Noninvasive electrical neuromodulation involving vagus nerve mechanism for functional constipation and irritable bowel syndrome with constipation

Abstract

Functional constipation (FC) and irritable bowel syndrome with constipation (IBS-C) are prevalent disorders of gut–brain interaction with limited effective treatments. The vagus nerve exerts considerable influence on the gastrointestinal (GI) tract, indicating that noninvasive electrical neuromodulation targeting this nerve could provide a promising therapeutic avenue for both FC and IBS-C. This review explores several emerging noninvasive neuromodulation techniques involving the vagus nerve, such as transcutaneous auricular vagal nerve stimulation, percutaneous electrical nerve field stimulation, and transcutaneous electrical acustimulation. The clinical applications of these methods in managing FC and IBS-C are evaluated. Existing evidence supports the efficacy and safety of noninvasive neuromodulation in relieving symptoms of these conditions. Future investigations should aim to refine these techniques, advance device technology, and further clarify the mechanisms of action.

Keywords

constipation gut microbiota irritable bowel syndrome neuromodulation non-invasive vagus nerve

Introduction

A comprehensive meta-analysis of 45 population-based surveys estimated the global prevalence of constipation at approximately 14%.¹ This condition is more prevalent among women, older adults, and individuals with lower socioeconomic status.^1,2 Evidence suggests that the prevalence of constipation has increased in recent decades, likely due to lifestyle and dietary changes.³ Furthermore, a bidirectional Mendelian randomization study indicated a potential association between constipation and colorectal cancer.⁴ In the United States, chronic constipation imposes a substantial economic burden, with direct medical costs estimated at $235 million in 2001, of which 95.3% was attributed to outpatient care.⁵ Although data on direct medical costs for constipation remain limited, estimates indicate that between 70% and 90% of affected individuals in the U.S. report persistent symptoms such as bloating, straining, and hard stools, which negatively impact their health-related quality of life over time.⁶

Disorders of gut–brain interaction (DGBI) pose significant challenges for both clinicians and researchers due to the considerable symptom overlap across various conditions. This overlap spans a range of disorders, from functional dyspepsia (FD) to irritable bowel syndrome (IBS), and is consistently observed in both population-based studies and clinical cases.^7,8 Some evidence suggests that FD is associated with low-grade duodenal inflammation in a subset of patients, although this remains an area of active investigation. IBS with constipation (IBS-C) and functional constipation (FC), exemplify this diagnostic overlap. Clinically, these conditions are difficult to distinguish, especially when symptoms exhibit temporal variability. Both IBS-C and FC typically present with similar bowel habits and frequently report comparable abdominal symptoms, including bloating.⁹ Rather than being distinct entities, FC and IBS-C represent a continuum of DGBI with shared pathophysiological mechanisms. When patients with constipation report significant abdominal pain, a diagnosis of IBS-C should be considered. However, if abdominal pain is mild, constipation is the predominant symptom, or if pain resolves with the relief of constipation, FC is the more appropriate diagnosis. This review focuses specifically on FC and IBS-C within the DGBI framework.

The Rome criteria are widely recognized as the definitive diagnostic standards for FC and IBS-C. The Rome IV Criteria,¹⁰ increasingly endorsed for clinical application, require that patients with FC demonstrate at least two of the following symptoms in at least 25% of bowel movements over the past 3 months: incomplete evacuation, straining, lumpy or hard stools, manual maneuvers to facilitate evacuation, difficulty passing stools, or fewer than three bowel movements per week. Similarly, abdominal symptoms are not included in the Rome III diagnostic criteria for FC, and patients cannot simultaneously meet the criteria for IBS, which necessitates the presence of abdominal pain or discomfort associated with changes in bowel function.¹¹ Therefore, within the Rome Criteria framework, the shared aspect between IBS-C and FC is related to bowel symptoms.

There is an overlap of therapeutic strategies for FC and IBS-C. Bulk-forming, stimulant, and osmotic laxatives are commonly used in clinical practice to alleviate constipation-related symptoms.¹² The American College of Gastroenterology issued 2022 guidelines on the diagnosis and management of IBS-C,¹³ recommending linaclotide as a first-line treatment (high certainty) and tenapanor, plecanatide, tegaserod, and lubiprostone as conditionally recommended options (moderate certainty). Polyethylene glycol, tricyclic antidepressants, and antispasmodics were classified as treatments with low certainty. While guanylate cyclase activators, such as linaclotide, are favored for IBS-C management, they may cause adverse effects, including severe diarrhea.¹⁴ Because of the unsatisfactory management of the medication, other therapeutic approaches are worth exploring. Psychological and behavioral therapies, including hypnotherapy, have been shown to improve all symptoms of IBS-C, but the effect on FC is controversial.¹⁵ Biofeedback for pelvic floor rehabilitation specifically benefits patients with dyssynergic defecation, which often overlaps with FC; however, emerging evidence also suggests that some patients with IBS may benefit from biofeedback, particularly those with coexisting dyssynergic defecation.¹⁶ Here, we thoroughly discuss non-invasive electrical neuromodulation techniques targeting the vagus nerve, as it has emerged as a novel and promising therapy for both IBS-C and FC.

Vagus nerve

The vagus nerve is a key component of the parasympathetic nervous system,¹⁷ comprising predominantly afferent fibers (approximately 80%) and a smaller proportion of efferent fibers (approximately 20%). It plays a pivotal role in regulating gastrointestinal (GI) sensitivity, motility, and immune responses.^18,19 The afferent fibers transmit signals from the gastrointestinal tract to the central nervous system, relaying essential information about the internal organs through their innervation of the digestive system.²⁰ This includes the transmission of peripheral sensations, such as pain, thereby playing a central role in visceral nociception.^21,22 Meanwhile, the efferent fibers modulate the activity of preganglionic parasympathetic neurons in the dorsal motor nucleus of the vagus (DMV) or preganglionic sympathetic neurons in the spinal cord, influencing gastrointestinal motility, immune responses, and nociceptive processes within the gastrointestinal tract.²³ The DMV is central to the communication pathways between the central nervous system and peripheral organs, particularly the gastrointestinal system. It is characterized by a neural-humoral circuit that enables its neurons to directly receive and process information from peripheral blood and cerebrospinal fluid. The DMV is enriched with a variety of neurotransmitters and receptors, including acetylcholine, catecholamines, and neuropeptides, and plays a pivotal role in the central regulation of gastrointestinal, cardiovascular, and endocrine functions. Activation of the DMV can significantly enhance intestinal peristalsis. The vagus nerve’s communication network is intricately linked with the enteric nervous system, facilitating a bidirectional exchange of information known as the brain-gut axis, which is essential for maintaining physiological homeostasis²⁴ (Figure 1).

Vagal dysfunction in IBS-C and FC

Notably, various subtypes of IBS exhibit distinct autonomic nervous system dysfunction characteristics. In IBS (including IBS-C), there is consistent evidence from heart rate variability (HRV) studies of reduced vagal tone (decreased parasympathetic activity), which correlates with symptom severity, visceral hypersensitivity, and psychological distress.^25
–28 Some studies suggest that cholinergic versus noradrenergic imbalances may differentiate constipation-predominant from diarrhea-predominant subtypes, but the evidence is not definitive.^29,30 The balance between the parasympathetic and sympathetic nervous systems, as measured by HRV (a key autonomic parameter), is disrupted during acute stress, with sympathetic activation dominating.³¹ Although this balance typically returns to normal after acute stress, it may remain altered under chronic stress conditions, as seen in various gastrointestinal diseases, including IBS.^32,33 Moreover, an imbalance between the autonomic nervous system and the hypothalamic–pituitary–adrenal (HPA) axis has been observed in these conditions, likely due to dysregulation between the prefrontal cortex and the amygdala, both of which are integral to the central autonomic network.³⁴ Consequently, abnormal vagal tone may be both a cause and a consequence of such imbalances.

Our previous study found that abnormal vagal tone was associated with FC and IBS-C.^35,36 In FC, the link between vagal function and FC is less clear. Patients with FC experiencing sleep deficiency exhibited significantly decreased vagal activity (p = 0.016) and increased sympathetic activity (p = 0.003) relative to those without sleep deficiency.³⁵ For IBS-C, vagal dysfunction is well-established. A prior study demonstrated that increased vagal activity ameliorated symptoms and modified rectal sensation in patients with IBS-C.³⁶ The result indicated that the impact of sleep-disordered breathing on IBS-C may be mediated through mechanisms related to autonomic nervous system responses.

Given the importance of abnormal vagal tone and the extensive innervation of the gastrointestinal tract by the vagus nerve, which plays a primary role in parasympathetic regulation of inflammation and motility, it represents a compelling target for managing gastrointestinal dysfunction and related symptoms such as abdominal pain. Thus, vagus nerve stimulation (VNS) is gaining recognition as a potential non-pharmacological therapeutic strategy for disorders characterized by gut–brain interactions.

Vagus nerve stimulation

VNS represents a bioelectric medicine approach that uses electrical impulses to activate the vagus nerve, thereby enhancing organ function and overall health, with a lower incidence of adverse effects compared to pharmacological treatments.^37,38 VNS therapy can be classified into two main types based on the method of administration: invasive and non-invasive. Invasive VNS (iVNS) requires the surgical implantation of electrodes onto the cervical vagal nerve, which are connected to a pulse generator implanted in the left infraclavicular pocket. This setup delivers intermittent electrical impulses that stimulate both afferent and efferent fibers of the vagus nerve. iVNS has been established as an effective treatment for refractory epilepsy.³⁹

Conversely, transcutaneous VNS (tVNS) provides non-invasive alternatives: transcutaneous cervical VNS (tcVNS) stimulates the cervical vagus nerve, while transcutaneous auricular VNS (taVNS) stimulates the auricular branch of the vagus nerve (ABVN), which is purely afferent.^40,41 Therefore, ABVN stimulation in this case stimulates only afferent fibers without direct efferent activation, whereas tcVNS can induce both afferent and efferent responses. The primary advantages of non-iVNS include a minimal side effect profile, although the long-term effects require further investigation, as well as the ability to adjust stimulation parameters to meet individual patient needs.⁴² Additionally, non-invasive auricular percutaneous electrical nerve field stimulation (PENFS) offers another neuro-modulatory technique. This method uses miniature needle electrodes to penetrate the skin of the external ear and influence the peripheral cranial neurovascular bundle, which includes cranial nerves V, VII, IX, and X. These cranial nerve afferents project to brainstem nuclei, such as the nucleus tractus solitarius (NTS), which are involved in vagal nerve signaling.⁴³ This review focuses on non-invasive electrical neuromodulation techniques targeting the vagus nerve for the treatment of FC and IBS-C, including taVNS, transcutaneous electrical acustimulation (TEA), and PENFS. These techniques include taVNS, TEA, and PENFS (Figure 2).

Transcutaneous electrical acustimulation

TEA is a non-invasive technique that delivers electrical stimulation to specific acupuncture points on the skin using surface electrodes. As a needle-free approach, TEA has gained widespread acceptance among patients and is derived from traditional Chinese acupuncture and EA, which historically involved needle insertion at acupuncture points.⁴⁴ TEA is commonly employed in the treatment of DGBI, with Neiguan (PC6) and Zusanli (ST36) being the most frequently targeted acupuncture points for this purpose.^44
–47 According to TCM practices, ST36 has been used to enhance the functional capacity of the stomach and intestines, particularly in cases of FC.⁴⁸ On the other hand, PC6 is traditionally employed to nourish the heart and restore mental equilibrium, and is also indicated for improving liver function in patients with symptoms of depression, anxiety, or insomnia.⁴⁹ The combined use of ST36 and PC6 is believed to help restore normal “qi” flow within the stomach and spleen meridians. TEA can be delivered through wearable devices resembling a wristwatch.^50
–52 Typical stimulation parameters include mid to low-frequency ranges (e.g., 2–100 Hz), pulse width of 0.1–0.5 ms, and on/off cycles (e.g., 30 s on, 30 s off), adjusted based on patient tolerability.^47,50,53,54 TEA is proposed to modulate vagal-sympathetic balance as measured by HRV.

Transcutaneous auricular VNS

taVNS involves the application of small surface electrodes placed near the ear canal to deliver diffuse electrical stimulation to the surrounding area, activating the auricular branches of the vagus nerve.^55,56 Research suggests that taVNS engages the same cerebral regions as iVNS.⁵⁷ Therapeutic stimulation typically occurs within a frequency range of 0.5–30 Hz. Higher frequencies, between 20 and 30 Hz, are employed to enhance vagus nerve activity, while lower frequencies, from 0.5 to 10 Hz, are used to modulate sympathetic nerve activity.^58,59 The capacity of taVNS to directly influence central viscerosensory processing has been supported by functional magnetic resonance imaging (fMRI) studies, which show significant changes in brain structures, particularly within the brainstem, including the NTS and the spinal nucleus of the trigeminal nerve.⁶⁰ Additionally, it is proposed that taVNS’ inhibitory anti-nociceptive effects counteract the facilitatory effects of pronociception as stimulation intensity increases.⁶¹ Thus, the intensity of taVNS may play a key role in activating specific neural circuits within the brainstem, particularly the NTS.⁵⁹ Notably, both prior research and the findings presented here suggest that the effects of taVNS on cerebral activity persist beyond the stimulation period, indicating long-lasting effects.⁶² This enduring impact has been observed in both persistent anti-nociceptive responses⁶³ and anti-inflammatory responses^64,65 following brief taVNS stimulation, potentially linked to neuroplasticity. Further mechanistic investigations in patient populations are necessary to clarify the exact mechanisms through which taVNS influences visceronociceptive processes.

Despite the growing interest in taVNS research, a consensus on optimal stimulation parameters remains elusive. Accurate measurement of target engagement is crucial for identifying effective stimulation patterns; however, the absence of direct measures of local target engagement requires that studies on taVNS adopt stimulation parameters similar to those used in implantable taVNS. Variations in electrode design, size, contact area, target fiber type, and fiber orientation can influence neural recruitment, potentially resulting in differing physiological effects between taVNS and iVNS. Thus, stimulation parameters derived from iVNS may not replicate the same physiological effects or fiber recruitment during taVNS.⁶⁶ Real-time data on neural target engagement would significantly enhance the refinement of stimulation parameters, electrode configurations, and control mechanisms.⁶⁷ A systematic analysis of optimal treatment frequencies for taVNS suggests that recommended stimulation parameters may include a rectangular pulse wave in a biphasic signal format. Furthermore, as commonly practiced in most taVNS studies, parameters include rectangular biphasic pulses, 20–30 Hz, 30-s on/off cycles, with current calibrated to suprathreshold intensity.⁶⁸ taVNS represents a non-invasive and effective therapeutic approach for IBS-C and FC. By activating the central nervous system via the ABVN, it transmits signals to the nucleus of the solitary tract (NTS) and projects to other nuclei (Figure 3).

Peripheral electrical nerve field stimulation

A noninvasive device for auricular PENFS has proven effective and received approval from the U.S. Food and Drug Administration for treating adolescents with IBS,⁶⁹ where PENFS was found to reduce abdominal pain scores in adolescents with IBS. In addition to the vagus nerve, several other nerves contain parasympathetic fibers that are likely influenced by the broader field stimulation. PENFS is believed to exert its effects by modulating central pain pathways, presumably through noninvasive electrical stimulation of the auricular branch of the vagus nerve. fMRI studies have demonstrated that therapies involving auricular neurostimulation, including PENFS, activate cerebral vagal afferents and related central networks, indicating its potential as a VNS intervention.⁶³ Given preclinical evidence suggesting that vagal neurocircuitry plays a protective role in maintaining intestinal permeability and regulating local immune responses,⁷⁰ PENFS may improve intestinal symptoms and alter the composition of the gut microbiome in individuals with IBS. An significant increase in the relative abundance of Blautia was noted in subjects exhibiting a favorable therapeutic response for PENFS.⁷¹

Clinical trials

Clinical trials of TEA in FC and IBS-C

TEA has been evaluated as a potential treatment for constipation resulting from ischemic stroke in a randomized, patient-blinded, sham-controlled trial.⁷² In this study, 43 participants received TEA at the acupoint ST36, while 32 were assigned to a sham group. After 2 weeks, the results showed that TEA significantly reduced stroke-related constipation, increased the frequency of bowel movements, improved stool consistency, and improved quality of life. Furthermore, TEA was found to modulate vagal and sympathetic activity, as assessed by HRV. These findings suggest that TEA may be a viable therapeutic option for constipation. A 2004 pilot study examined the use of TEA for managing diarrhea-predominant IBS (IBS-D),⁷³ showing evidence of its efficacy in alleviating abdominal pain and rectal sensation in affected patients. More recent trials have demonstrated that a 2-week course of TEA effectively alleviates constipation and boosts vagal activity in individuals with constipation-predominant IBS (IBS-C)⁷⁴ and FC.⁷⁵ Notably, the benefits of constipation relief were sustained for 4 weeks after TEA treatment ceased.⁷⁴ Huang et al.⁷⁶ reported that TEA accelerated colonic transit and reduced rectal sensation via autonomic mechanisms.

Clinical trials of taVNS in FC and IBS-C

In a study on taVNS in IBS, Mion et al.⁷⁷ assessed 12 female patients undergoing taVNS treatment for 6 months. The evaluation focused on abdominal symptom improvement, feasibility, and physiological and biological parameters. Of the 12 participants, 9 completed the trial, reporting significant symptom relief at both 3 and 6 months. These preliminary results suggest that taVNS may be a feasible and effective intervention for IBS, warranting further investigation through randomized controlled trials. Previous research has suggested that the effects of taVNS may result from its dual neuromodulatory influence on both the gastrointestinal system and the brain, mediated through increased vagal nerve activity.⁷⁸ Kornum et al.⁷⁹ conducted a randomized, double-blind, sham-controlled, multicenter trial of tcVNS for gastrointestinal symptoms in diabetes. Although focused on diabetic gastroparesis, the study showed significant improvements in upper GI symptoms but not consistently in bowel habits, highlighting the need for disease-specific trials in constipation. And similar therapeutic effects of taVNS have been confirmed by Shi et al.⁸⁰ A recent single-blind RCT by Liu et al.⁸¹ demonstrated that taVNS significantly improved weekly spontaneous bowel movements (SBM), complete SBM (CSBM), abdominal pain Visual Analog Scale, IBS Symptom Severity System Score, and IBS Quality of Life in IBS-C patients compared to sham, with sustained effects for 4 weeks.⁸¹

Clinical trials of PENFS in FC and IBS-C

A recent prospective study investigated the effects of PENFS therapy over a 4-week period, using stool samples collected before and after the intervention. The authors found that alpha diversity was significantly higher in responders compared to non-responders at the 4-week mark. Additionally, the abundance of Blautia was greater in individuals classified as excellent responders compared to non-responders.⁸² Krasaelap et al.⁶⁹ conducted a randomized, double-blind trial of PENFS in adolescents with IBS, demonstrating significant reductions in abdominal pain scores. Bora et al.⁷¹ reported that PENFS altered gut microbiome composition in adolescent IBS patients, with responders showing increased alpha diversity and greater Blautia abundance. While PENFS is primarily studied in IBS, its effects on constipation symptoms are promising and warrant further research.

Summary of evidence

Across techniques, non-invasive vagal neuromodulation consistently improves constipation symptoms, abdominal pain, and quality of life in FC and IBS-C.^80–83 However, head-to-head comparisons are lacking, and long-term follow-up data beyond 6 months remain limited. Future studies should standardize stimulation parameters and evaluate the durability of effects. Supplemental Table 1 is provided in the Supplemental Materials with columns for study design, sample size, primary outcome measure, key finding, and adverse events.

Potential mechanism

The vagus nerve activates the cholinergic anti-inflammatory pathway through the α7 nicotinic acetylcholine receptor (nAChR). A recent study showed that chronic unpredictable mild stress induced depressive-like behaviors in rats, which were accompanied by neuroinflammation in the hypothalamus, characterized by microglial activation, a downregulation of α7 nAChR expression, and an upregulation of NF-κB p65, phosphorylated NF-κB p65, and interleukin-1 beta (IL-1β) expression. Notably, taVNS significantly reversed these changes. This suggests that the hypothalamic α7 nAChR/NF-κB signaling pathway may play a critical role in the antidepressant-like effects of taVNS.⁸⁴ Both IBS-C and FC are closely linked to dysfunctions in the intestinal nervous system, gastrointestinal motility disorders, visceral hypersensitivity, dysbiosis of gut microbiota, and psychological disturbances. Thus, the therapeutic effects of taVNS in IBS and FC may involve multiple mechanisms, including the regulation of gastrointestinal motility and secretion, attenuation of visceral hypersensitivity, reduction of inflammatory responses to alleviate abdominal pain, modulation of depressive-like behaviors through the downregulation of the hyperactive HPA axis, regulation of gut microbiota through the brain-gut microbiota axis, and overall health improvement.

Modulating gut motility and secretion

The vagus nerve is integral to the pathogenesis and progression of various gastrointestinal disorders, including DGBI and postoperative ileus.⁸⁵ Electrical stimulation has been shown to induce gastrointestinal contractions, highlighting the vagus nerve’s regulatory role in the gastrointestinal tract.⁸⁶ Experimental studies have demonstrated that ear VNS significantly improves gastric emptying rates, enhances gastric motility, reduces gastric sensitivity, and alleviates low-grade inflammation in FD models.⁸⁷ The therapeutic mechanisms of taVNS likely involve the regulation of the HPA axis, alongside anti-inflammatory effects mediated by both the vagal afferent and efferent neural pathways.⁸⁸ Clinical research has shown that taVNS enhances gastric adaptive capacity, increases normal gastric slow wave activity and vagal tone, and alleviates digestive symptoms in patients with FD, suggesting its potential for treating mild FD.⁸⁹ Recent animal studies indicate that taVNS alleviates IBS-C symptoms by restoring the abundance of lactic acid bacteria, enhancing the prevalence of probiotic bifidobacteria, and increasing the number of c-Kit positive cells in the intestinal myenteric plexus.⁹⁰ In addition to its role in DGBI, taVNS has been shown to prevent intestinal and systemic inflammation by reducing the release of pro-inflammatory factors.⁹¹ Basic research indicates that taVNS restores autonomic nervous system functionality and cellular morphology, reducing oxidative damage.⁹² Furthermore, studies have demonstrated that taVNS activates the NTS and DMV, leading to decreased intestinal cytokine expression and a reduction in the recruitment of white blood cells to affected intestinal segments.⁹¹

Reducing visceral hypersensitivity

The management of visceral hypersensitivity remains a significant clinical challenge, with a lack of safe and effective pharmacological treatments aimed at alleviating this condition. Research by Zhou et al.⁹³ demonstrated that transcranial magnetic stimulation, when applied with specific parameters, significantly reduced gastric hypersensitivity in rat models of FD. This effect was attributed to the enhancement of the sympathetic-parasympathetic balance.⁹³ Additionally, a study indicated that tVNS alleviated pain in patients with gastrointestinal motility disorders, with the underlying mechanism believed to involve modulation of reflex parasympathetic activity.⁵⁵ Another clinical investigation reported that regulating vagus nerve tone facilitated gastric and duodenal motility while concurrently reducing sensitivity to physical pain.⁹⁴ Given the extensive vagus nerve innervation of the stomach and its central role in regulating gastric inflammation and motility, vagus nerve intervention is proposed as a potent therapeutic target for reducing visceral hypersensitivity.⁸⁹ Moreover, the vagus nerve plays a pivotal role in anti-inflammatory processes. Its peripheral effects inhibit neural pathways activated by macrophages.⁹⁵ The peripheral activation of the vagus nerve induces acetylcholine release from various organs in the reticuloendothelial system, including the liver, heart, spleen, and gastrointestinal tract. Acetylcholine interacts with α-nAChRs on tissue macrophages, thereby inhibiting the NF-κBp65 signaling pathway and reducing the release of pro-inflammatory cytokines, such as TNF and IL-1.^95,96 Previous studies have shown elevated levels of NF-κBp65 in the duodenum of mice treated with iodoacetamide (IA), with this low-grade inflammation mitigated by taVNS. Importantly, these effects were abolished following vagotomy, suggesting that the anti-inflammatory impact of auricular VNS may be mediated through a vagal afferent-efferent reflex mechanism.⁸⁸ Additionally, IA exposure has been linked to damage to the intestinal epithelial barrier, evidenced by a reduction in tight junctions and adhesion proteins in the intestines of affected mice. Conversely, taVNS has been shown to enhance the integrity and functionality of the intestinal epithelial barrier. In conclusion, auricular VNS may alleviate visceral hypersensitivity by activating the vagus nerve’s anti-inflammatory properties and improving mucosal integrity, thereby mitigating visceral pain.

Downregulating the highly active HPA axis

The observed reduction in salivary cortisol (sCort) levels during tVNS suggests that tVNS may modulate the regulation of stress-responsive neuroendocrine systems, particularly the HPA axis.⁹⁷ Anatomically, the ear nail is innervated by the ABVN, and ABVN signals project to the NTS.⁹⁸ Therefore, taVNS likely activates the NTS, which in turn projects to neurons in other brain nuclei. Mice treated with IA exhibit significant declines in both horizontal and vertical scores in open field tests,⁹⁰ indicating anxiety and depression-like behaviors.^99
–101 These behaviors were reversed by taVNS, likely through the inhibition of excessive HPA axis activation. Previous research has established that taVNS is a safe and cost-effective method for treating depressive disorders.¹⁰² Clinically, a cohort study of 40,394 individuals over 11 years revealed that the incidence rate of FD in the depressed group was 1.7 times higher than in the non-depressed group.¹⁰³ A 12-year prospective study found that depressed patients without gastrointestinal symptoms at baseline were more likely to develop FD.¹⁰⁴ In animal studies, taVNS was shown to significantly reverse depression-like behavior by downregulating excessive HPA axis activity.¹⁰⁵ Additionally, the corticotropin-releasing factor signal in the brain plays a critical role in stress-related gastrointestinal dysfunction, including inhibition of gastric acid secretion, gastrointestinal motility, and visceral hypersensitivity, likely mediated through the autonomic nervous system.^106
–109

Modulating gut microbiota

VNS can impact intestinal permeability and function.¹⁸ Specifically, VNS administered following severe burn injuries has been shown to enhance intestinal integrity, increase villus height, and improve the expression of the tight junction protein occludin.⁸⁹ taVNS appears to activate intestinal glial cells, which may contribute to maintaining the integrity of the intestinal barrier and modulating the expression of tight junction proteins. This area represents a promising direction for future research and holds substantial implications for understanding the brain-gut microbiota axis and the therapeutic potential of taVNS.¹¹⁰ The effects of taVNS extend beyond the intestinal wall, influencing gut microbiota composition. Invasive transcranial vagus nerve electrical stimulation can significantly increase levels of microbiota, which may correlate with its therapeutic effects.¹¹¹ Human symbiotic bacterial strains can substantially impact neurotransmitter release, influencing brain excitability and contributing to anxiety disorders. For example, Lactobacilli, Pseudomonas, and Bifidobacteria help maintain gamma-aminobutyric acid levels, affecting brain excitability.¹¹² Our previous studies revealed that taVNS restored the abundance of Lactobacilli and increased Bifidobacteria at the genus level, thereby improving gut microbiota balance and potentially enhancing overall gut health.⁹⁰ Clinical trials indicated that taVNS not only alleviated clinical symptoms in patients with IBS-C but also elevated levels of Bifidobacteria and short-chain fatty acids, such as acetic acid, butyric acid, and propionic acid. Additionally, taVNS was associated with a reduction in tryptophan metabolism, including lower levels of 3-hydroxyanthranilic acid, anthranilic acid, and L-tryptophan.⁸¹ The Brunner’s glands, located in the duodenum, are linked to the vagus nerve, which connects the central amygdala with these glands and mediates synaptic circuits linking pressure-sensitive neural pathways and gut microbiota. This connection may enhance the effectiveness of Lactobacilli species in the gut during VNS treatment.^113,114

Safety

The most commonly reported side effects of these techniques are mild and localized, such as transient erythema, palpitations, headaches, and dizziness, which typically resolve spontaneously.^69,81 No serious adverse events, such as cardiac arrhythmias or nerve injury, have been directly attributed to these techniques in constipation trials. This stands in contrast to pharmacological treatments, such as linaclotide-induced severe diarrhea or lubiprostone-related nausea. While short-term safety data are robust, information on long-term safety beyond 6 months remains limited.¹¹⁵ Ongoing studies are needed to evaluate long-term tolerability and establish standardized protocols to further confirm the safety of these approaches.

Conclusion and perspectives

While recent studies on VNS for gastrointestinal disorders have been extensively documented,^116,117 this review specifically concentrates on clinical research pertaining to the treatment of FC and IBS-C. In summary, non-invasive electrical neuromodulation techniques targeting the vagus nerve, including taVNS, TEA, and PENFS, demonstrate a favorable safety profile in managing FC and IBS-C. However, further research is necessary to more accurately determine the efficacy of these approaches, especially considering the heterogeneous, multifactorial nature, chronicity, and significant placebo response associated with these conditions. Long-term randomized controlled trials are essential to substantiate the sustained effects of non-invasive electrical neuromodulation.

Supplemental Material

sj-docx-1-tag-10.1177_17562848261469142 – Supplemental material for Noninvasive electrical neuromodulation involving vagus nerve mechanism for functional constipation and irritable bowel syndrome with constipation

Supplemental material, sj-docx-1-tag-10.1177_17562848261469142 for Noninvasive electrical neuromodulation involving vagus nerve mechanism for functional constipation and irritable bowel syndrome with constipation by Jie Liu, Chanlan Lv, Xiuli Zhu, Na Hong, Yizhou Huang, Chenyu Sun, Yichen Wang, Yan Yan, Yuting Huang and Yue Yu in Therapeutic Advances in Gastroenterology

Footnotes

Acknowledgements

We thank Bullet Edits Limited for the linguistic editing and proofreading of the manuscript.

Declarations

ORCID iD

Jie Liu

Supplemental material

Supplemental material for this article is available online.

References

Suares

Ford

AC.

Prevalence of, and risk factors for, chronic idiopathic constipation in the community: systematic review and meta-analysis. Am J Gastroenterol 2011; 106(9): 1582–1592.

Camilleri

Ford

Mawe

, et al. Chronic constipation. Nat Rev Dis Primers 2017; 3: 17095.

Shah

Chitkara

Locke

, et al. Ambulatory care for constipation in the United States, 1993–2004. Am J Gastroenterol 2008; 103(7): 1746–1753.

Huang

, et al. Causal association between constipation and risk of colorectal cancer: a bidirectional two-sample Mendelian randomization study. Front Oncol 2023; 13: 1282066.

Martin

Barghout

Cerulli

Direct medical costs of constipation in the United States. Manag Care Interface 2006; 19(12): 43–49.

Johanson

Kralstein

Chronic constipation: a survey of the patient perspective. Aliment Pharmacol Ther 2007; 25(5): 599–608.

Huang

Wang

, et al. Irritable bowel syndrome: epidemiology, overlap disorders, pathophysiology and treatment. World J Gastroenterol 2023; 29(26): 4120–4135.

Bouchoucha

Deutsch

Uong

, et al. Characteristics of patients with overlap functional gastrointestinal disorders. J Gastroenterol Hepatol 2021; 36(8): 2171–2179.

Jiang

Locke

3rd Choung

, et al. Prevalence and risk factors for abdominal bloating and visible distention: a population-based study. Gut 2008; 57(6): 756–763.

10.

Aziz

Whitehead

Palsson

, et al. An approach to the diagnosis and management of Rome IV functional disorders of chronic constipation. Expert Rev Gastroenterol Hepatol 2020; 14(1): 39–46.

11.

Wong

Palsson

Turner

, et al. Inability of the Rome III criteria to distinguish functional constipation from constipation-subtype irritable bowel syndrome. Am J Gastroenterol 2010; 105(10): 2228–2234.

12.

Ford

Moayyedi

Lacy

, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol 2014; 109(Suppl. 1): S2–S27.

13.

Chang

Sultan

Lembo

, et al. AGA Clinical Practice Guideline on the pharmacological management of irritable bowel syndrome with constipation. Gastroenterology 2022; 163(1): 118–136.

14.

Lacy

Pimentel

Brenner

, et al. ACG clinical guideline: management of irritable bowel syndrome. Am J Gastroenterol 2021; 116(1): 17–44.

15.

Ford

Talley

Schoenfeld

, et al. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut 2009; 58(3): 367–378.

16.

Chiarioni

Salandini

Whitehead

WE.

Biofeedback benefits only patients with outlet dysfunction, not patients with isolated slow transit constipation. Gastroenterology 2005; 129(1): 86–97.

17.

Wang

Hashimoto

The vagus nerve: an old but new player in brain-body communication. Brain Behav Immun 2025; 124: 28–39.

18.

Bonaz

Bazin

Pellissier

The vagus nerve at the interface of the microbiota-gut-brain axis. Front Neurosci 2018; 12: 49.

19.

Bonaz

Sinniger

Pellissier

Vagal tone: effects on sensitivity, motility, and inflammation. Neurogastroenterol Motil 2016; 28(4): 455–462.

20.

Gottfried-Blackmore

Habtezion

Nguyen

Noninvasive vagal nerve stimulation for gastroenterology pain disorders. Pain Manag 2021; 11(1): 89–96.

21.

Zhang

Weng

, et al. A vagus nerve dominant tetra-synaptic ascending pathway for gastric pain processing. Nat Commun 2024; 15(1): 9824.

22.

Farmer

Aziz

Gut pain & visceral hypersensitivity. Br J Pain 2013; 7(1): 39–47.

23.

Zhang

Meng

, et al. Auricular vagal nerve stimulation improves constipation by enhancing colon motility via the central-vagal efferent pathway in opioid-induced constipated rats. Neuromodulation 2021; 24(7): 1258–1268.

24.

Dicks

LMT

. Our mental health is determined by an intrinsic interplay between the central nervous system, enteric nerves, and gut microbiota. Int J Mol Sci 2023; 25(1): 38.

25.

Robert

Elsenbruch

Orr

WC.

Sleep-related autonomic disturbances in symptom subgroups of women with irritable bowel syndrome. Dig Dis Sci 2006; 51(12): 2121–2127.

26.

Aggarwal

Cutts

Abell

, et al. Predominant symptoms in irritable bowel syndrome correlate with specific autonomic nervous system abnormalities. Gastroenterology 1994; 106(4): 945–950.

27.

Pellissier

Dantzer

Canini

, et al. Psychological adjustment and autonomic disturbances in inflammatory bowel diseases and irritable bowel syndrome. Psychoneuroendocrinology 2010; 35(5): 653–662.

28.

Pellissier

Dantzer

Mondillon

, et al. Relationship between vagal tone, cortisol, TNF-alpha, epinephrine and negative affects in Crohn’s disease and irritable bowel syndrome. PLoS One 2014; 9(9): e105328.

29.

Elsenbruch

Orr

WC.

Diarrhea- and constipation-predominant IBS patients differ in postprandial autonomic and cortisol responses. Am J Gastroenterol 2001; 96(2): 460–466.

30.

Manabe

Tanaka

Hata

, et al. Pathophysiology underlying irritable bowel syndrome—from the viewpoint of dysfunction of autonomic nervous system activity. J Smooth Muscle Res 2009; 45(1): 15–23.

31.

Taché

Bonaz

Corticotropin-releasing factor receptors and stress-related alterations of gut motor function. J Clin Invest 2007; 117(1): 33–40.

32.

Bonaz

Bernstein

CN.

Brain-gut interactions in inflammatory bowel disease. Gastroenterology 2013; 144(1): 36–49.

33.

Mulak

Bonaz

Irritable bowel syndrome: a model of the brain-gut interactions. Med Sci Monit 2004; 10(4): RA55–RA62.

34.

Hosoi

Okuma

Nomura

Electrical stimulation of afferent vagus nerve induces IL-1beta expression in the brain and activates HPA axis. Am J Physiol Regul Integr Comp Physiol 2000; 279(1): R141–R147.

35.

Liu

Wang

Tian

, et al. Sleep deficiency is associated with exacerbation of symptoms and impairment of anorectal and autonomic functions in patients with functional constipation. Front Neurosci 2022; 16: 912442.

36.

Liu

Wang

, et al. Slow, deep breathing intervention improved symptoms and altered rectal sensitivity in patients with constipation-predominant irritable bowel syndrome. Front Neurosci 2022; 16: 1034547.

37.

Bonaz

Sinniger

Pellissier

Therapeutic potential of vagus nerve stimulation for inflammatory bowel diseases. Front Neurosci 2021; 15: 650971.

38.

Olofsson

Tracey

KJ.

Bioelectronic medicine: technology targeting molecular mechanisms for therapy. J Intern Med 2017; 282(1): 3–4.

39.

Toffa

Touma

El Meskine

, et al. Learnings from 30 years of reported efficacy and safety of vagus nerve stimulation (VNS) for epilepsy treatment: a critical review. Seizure 2020; 83: 104–123.

40.

Hilz

MJ.

Transcutaneous vagus nerve stimulation—a brief introduction and overview. Auton Neurosci 2022; 243: 103038.

41.

Wang

, et al. Transcutaneous auricular vagus nerve stimulation: from concept to application. Neurosci Bull 2021; 37(6): 853–862.

42.

Hesampour

Tshikudi

Bernstein

, et al. Exploring the efficacy of transcutaneous auricular vagus nerve stimulation (VNS) in modulating local and systemic inflammation in experimental models of colitis. Bioelectron Med 2024; 10(1): 29.

43.

Babygirija

Sood

Kannampalli

, et al. Percutaneous electrical nerve field stimulation modulates central pain pathways and attenuates post-inflammatory visceral and somatic hyperalgesia in rats. Neuroscience 2017; 356: 11–21.

44.

Yin

Chen

JD.

Gastrointestinal motility disorders and acupuncture. Auton Neurosci 2010; 157(1–2): 31–37.

45.

Ouyang

Chen

JD.

Review article: therapeutic roles of acupuncture in functional gastrointestinal disorders. Aliment Pharmacol Ther 2004; 20(8): 831–841.

46.

Sarosiek

Song

Sun

, et al. Central and peripheral effects of transcutaneous acupuncture treatment for nausea in patients with diabetic gastroparesis. J Neurogastroenterol Motil 2017; 23(2): 245–253.

47.

Zhang

, et al. Transcutaneous electrical acustimulation synchronized with inspiration improves gastric accommodation impaired by cold stress in healthy subjects. Neurogastroenterol Motil 2019; 31(2): e13491.

48.

Sun

, et al. Transcutaneous neuromodulation at ST36 (Zusanli) is more effective than transcutaneous tibial nerve stimulation in treating constipation. J Clin Gastroenterol 2020; 54(6): 536–544.

49.

Nystrom

Ridderstrom

Leffler

AS.

Manual acupuncture as an adjunctive treatment of nausea in patients with cancer in palliative care—a prospective, observational pilot study. Acupunct Med 2008; 26(1): 27–32.

50.

Lin

, et al. An alternative to current therapies of functional dyspepsia: self-administrated transcutaneous electroacupuncture improves dyspeptic symptoms. Evid Based Complement Alternat Med 2014; 2014: 832523.

51.

Meng

Chen

, et al. Effects of transcutaneous electrical acustimulation on refractory gastroesophageal reflux disease. Evid Based Complement Alternat Med 2016; 2016: 8246171.

52.

Wei

Liu

, et al. Ameliorating effects of transcutaneous electrical acustimulation combined with deep breathing training on refractory gastroesophageal reflux disease mediated via the autonomic pathway. Neuromodulation 2019; 22(6): 751–757.

53.

Long

Nojkov

, et al. Efficacy and safety of noninvasive electrical neuromodulation for treatment of functional constipation: a systematic review and meta-analysis of randomized controlled trials. Neuromodulation 2025; 28(1): 54–67.

54.

Zhang

, et al. Needleless transcutaneous electrical acustimulation: a pilot study evaluating improvement in post-operative recovery. Am J Gastroenterol 2018; 113(7): 1026–1035.

55.

Frøkjaer

Bergmann

Brock

, et al. Modulation of vagal tone enhances gastroduodenal motility and reduces somatic pain sensitivity. Neurogastroenterol Motil 2016; 28(4): 592–598.

56.

Farmer

Albusoda

Amarasinghe

, et al. Transcutaneous vagus nerve stimulation prevents the development of, and reverses, established oesophageal pain hypersensitivity. Aliment Pharmacol Ther 2020; 52(6): 988–996.

57.

Badran

Dowdle

Mithoefer

, et al. Neurophysiologic effects of transcutaneous auricular vagus nerve stimulation (VNS) via electrical stimulation of the tragus: a concurrent VNS/fMRI study and review. Brain Stimul 2018; 11(3): 492–500.

58.

Yap

JYY

Keatch

Lambert

, et al. Critical review of transcutaneous vagus nerve stimulation: challenges for translation to clinical practice. Front Neurosci 2020; 14: 284.

59.

Kaniusas

Kampusch

Tittgemeyer

, et al. Current directions in the auricular vagus nerve stimulation I—a physiological perspective. Front Neurosci 2019; 13: 854.

60.

Chae

Nahas

Lomarev

, et al. A review of functional neuroimaging studies of vagus nerve stimulation (VNS). J Psychiatr Res 2003; 37(6): 443–455.

61.

Randich

Gebhart

GF.

Vagal afferent modulation of nociception. Brain Res Brain Res Rev 1992; 17(2): 77–99.

62.

Frangos

Ellrich

Komisaruk

BR.

Non-invasive access to the vagus nerve central projections via electrical stimulation of the external ear: fMRI evidence in humans. Brain Stimul 2015; 8(3): 624–636.

63.

Kovacic

Hainsworth

Sood

, et al. Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial. Lancet Gastroenterol Hepatol 2017; 2(10): 727–737.

64.

Sahn

Pascuma

Kohn

, et al. Transcutaneous auricular vagus nerve stimulation attenuates inflammatory bowel disease in children: a proof-of-concept clinical trial. Bioelectron Med 2023; 9(1): 23.

65.

Han

Peng

Zhuo

, et al. Cholinergic reflex control of inflammation: mechanistic and translational advances in transcutaneous auricular vagus nerve stimulation across rheumatic, metabolic, and postoperative disorders. Front Immunol 2026; 16: 1702185.

66.

Verma

Mudge

Kasole

, et al. Auricular vagus neuromodulation—a systematic review on quality of evidence and clinical effects. Front Neurosci 2021; 15: 664740.

67.

Chang

Cracchiolo

Ahmed

, et al. Quantitative estimation of nerve fiber engagement by vagus nerve stimulation using physiological markers. Brain Stimul 2020; 13(6): 1617–1630.

68.

Thompson

O’Leary

Austelle

, et al. A review of parameter settings for invasive and non-invasive vagus nerve stimulation (VNS) applied in neurological and psychiatric disorders. Front Neurosci 2021; 15: 709436.

69.

Krasaelap

Sood

BUK

, et al. Efficacy of auricular neurostimulation in adolescents with irritable bowel syndrome in a randomized, double-blind trial. Clin Gastroenterol Hepatol 2020; 18(9): 1987–1994.e2.

70.

Matteoli

Boeckxstaens

GE.

The vagal innervation of the gut and immune homeostasis. Gut 2013; 62(8): 1214–1222.

71.

Bora

Atkinson

Pan

, et al. Impact of auricular percutaneous electrical nerve field stimulation on gut microbiome in adolescents with irritable bowel syndrome: a pilot study. J Dig Dis 2023; 24(5): 348–358.

72.

Liu

, et al. Preventive effects of transcutaneous electrical acustimulation on ischemic stroke-induced constipation mediated via the autonomic pathway. Am J Physiol Gastrointest Liver Physiol 2018; 315(2): G293–G301.

73.

Xiao

Liu

YL.

Rectal hypersensitivity reduced by acupoint TENS in patients with diarrhea-predominant irritable bowel syndrome: a pilot study. Dig Dis Sci 2004; 49(2): 312–319.

74.

Zhou

Wang

Ning

, et al. Sustained ameliorating effects and autonomic mechanisms of transcutaneous electrical acustimulation at ST36 in patients with chronic constipation. Front Neurosci 2022; 16: 1038922.

75.

Xiao

Lin

, et al. Transcutaneous electrical acustimulation improves constipation by enhancing rectal sensation in patients with functional constipation and lack of rectal sensation. Clin Transl Gastroenterol 2022; 13(5): e00485.

76.

Huang

Lin

, et al. Transcutaneous electrical acustimulation improves irritable bowel syndrome with constipation by accelerating colon transit and reducing rectal sensation using autonomic mechanisms. Am J Gastroenterol 2022; 117(9): 1491–1501.

77.

Mion

Pellissier

Garros

, et al. Transcutaneous auricular vagus nerve stimulation for the treatment of irritable bowel syndrome: a pilot, open-label study. Bioelectron Med 2020; 3(1): 5–12.

78.

Wang

Zhang

, et al. Transcutaneous auricular vagal nerve stimulation improves functional dyspepsia with sleep disturbance via enhanced vagal activity: a randomized controlled trial. Int J Surg 2026; 112(1): 961–972.

79.

Kornum

Bertoli

Kufaishi

, et al. Transcutaneous vagal nerve stimulation for treating gastrointestinal symptoms in individuals with diabetes: a randomised, double-blind, sham-controlled, multicentre trial. Diabetologia 2024; 67(6): 1122–1137.

80.

Shi

Zhang

, et al. Ameliorating effects and mechanisms of transcutaneous auricular vagal nerve stimulation on abdominal pain and constipation. JCI Insight 2021; 6(14): e150052.

81.

Liu

Yin

, et al. Efficacy and safety of transcutaneous auricular vagus nerve stimulation in patients with constipation-predominant irritable bowel syndrome: a single-center, single-blind, randomized controlled trial. Am J Gastroenterol 2025; 120(9): 2139–2153.

82.

Yang

Guo

, et al. Transcutaneous electrical acustimulation improves constipation symptoms and accelerates colonic transit in patients with slow transit constipation through autonomic mechanism. Neuromodulation 2024; 27(2): 382–391.

83.

Liu

Chen

, et al. Ameliorating effects of transcutaneous electrical acustimulation at Neiguan (PC6) and Zusanli (ST36) acupoints combined with adaptive biofeedback training on functional outlet obstruction constipation. Evid Based Complement Alternat Med 2020; 2020: 8798974.

84.

Wang

Zhang

Chen

, et al. Mechanisms underlying antidepressant effect of transcutaneous auricular vagus nerve stimulation on CUMS model rats based on hippocampal α7nAchR/NF-κB signal pathway. J Neuroinflammation 2021; 18(1): 291.

85.

Han

Wang

Rong

, et al. Systematic review and meta-analysis of the therapeutic effect on functional dyspepsia treated with acupuncture and electroacupuncture. World J Acupunct Mox 2021; 31(1): 44–51.

86.

Gao

Zhang

Zhu

, et al. Investigation of specificity of auricular acupuncture points in regulation of autonomic function in anesthetized rats. Auton Neurosci 2008; 138(1–2): 50–56.

87.

Hou

Fang

Zhang

, et al. Auricular vagus nerve stimulation ameliorates functional dyspepsia with depressive-like behavior and inhibits the hypothalamus-pituitary-adrenal axis in a rat model. Dig Dis Sci 2022; 67(10): 4719–4731.

88.

Hou

Rong

Yang

, et al. Auricular vagus nerve stimulation improves visceral hypersensitivity and gastric motility and depression-like behaviors via vago-vagal pathway in a rat model of functional dyspepsia. Brain Sci 2023; 13(2): 253.

89.

Zhu

, et al. Transcutaneous auricular vagal nerve stimulation improves functional dyspepsia by enhancing vagal efferent activity. Am J Physiol Gastrointest Liver Physiol 2021; 320(5): G700–G711.

90.

Liu

Dai

, et al. Ameliorating effects of transcutaneous auricular vagus nerve stimulation on a mouse model of constipation-predominant irritable bowel syndrome. Neurobiol Dis 2024; 193: 106440.

91.

Hong

Zillekens

Schneiker

, et al. Non-invasive transcutaneous auricular vagus nerve stimulation prevents postoperative ileus and endotoxemia in mice. Neurogastroenterol Motil 2019; 31(3): e13501.

92.

Rawat

Roy

Singh

, et al. Transcutaneous vagus nerve stimulation regulates the cholinergic anti-inflammatory pathway to counteract 1, 2-dimethylhydrazine induced colon carcinogenesis in Albino Wistar rats. Front Pharmacol 2019; 10: 353.

93.

Zhou

Wang

, et al. Effects and mechanisms of auricular electroacupuncture on gastric hypersensitivity in a rodent model of functional dyspepsia. PLoS One 2017; 12(3): e0174568.

94.

Gottfried-Blackmore

Adler

Fernandez-Becker

, et al. Open-label pilot study: non-invasive vagal nerve stimulation improves symptoms and gastric emptying in patients with idiopathic gastroparesis. Neurogastroenterol Motil 2020; 32(4): e13769.

95.

Tracey

KJ.

The inflammatory reflex. Nature 2002; 420(6917): 853–859.

96.

Tracey

KJ.

Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 2007; 117(2): 289–296.

97.

Doerr

Juenemann

Hakel

, et al. Effect of transcutaneous vagus nerve stimulation on stress-reactive neuroendocrine measures in a sample of persons with temporal lobe epilepsy. Epilepsia Open 2023; 8(3): 1013–1020.

98.

Jing

Zhu

, et al. The auriculo-vagal afferent pathway and its role in seizure suppression in rats. BMC Neurosci 2013; 14: 85.

99.

Rahman

Ali

Hao

, et al. Xanthohumol attenuates lipopolysaccharide-induced depressive like behavior in mice: involvement of NF-κB/Nrf2 signaling pathways. Neurochem Res 2021; 46(12): 3135–3148.

100.

Wang

Chen

Liu

, et al. Antidepressant mechanism of catalpol: involvement of the PI3K/Akt/Nrf2/HO-1 signaling pathway in rat hippocampus. Eur J Pharmacol 2021; 909: 174396.

101.

Khakpai

Ramezanikhah

Valizadegan

, et al. Synergistic effect between imipramine and citicoline upon induction of analgesic and antidepressant effects in mice. Neurosci Lett 2021; 760: 136095.

102.

Rong

Liu

Wang

, et al. Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: a nonrandomized controlled pilot study. J Affect Disord 2016; 195: 172–179.

103.

Kao

Sung

Huang

, et al. Functional dyspepsia in depression: a population-based cohort study. Eur J Clin Invest 2021; 51(6): e13506.

104.

Koloski

Jones

Kalantar

, et al. The brain–gut pathway in functional gastrointestinal disorders is bidirectional: a 12-year prospective population-based study. Gut 2012; 61(9): 1284–1290.

105.

Wang

Gao

, et al. Transcutaneous auricular vagus nerve stimulation at 20 Hz improves depression-like behaviors and down-regulates the hyperactivity of HPA axis in chronic unpredictable mild stress model rats. Front Neurosci 2020; 14: 680.

106.

Bonaz

Sinniger

Pellissier

Vagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease. J Intern Med 2017; 282(1): 46–63.

107.

Wang

Dong

Wang

, et al. Gastrodiae Rhizoma water extract ameliorates hypothalamic-pituitary-adrenal axis hyperactivity and inflammation induced by chronic unpredictable mild stress in rats. Biomed Res Int 2020; 2020: 8374614.

108.

Niemegeers

De Boer

Dumont

GJH

, et al. Differential effects of inflammatory and psychosocial stress on mood, hypothalamic-pituitary-adrenal axis, and inflammation in remitted depression. Neuropsychobiology 2016; 74(3): 150–158.

109.

Rodiño-Janeiro

Alonso-Cotoner

Pigrau

, et al. Role of corticotropin-releasing factor in gastrointestinal permeability. J Neurogastroenterol Motil 2015; 21(1): 33–50.

110.

Costantini

Bansal

Peterson

, et al. Efferent vagal nerve stimulation attenuates gut barrier injury after burn: modulation of intestinal occludin expression. J Trauma 2010; 68(6): 1349–1356.

111.

Faraji

Payami

Ebadpour

, et al. Vagus nerve stimulation and gut microbiota interactions: a novel therapeutic avenue for neuropsychiatric disorders. Neurosci Biobehav Rev 2025; 169: 105990.

112.

Barrett

Ross

O’Toole

, et al. γ-Aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol 2012; 113(2): 411–417.

113.

Bonaz

Sinniger

Pellissier

Vagus nerve stimulation at the interface of brain-gut interactions. Cold Spring Harb Perspect Med 2019; 9(8): a034199.

114.

Chang

Perkins

Novaes

, et al. Stress-sensitive neural circuits change the gut microbiome via duodenal glands. Cell 2024; 187(19): 5393–5412.e30.

115.

Fassov

Høyer

Lundby

, et al. Long-term efficacy and safety of sacral neuromodulation for diarrhoea-predominant and mixed irritable bowel syndrome. Tech Coloproctol 2025; 29(1): 41.

116.

Barahona

de Barahona

Sidhu

, et al. Non-invasive vagal nerve stimulation decreases the need for rescue medication for nausea exacerbation in patients with chronic nausea and vomiting. Dig Dis Sci 2026; 71(3): 1003–1014.

117.

Dai

Tian

Electroconvulsive therapy improves distal colonic motility via the subdiaphragmatic vagus nerve in depressive-like mice. Sci Rep 2025; 15(1): 19597.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.02 MB