Scaling beyond the vagus nerve: historical and contemporary progress on electrode-based small-diameter peripheral nerve interfaces.

This study measured the vagus and phrenic nerves from 12 adult cadavers. We found that the width and thickness of the vagus and phrenic nerves were different in the chest. The distance from the point of the vagus nerve and phrenic nerve on the plane of the inferior border of portal pulmonary arteries (T point) was approximately 7 cm to the diaphragm and was approximately 10 cm to the clavicle level. The number of motor fibers in the vagus nerves was 1 716 ± 362, and the number of nerve fibers was 4 473 ± 653. The number of motor fibers in the phrenic nerves ranged from 3 078 ± 684 to 4 794 ± 638, and the number of nerve fibers ranged from 3 437 ± 642 to 5 071 ± 723. No significant difference was found in the total number of nerve fibers. The results suggest that width, thickness, and total number of nerve fibers are similar between the vagus and phrenic nerves, but the number of motor fibers is different between them.

In order to control neural prosthetics by recording signals from peripheral nerves with the required specificity, high density electrode arrays that can be easily implanted on very small peripheral nerves (50μm-500μm) are needed. Interfacing with these small nerves is surgically challenging due to their size and fragile nature. To address this problem, a Flexible MicroChannel Electrode Array for interfacing with small diameter peripheral nerves and nerve fascicles was developed. The electrochemical characterization and electrophysiological recordings from the common peroneal nerve of a rat are presented along with demonstration of the surgical ease-of-use of the array.

Neural modulation technology and the capability to affect organ function have spawned the new field of bioelectronic medicine. Therapeutic interventions depend on wireless bioelectronic neural interfaces that can conformally and easily attach to small (few hundred micrometers) nerves located deep in the body without neural damage. Besides size, factors like flexibility and compliance to attach and adapt to visceral nerves associated moving organs are of paramount importance and have not been previously addressed. This study proposes a novel flexible neural clip (FNC) that can be used to interface with a variety of different peripheral nerves. To illustrate the flexibility of the design, this study stimulates the pelvic nerve, the vagus nerve, and branches of the sciatic nerve and evaluates the feasibility of the design in modulating the function of each of these nerves. It is found that this FNC allows fine‐tuning of physiological processes such as micturition, heart rate, and muscle contractions. Furthermore, this study also tests the ability of wirelessly powered FNC to enable remote modulation of visceral pelvic nerves located deep in the body. These results show that the FNC can be used with a range of different nerves, providing one of the critical pieces in the field of bioelectronics medicines.

Bioelectronic Medicine (BM) has been recognized as a new type of medicine to treat/manage chronic diseases and injuries that currently cannot be cured pharmaceutically. Unlike conventional pharmaceutical approaches in which pharmacological agents are delivered at the targeted molecular/cell mechanism related to the targeted tissues/organs via systemic blood circulation, lacking of anatomical/cellular specificity and the adaptability to each individual treatment, as a result the undesirable side effect is usually accompanied. On the other hand, bioelectronic medicine stands at the nexus of engineering, medical device, computation science, biology, physiology, neuroscience, as well as clinical science, aiming to regulate the electro-chemical molecular/cellular mechanism that directly relates to the diseases via electrical neuromodulation at the nervous systems using miniaturized devices, thus potentially avoids the side effects. Thus contrasting to conventional biomolecular based medicine, the practicing clinicians of bioelectronic medicine will prescribe patients with dosage in electrical and magnetic signals, rather than prescribing the dosage of drugs as in the conventional medicine.

Editorial: Women in Neuroscience of Bioelectronic Medicine.Bioelectronic Medicine is becoming the landmark of a new era of therapies, where pharmacological treatments are replaced or combined with the leverage of electricity to restore optimal function of organs and systems. The list of applications is becoming countless, converging with the necessity of mechanistic biological understanding, the advancement of technologies in biocompatible and conductive materials, the integration of computational and electronical approaches, and the translation of basic science into the clinic. The complexity behind the development of translational treatments relies on its inherent multidisciplinary nature, which has prompted international instances to foster the creation of centers and programs to enhance collaborative efforts. The research topic collection:"Women in Neuroscience of Bioelectronic Medicine" was initiated not only to promote the integration of neurosciences with multiple other disciplines, but also to encourage the participation of women, historically underrepresented in science. This topic collection has 100 % participation of women in the editorial, 80 % as first author, and 60 % of all authors.The nervous system conveys exquisite specialization to integrate multiple functions and maintain systemic homeostasis, and our research topic collection features research in both central and peripheral nervous systems. Neuroscience is often associated with the study of the brain. However, the study of peripheral (somatic and autonomic) nerve circuitry and brain-peripheral interactions is equally important to understand systemic disorders and develop precision therapies with little to no off-target side effects. The research presented by Rodriguez-Arzate et al. is an example, they discuss the use of non-photic electroretinogram (ERG) as a non-invasive method commonly used in eye care, for the high-resolution capture of retinal function. Their work compared spontaneous retinal oscillations from different species and proposed as a biomarker to study dysfunction in retinal pathophysiology and to diagnose retinal and other neuronal pathologies at early stage (i.e., hereditary retinal dystrophy and multiple sclerosis). Seicol et al. present a perspective on the use of neuromodulation to reduce inflammation and prevent hearing loss due to inflammation in the auditory system. On the peripheral nerve side, Alvardo-Navarrete et al. integrate concepts on the spinal cord and vestibular input through the study of Hoffman's reflex to evaluate transient excitability outputs on descending pathways. This allowed them to identify biomarkers in the evaluation of the integrity of vestibulospinal tracts, often disrupted in injured patients or during neurodegenerative diseases.Our research topic collection also features a special and comprehensive multidisciplinary review by Gonzalez-Gonzalez et al. "Bioelectronic Medicine: a multidisciplinary roadmap from biophysics to precision therapies". This review brings together scientists from different fields to discuss concepts with relevance to Bioelectronic Medicine. The highlights include a historic literature compilation of this emerging field, followed by core concepts on the biophysics of the neuronal membrane presented by the esteemed biophysicist Ramon Latorre. A special emphasis is provided to the refractory period, referring to the inactivation of neurons immediately after all voltage dependent Na + channels are opened due to an action potential event. This concept is very relevant to the design of neuromodulation treatments, often modifying frequency, amplitude, and pulse duration of the electrical stimulus.The phenomenon of neurotransmitter switching was discovered by the group of Nicholas Spitzer, who, along with Marta Pratelli, discussed in the review the importance of taking this phenomenon into account when designing long-term treatments. Their research opens the possibility to understand nervous system plasticity through the lens of neuromodulation that modifies the nature of neurotransmitters and their corresponding receptors in the post synapse. This concept could impact the design of psychiatric treatments, and hopefully replace or reduce the use of neuroactive drugs with deleterious side effects or limited efficacy. Thébault, Conde and Gonzalez further provide an overview of core concepts pertaining to the physiology of the cell and the advancement in system neuroscience.They discuss the concept of field potentials, which is the temporal summation of synchronous activity among neuronal populations modulated not only by the activity of glial and endothelial cells, but also

<p dir="ltr">The regulation of inflammatory and metabolic pathways in adipose and liver tissues is complex, involving various cellular mechanisms and molecular pathways1-3. It has been demonstrated that the cholinergic vagus nerve, through its efferent branch, regulates inflammatory and anti-inflammatory cytokine release to maintain homeostasis in the spleen and beyond4,5. However, much remains to be explored on the role of cholinergic signaling in specific organs such as liver and adipose tissue homeostasis.</p><p dir="ltr">Over recent decades, there has been a multitude of impactful discoveries on neural regulation of inflammation and metabolism4,6,7, but we are only at the beginning of understanding the detailed mechanisms of how neural reflexes regulate organ function. This thesis explores aspects of this biology in the liver and adipose tissue with the aim of providing additional insights that ultimately can help improve tools for disease diagnosis, prevention, and treatment of inflammatory and metabolic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD) and certain adipose tissue dysfunction. Studies over the last thirty years have shown that the central and peripheral nervous systems, along with the immune and metabolic systems, collaboratively regulate inflammation and metabolism4,6,8-10. The vagus nerve is one of the systems that have been widely studied in this context and found to be important in regulating inflammation and metabolism5,11,12. The work in this thesis builds on these studies and aims to further improve the understanding of neural regulation of inflammation and metabolism in liver and adipose tissue.</p><p dir="ltr">In project I, we found that statin therapy in individuals with metabolic syndrome was associated with increased Patatin-like phospholipase domain-containing 3 (PNPLA3) and liver transcriptional changes linked to worse metabolic control. The observations underscore the importance of considering the implications on liver pathophysiology of lipid-lowering therapy in patients with the metabolic syndrome, including the need for improved mechanistic understanding of the regulation of liver inflammation and metabolism in this patient group.</p><p dir="ltr">In project II, we investigated the role of the vagus nerve in acute liver inflammation, particularly its effect on the key cells in the development of metabolism- associated steatohepatitis, hepatic stellate cells.</p><p dir="ltr">In project III, we summarized the available literature on the role of cholinergic signaling in adipose tissue.</p><p dir="ltr">In project IV, we studied the mechanisms of vagus nerve control of weight loss and adipose tissue physiology in this context and discovered a new role for neutrophils in vagotomy-mediated weight loss.</p><p dir="ltr">This thesis improves our understanding of the physiological effects of vagus nerve signals in the context of inflammation and metabolism. The observation that a loss of vagus nerve signals affects hepatic stellate cell activity and the discovery of a link between the vagus nerve, neutrophils, and weight loss provide a new perspective on the neural regulation of fatty liver disease and weight loss. The insights certainly encourage further studies on cholinergic control of inflammation and metabolism and suggest a potential for neuro-immune interventions in the regulation of fat turnover and body weight.</p><h3>List of scientific papers</h3><p dir="ltr">I. Ahmed, O., Shavva, V. S., Tarnawski, L., Dai, W., Borg, F., Olofsson, V. V., <b>Liu, T.</b>, Saliba-Gustafsson, P., Simini, C., Pedrelli, M., Bergman, O., Norata, G. D., Parini, P., Franco-Cereceda, A., Eriksson, P., Malin, S. G., Björck, H. M., & Olofsson, P. S. (2025). Statin-associated regulation of hepatic PNPLA3 in patients without known liver disease. Journal of internal medicine, 297(1), 47-59.<br><a href="https://doi.org/10.1111/joim.20032" rel="noreferrer" target="_blank">https://doi.org/10.1111/joim.20032</a><br><br></p><p dir="ltr">II. Ahmed, O., Caravaca, A. S., Crespo, M., Dai, W., <b>Liu, T.</b>, Guo, Q., Leiva, M., Sabio, G., Shavva, V. S., Malin, S. G., & Olofsson, P. S. (2023). Hepatic stellate cell activation markers are regulated by the vagus nerve in systemic inflammation. Bioelectronic medicine, 9(1), 6.<br><a href="https://doi.org/10.1186/s42234-023-00108-3" rel="noreferrer" target="_blank">https://doi.org/10.1186/s42234-023-00108-3</a><br><br></p><p dir="ltr">III. Shavva, V. S., Tarnawski, L., <b>Liu, T.</b>, Ahmed, O., Olofsson, P. S. (2024). Cholinergic signaling in adipose tissue. Current Opinion in Endocrine and Metabolic Research. 37. 100546.<br><a href="https://doi.org/10.1016/j.coemr.2024.100546" rel="noreferrer" target="_blank">https://doi.org/10.1016/j.coemr.2024.100546</a><br><br></p><p dir="ltr">IV. <b>Liu T.</b>, Caravaca A.S., Cai M., Mendes P., Dai W., Vacquie J.J., Guo Q., Zhang Y., Schipper R., Simón R.R., Pei S., Karlsson M., Shavva V.S., Hagberg C.E., Tarnawski L .* , Olofsson P.S .* A lymphocyte antigen 6G-dependent mechanism regulates hormone-sensitive lipase phosphorylation in white adipose tissue. [Manuscript]</p>

<p dir="ltr">The regulation of inflammatory and metabolic pathways in adipose and liver tissues is complex, involving various cellular mechanisms and molecular pathways1-3. It has been demonstrated that the cholinergic vagus nerve, through its efferent branch, regulates inflammatory and anti-inflammatory cytokine release to maintain homeostasis in the spleen and beyond4,5. However, much remains to be explored on the role of cholinergic signaling in specific organs such as liver and adipose tissue homeostasis.</p><p dir="ltr">Over recent decades, there has been a multitude of impactful discoveries on neural regulation of inflammation and metabolism4,6,7, but we are only at the beginning of understanding the detailed mechanisms of how neural reflexes regulate organ function. This thesis explores aspects of this biology in the liver and adipose tissue with the aim of providing additional insights that ultimately can help improve tools for disease diagnosis, prevention, and treatment of inflammatory and metabolic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD) and certain adipose tissue dysfunction. Studies over the last thirty years have shown that the central and peripheral nervous systems, along with the immune and metabolic systems, collaboratively regulate inflammation and metabolism4,6,8-10. The vagus nerve is one of the systems that have been widely studied in this context and found to be important in regulating inflammation and metabolism5,11,12. The work in this thesis builds on these studies and aims to further improve the understanding of neural regulation of inflammation and metabolism in liver and adipose tissue.</p><p dir="ltr">In project I, we found that statin therapy in individuals with metabolic syndrome was associated with increased Patatin-like phospholipase domain-containing 3 (PNPLA3) and liver transcriptional changes linked to worse metabolic control. The observations underscore the importance of considering the implications on liver pathophysiology of lipid-lowering therapy in patients with the metabolic syndrome, including the need for improved mechanistic understanding of the regulation of liver inflammation and metabolism in this patient group.</p><p dir="ltr">In project II, we investigated the role of the vagus nerve in acute liver inflammation, particularly its effect on the key cells in the development of metabolism- associated steatohepatitis, hepatic stellate cells.</p><p dir="ltr">In project III, we summarized the available literature on the role of cholinergic signaling in adipose tissue.</p><p dir="ltr">In project IV, we studied the mechanisms of vagus nerve control of weight loss and adipose tissue physiology in this context and discovered a new role for neutrophils in vagotomy-mediated weight loss.</p><p dir="ltr">This thesis improves our understanding of the physiological effects of vagus nerve signals in the context of inflammation and metabolism. The observation that a loss of vagus nerve signals affects hepatic stellate cell activity and the discovery of a link between the vagus nerve, neutrophils, and weight loss provide a new perspective on the neural regulation of fatty liver disease and weight loss. The insights certainly encourage further studies on cholinergic control of inflammation and metabolism and suggest a potential for neuro-immune interventions in the regulation of fat turnover and body weight.</p><h3>List of scientific papers</h3><p dir="ltr">I. Ahmed, O., Shavva, V. S., Tarnawski, L., Dai, W., Borg, F., Olofsson, V. V., <b>Liu, T.</b>, Saliba-Gustafsson, P., Simini, C., Pedrelli, M., Bergman, O., Norata, G. D., Parini, P., Franco-Cereceda, A., Eriksson, P., Malin, S. G., Björck, H. M., & Olofsson, P. S. (2025). Statin-associated regulation of hepatic PNPLA3 in patients without known liver disease. Journal of internal medicine, 297(1), 47-59.<br><a href="https://doi.org/10.1111/joim.20032" rel="noreferrer" target="_blank">https://doi.org/10.1111/joim.20032</a><br><br></p><p dir="ltr">II. Ahmed, O., Caravaca, A. S., Crespo, M., Dai, W., <b>Liu, T.</b>, Guo, Q., Leiva, M., Sabio, G., Shavva, V. S., Malin, S. G., & Olofsson, P. S. (2023). Hepatic stellate cell activation markers are regulated by the vagus nerve in systemic inflammation. Bioelectronic medicine, 9(1), 6.<br><a href="https://doi.org/10.1186/s42234-023-00108-3" rel="noreferrer" target="_blank">https://doi.org/10.1186/s42234-023-00108-3</a><br><br></p><p dir="ltr">III. Shavva, V. S., Tarnawski, L., <b>Liu, T.</b>, Ahmed, O., Olofsson, P. S. (2024). Cholinergic signaling in adipose tissue. Current Opinion in Endocrine and Metabolic Research. 37. 100546.<br><a href="https://doi.org/10.1016/j.coemr.2024.100546" rel="noreferrer" target="_blank">https://doi.org/10.1016/j.coemr.2024.100546</a><br><br></p><p dir="ltr">IV. <b>Liu T.</b>, Caravaca A.S., Cai M., Mendes P., Dai W., Vacquie J.J., Guo Q., Zhang Y., Schipper R., Simón R.R., Pei S., Karlsson M., Shavva V.S., Hagberg C.E., Tarnawski L .* , Olofsson P.S .* A lymphocyte antigen 6G-dependent mechanism regulates hormone-sensitive lipase phosphorylation in white adipose tissue. [Manuscript]</p>

Bioelectronic medicine is an evolving field in which new insights into the regulatory role of the nervous system and new developments in bioelectronic technology result in novel approaches in disease diagnosis and treatment. Studies on the immunoregulatory function of the vagus nerve and the inflammatory reflex have a specific place in bioelectronic medicine. These studies recently led to clinical trials with bioelectronic vagus nerve stimulation in inflammatory diseases and other conditions. Here, we outline key findings from this preclinical and clinical research. We also point to other aspects and pillars of interdisciplinary research and technological developments in bioelectronic medicine.

High-resolution imaging has transformed the evaluation of small superficial peripheral nerves, enabling earlier detection of neuropathies, traumatic injuries, and entrapments. Among available modalities, ultrasound is particularly well suited for this purpose owing to its high spatial resolution, dynamic assessment capabilities, and ability to guide interventions. Normal nerves can be recognized on ultrasound by their fascicular architecture and characteristic honeycomb appearance, which helps distinguish them from adjacent tendons, vessels, and connective tissue. High-frequency transducers allow improved delineation of fascicular detail, while small-footprint probes enable imaging of nerves in anatomically constrained regions, establishing ultrasound as a reliable and cost-effective tool for evaluating peripheral nerve injuries. Because of spatial resolution limitations, magnetic resonance imaging has restricted ability to evaluate submillimeter-sized nerves; high-resolution ultrasound is therefore particularly effective in localizing pathological nerves - both in terms of the exact site of involvement and the length of the affected segment. This review article highlights in detail the sonographic techniques, pitfalls, and key anatomic landmarks for visualizing small peripheral nerves in the upper and lower extremities, with particular emphasis on nerves that are frequently under-evaluated in routine clinical practice yet often contribute to allodynia. Normal anatomical appearance on ultrasound is provided for better understanding along with examples of pathologies affecting these nerves.

Studies on the role of the vagus nerve in the regulation of immunity and inflammation have contributed to current preclinical and clinical efforts in bioelectronic medicine. In parallel, this research has generated new insights into the cellular and molecular mechanisms underlying the immunoregulatory functions of the vagus nerve within the inflammatory reflex. The vagus nerve and other cellular components of the inflammatory reflex are implicated in the regulation of bleeding, cancer, obesity, blood pressure, viral infections and other conditions. This collateral benefit broadens scientific horizons and provides new rationale for technological advances and therapeutic implications.

Objective. The vagus nerve has been implicated in a variety of immune responses, and the number of studies using mouse models to unravel key mechanisms has increased. However, as of yet, there is no electrode that can chronically record neural activity from the mouse vagus nerve due to its small diameter. Such recordings are critical to understand the role of these biomarkers for translational research. Approach. In this study, we developed a methodology for surgically implanting the wrappable microwires onto the vagus nerve of mice. Similar to a cuff electrode, we wrapped de-insulated ends of microwires around the vagus nerve and re-insulated them on the nerve with Kwik-Sil. The recording fidelity of the wrappable microwire on the vagus nerve was validated in an acute, anesthetized model by comparing performance to commercially-available electrodes. A chronic, awake mouse model was then developed to record spontaneous compound action potentials (CAPs). Main results. In an acute setting, the wrappable microwire successfully recorded spontaneous CAPs with similar signal-to-noise ratios (SNR) and peak-to-peak amplitude to commercially available electrodes. In chronic, awake recordings, viable SNRs were obtained from the wrappable microwires between 30 and 60 d (n = 8). Weekly impedance measurements showed no correlation with SNR or time, indicating device stability, and the electrodes recorded CAPs for the duration of the recording period. Significance. To the best of our knowledge, this is the first reported chronic, awake neural interface with the mouse vagus nerve. This approach can facilitate clinical translation for bioelectronic medicine in preclinical disease models of interest with the creation of more clinically relevant preclinical models.

A method to establish functional vagus nerve topography from electro-neurographic spontaneous activity

Next-generation medical devices in bioelectronic medicine integrate neurotechnology with precision therapy to modulate physiological functions in real time. Bioelectronic medicine is an emerging interdisciplinary field that combines biology, electronics, and medicine to provide novel therapeutic solutions for various chronic and acute diseases. With advancements in neurotechnology and biomedical engineering, bioelectronic devices are increasingly being considered alternatives or adjuncts to traditional pharmacological therapies. This paper explores the urgent need for bioelectronic medicine, emphasizing its potential to revolutionize modern health care by reducing drug dependency, minimizing side effects, and addressing economic challenges. Key research goals include the development of a visceral nerve atlas, early validation of therapeutic possibilities, and advancements in neural interfacing technologies. Technical milestones such as the discovery of the inflammatory reflex, innovations in electric implants, and modulation of the vagus nerve have further enhanced therapeutic applications. The clinical relevance of a wide range of bioelectronic devices—including artificial pacemakers, bioelectronic noses, biosensors, and visual prostheses—is discussed. The integration of bioelectronics in health care has shown promising results in treating conditions such as hypertension, diabetes mellitus, central nervous system disorders, rheumatoid arthritis, blindness, and spinal cord injuries. Technological advancements continue to refine signal decoding and device miniaturization, broadening the scope of bioelectronic interventions. However, challenges such as biocompatibility, long-term safety, accessibility, and ethical concerns must be addressed for successful widespread adoption. The article concludes with future directives focused on personalized bioelectronic therapies, regulatory frameworks, and collaborative research, highlighting the potential of bioelectronic medicine to become a cornerstone of precision medicine along with its ethical implications.

The peripheral nervous system plays a major role in the maintenance of our physiology. Several peripheral nerves intimately regulate the state of the brain, spinal cord, and visceral systems. A new class of therapeutics, called bioelectronic medicines, are being developed to precisely regulate physiology and treat dysfunction using peripheral nerve stimulation. In this review, we first discuss new work using closed-loop bioelectronic medicine to treat upper limb paralysis. In contrast to open-loop bioelectronic medicines, closed-loop approaches trigger ‘on demand’ peripheral nerve stimulation due to a change in function (e.g., during an upper limb movement or a change in cardiopulmonary state). We also outline our perspective on timing rules for closed-loop bioelectronic stimulation, interface features for non-invasively stimulating peripheral nerves, and machine learning algorithms to recognize disease events for closed-loop stimulation control. Although there will be several challenges for this emerging field, we look forward to future bioelectronic medicines that can autonomously sense changes in the body, to provide closed-loop peripheral nerve stimulation and treat disease.

Objective To evaluate the relationship between α7 nicotinic acetylcholine receptor (α7nAChR) signaling pathway and regulatory T cells (Tregs) during vagus nerve stimulation-induced reduction of endotoxin-caused acute lung injury (ALI) in mice. Methods Clean-grade healthy male C57BL/6 mice, aged 6-8 weeks, weighing 22-25 g, were divided into 5 groups (n=10 each) using a random number table method: control group (group C), group ALI, vagus nerve stimulation group (group VNS), α-BGT group (group α-BGT) and vagus nerve stimulation plus α-BGT group (group VNS + α-BGT). After successful establishment of the model, the vagus nerve was stimulated for 30 s with a stimulus intensity of 0.5 mA, frequency of 20 Hz, an interval of 5 min, 60 min in total.Sterile normal saline 100 μl was injected into the trachea, and the vagus nerve was only exposed but not stimulated in group C. In group ALI, the ALI model was established, and the vagus nerve was isolated but not stimulated.In group α-BGT, α-BGT 1 μg/kg was intraperitoneally injected, the ALI model was established 1 h later, and the vagus nerve was isolated but not stimulated.In group VNS+ α-BGT, α-BGT 1 μg/kg was intraperitoneally injected, the ALI model was established 1 h later, and the vagus nerve was stimulated at 1 h after the end of establishment.Animals were sacrificed at 72 h after establishing the model, and lungs were removed for determination of lung water content, percentage of Tregs (using flow cytometry), myeloperoxidase (MPO) activity (by colorimetric assay), expression of α7nAChR (by Western blot) and contents of interleukin-10 (IL-10), transforming growth factor-β (TGF-β) and IL-1β (by enzyme-linked immunosorbent assay). Results Compared with group C, the lung water content, MPO activity and IL-1β content were significantly increased in the other four groups, the expression of α7nAChR was significantly down-regulated in ALI, α-BGT and VNS+ α-BGT groups, the percentage of Tregs was significantly increased in group VNS, the IL-10 content was significantly decreased in ALI and α-BGT groups and increased in VNS and VNS+ α-BGT groups, and TGF-β contents were significantly decreased in ALI, α-BGT and VNS+ α-BGT groups and increased in group VNS (P<0.05). Compared with group ALI, the lung water content, MPO activity and IL-1β content were significantly decreased, the expression of α7nAChR was up-regulated, and the percentage of Tregs and contents of IL-10 and TGF-β were increased in group VNS, and the TGF-β content in group α-BGT and contents of IL-10 and TGF-β in group VNS+ α-BGT were significantly increased (P<0.05). Compared with group VNS, the lung water content, MPO activity and IL-1β content were significantly increased, the expression of α7nAChR was down-regulated, and the percentage of Tregs and contents of IL-10 and TGF-β were decreased in α-BGT and VNS+ α-BGT groups (P<0.05). The contents of IL-10 and TGF-β were significantly higher in group VNS+ α-BGT than in group α-BGT (P<0.05). Conclusion Vagus nerve stimulation can activate α7nAChR signaling pathway and raise the percentage of Tregs, thus reducing ALI in mice. Key words: Vagus nerve; Respiratory distress syndrome, adult; T-Lymphocytes, regulatory; Receptors, nicotinic