmark of disorders of gut-brain interaction (DGBIs), affecting up to 25% of the U.S. population. Six clinical trials have explored tVNS for pain relief:
taVNS in FD: A multicenter RCT with 330 FD patients showed that 4 weeks of taVNS (10 Hz or 25 Hz) significantly reduced stomach pain compared to sham (75–82.8% vs. 61.5% response). Improvements were also seen in bloating and fullness.
taVNS in IBS-C: A study of 42 patients reported a 64% reduction in abdominal pain and tripled weekly bowel movements after 4 weeks of taVNS.
tcVNS in Gastroparesis: An open-label trial using a handheld stimulator (gammaCore) improved pain and GI symptoms in 15 patients, though autonomic function remained unchanged.
PENFS in Adolescents: RCTs demonstrated sustained reductions in worst abdominal pain and improved well-being in IBS patients after 3 weeks of PENFS.
Non-invasive VNS for Inflammatory Bowel Disease
One pilot study in 22 pediatric IBD patients (Crohn's disease and ulcerative colitis) investigated taVNS (20 Hz). After 16 weeks, 50% of CD and 33% of UC patients achieved clinical remission, and 64.7% showed ≥50% reduction in fecal calprotectin, indicating anti-inflammatory effects. Limitations include small sample size and lack of prolonged sham control.
Non-invasive VNS for GI Motility
GI dysmotility contributes significantly to symptoms in DGBIs. Three trials evaluated tVNS:
Esophageal Motility: taVNS enhanced upper and lower esophageal sphincter pressures in patients with laryngopharyngeal reflux.
Gastric Accommodation and Slow Waves: In FD patients, taVNS improved gastric accommodation and normalized slow waves.
Colonic and Anorectal Function: In IBS-C, taVNS enhanced rectal sensation and improved reflex activity, alongside reduced proinflammatory cytokines (TNF-α, IL-6).
Mechanisms of Action
tVNS exerts therapeutic effects through multiple pathways:
Anti-nociceptive Effects: Modulates visceral hypersensitivity via vagal afferents to the NTS, influencing pain-processing regions (e.g., hypothalamus, amygdala).
Anti-inflammatory Effects: Activates the cholinergic anti-inflammatory pathway, where acetylcholine binds α7nAChR on macrophages, suppressing TNF-α, IL-6, and IL-1β.
Prokinetic Effects: Enhances vagal efferent activity, improving GI slow waves, accommodation, and transit. HRV studies confirm increased parasympathetic tone.
Central Mechanisms: fMRI studies in migraine show taVNS activates NTS and modulates pain networks; similar mechanisms are hypothesized for GI disorders.
Limitations and Future Directions
Current evidence is limited by small sample sizes, variability in stimulation parameters (frequency, duration, site), and lack of consensus on optimal protocols. Preclinical studies suggest higher frequencies (e.g., 100 Hz) may be more effective for pain, while lower frequencies (25 Hz) improve motility, but clinical translation is needed. Future research should focus on:
Large-scale, multicenter RCTs.
Standardization of stimulation protocols.
Integration with multi-omics and neuroimaging.
Personalized approaches based on autonomic profiling.
Conclusion
Transcutaneous VNS represents a novel, non-invasive, and safe therapy for GI disorders, with demonstrated benefits in pain relief, inflammation reduction, and motility enhancement. Its mechanisms involve modulation of vagal pathways, central pain processing, and immune responses. While promising, broader clinical adoption requires further high-quality studies to establish optimized parameters and confirm efficacy across diverse GI conditions.
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The study was recently published in the Journal of Translational Gastroenterology .
Journal of Translational Gastroenterology (JTG) dedicates to improving clinical diagnosis and treatment, advancing understanding of the molecular mechanisms, and promoting translation from bench to bedside of gastrointestinal, hepatobiliary, and pancreatic diseases. The aim of JTG is to provide a forum for the exchange of ideas and concepts on basic, translational, and clinical aspects of gastroenterology, and promote cross-disciplinary research and collaboration.
