Vagus nerve neuromodulation: A promising method for treating gastrointestinal dysmotility

Abstract

Zhang et al delivered a paradigm-shifting understanding of electroacupuncture (EA)’s action in diabetic gastroparesis through a well-defined vagal pathway. Their work bridged traditional acupuncture and modern neurogastroenterology, highlighting EA as a viable strategy for refractory diabetic gastroparesis. The study integrated electrophysiology (gastric slow-wave recordings), functional assays (phenol red gastric emptying, and intestinal propulsion), dynamic positron emission tomography/computed tomography imaging, histopathology, and molecular biology (Western blot, immunofluorescence, and enzyme-linked immunosorbent assay). This comprehensive approach robustly confirmed EA’s efficacy in restoring gastric motility, interstitial cells of Cajal function, and neuropeptide balance. Future studies should prioritize clinical translation and explore synergies with pharmacological agents.

Key Words: Electroacupuncture; Gastroparesis; Vagus nerve; Gastric motility; Neuromodulation

Core Tip: The study by Zhang et al offers compelling mechanistic insights into how electroacupuncture at the stomach 36 (Zusanli) acupuncture point improves gastric dysmotility in diabetic gastroparesis via the nucleus tractus solitarius-vagal axis. This work significantly advances the understanding of acupuncture’s neuromodulatory effects, providing a scientific foundation for non-pharmacological management of diabetic gastroparesis. The authors identified a peripheral-to-central pathway: Electroacupuncture at the stomach 36 activated cholinergic targets, specifically choline acetyltransferase and the alpha 7 nicotinic acetylcholine receptor. This activation initiated signal transmission through spinal afferents in the L4 to L6 segments of the spinal cord, which were then integrated within the nucleus tractus solitarius, resulting in vagal efferent modulation of gastric targets.

TO THE EDITOR

The vagus nerve, a principal component of the parasympathetic nervous system, forms a critical bidirectional communication highway—the gut-brain axis[1]. This axis profoundly influences gastrointestinal (GI) functions, including gastric emptying, intestinal peristalsis, secretion, and blood flow. Efferent vagal fibers directly innervate the enteric nervous system, the “second brain” within the gut wall, promoting coordinated motor activity through excitatory cholinergic pathways. Conversely, afferent fibers relay critical sensory information about the gut’s state—such as distension, inflammation, and nutrient content—back to the brainstem[2]. In dysmotility disorders, this intricate vagal signaling can be disrupted by inflammation, neurodegeneration, surgical injury, or metabolic imbalances, leading to uncoordinated or absent contractions[3].

Neuromodulation strategies aim to therapeutically stimulate or inhibit specific neural pathways. Vagus nerve stimulation (VNS) for GI dysmotility primarily targets efferent pathways to enhance prokinetic signals or modulates afferent signaling to reduce inhibitory reflexes and pain perception[4]. Several techniques, including electroacupuncture (EA) at acupoints, transcutaneous VNS, and transcutaneous auricular VNS, have emerged as promising methods for treating GI dysmotility[5,6].

The appeal of vagal neuromodulation lies in its mechanism-based approach. Unlike pharmacological treatments that broadly affect neurotransmitter systems, it directly corrects dysfunctional neural signaling underlying dysmotility. Preclinical models consistently show that VNS enhances gastric emptying and intestinal transit[6]. Clinically, studies report symptom improvements often surpassing placebo effects[7], with some patients experiencing significant relief where other treatments have failed. The effects of VNS may extend beyond motility, potentially modulating inflammation through the cholinergic anti-inflammatory pathway and influencing central pain processing, addressing common comorbidities observed in disorders like irritable bowel syndrome[8].

Meanwhile, significant challenges remain. Optimal stimulation parameters (frequency, intensity, and duration) are still being defined for different conditions and modalities. Patient selection criteria require refinement, as responsiveness varies. Long-term efficacy and safety data, particularly for newer non-invasive methods, necessitate further large-scale, rigorous clinical trials. Future clinical trials should focus on investigating the effect of EA on potential mechanisms underlying targeted neural circuit activation [specifically the stomach 36 (ST36)-nucleus tractus solitarii-vagal efferent pathways] in conjunction with the recovery of interstitial cells of Cajal function. Cost and accessibility, particularly for implanted devices, are also important considerations.

The study by Zhang et al[9] offers compelling mechanistic insights into how EA at the ST36 (Zusanli) acupuncture point improves gastric dysmotility in diabetic gastroparesis (DGP) via the nucleus tractus solitarius-vagal axis. This work significantly advances the understanding of acupuncture’s neuromodulatory effects, providing a scientific foundation for non-pharmacological management of DGP. The authors identified a peripheral-to-central pathway: EA at ST36 activated cholinergic targets, specifically choline acetyltransferase and the α7 nicotinic acetylcholine receptor. This activation initiated signal transmission through spinal afferents in the L4 to L6 segments of the spinal cord, which were then integrated within the nucleus tractus solitarius, resulting in vagal efferent modulation of gastric targets. Moreover, the implementation of subdiaphragmatic vagotomy completely eliminated the benefits induced by VNS, confirming the critical role of vagal efferents in this pathway. However, it did not systematically examine other regulatory pathways, including sympathetic innervation and inflammatory processes, which may result in the neglect of potential interactions between the neural and immune systems in the pathogenesis of DGP.

GI dysmotility, characterized by impaired muscle contractions and dysfunctional nerve signaling within the digestive tract, poses a significant clinical challenge[10]. GI dysmotility increases susceptibility to colitis by altering gut microbiota composition and the metabolism of linoleic acid, which warrants serious attention[11]. Conditions such as gastroparesis, chronic constipation, irritable bowel syndrome, and postoperative ileus severely impair quality of life and often prove refractory to conventional pharmacological treatments, which may offer limited efficacy or cause substantial side effects[12]. In this context, neuromodulation targeting the vagus nerve emerges as a highly promising therapeutic strategy, offering a novel approach to restoring functional gut motility by harnessing the body’s intrinsic neural circuits[13].

Overall, the study by Zhang et al[9] indicated an integrated regulatory circuit involving peripheral stimulation, spinal afferent pathways, brainstem integration, and vagal efferent activity. Nevertheless, neuromodulation targeting the vagus nerve represents a paradigm shift in the management of GI dysmotility. By directly interfacing with critical neural pathways governing gut function, it offers a targeted, potentially reversible, and adjustable therapeutic strategy with a more favorable side effect profile compared to many pharmacological treatments. As research advances, with refined techniques, optimal candidate identification, and the demonstration of sustained benefits, vagus nerve neuromodulation holds immense promise for restoring normal digestive function and improving the lives of patients suffering from debilitating motility disorders.