Targeting the anti-inflammatory properties of the vagus nerve through vagus nerve stimulation: Therapeutic implications for inflammatory bowel diseases and other inflammatory conditions


  • Bruno Bonaz Grenoble Institute Neurosciences, University of Grenoble Alpes; Division of Hepato-Gastroenterology, CHU Grenoble Alpes


Ключевые слова:

vagus nerve, vagus nerve stimulation, cholinergic anti-inflammatory pathway, hypothalamic-pituitary adrenal axis, inflammatory bowel diseases, rheumatoid arthritis


The vagus nerve (VN) is the longest nerve of the organism that innervates major organs such as the heart, lungs and gastro-intestinal tract and is a major component of the autonomic nervous system at the interface of the central nervous system and the body. The VN has anti-inflammatory properties both through its afferent fibers, activating the hypothalamic-pituitary adrenal axis, and its efferent fibers activating the cholinergic anti-inflammatory pathway. Targeting these anti-inflammatory pathways is of interest for various inflammatory conditions. Bioelectronic medicine through VN stimulation (VNS) appears as an interesting tool to release inflammatory conditions. VNS is approved for the treatment of drug-resistant epilepsy and has potential therapeutic applications in chronic inflammatory disorders such as inflammatory bowel diseases and others. Preclinical data and pilot clinical studies argue for such an effect. However, larger randomized double-blinded control study and a long-lasting follow-up of the patients to confirm these promising results are awaiting. In addition, the optimal neurostimulation parameters to better treat common conditions and diseases that involve immune regulation need to be determined.

Библиографические ссылки

Abe, C., Inoue, T., Inglis, M. A. et al. (2017) C1 neurons mediate a stress-induced anti-inflammatory reflex in mice. Nature Neuroscience, vol. 20, no. 5, pp. 700–707. DOI: 10.1038/nn.4526 (In English)

Altschuler, S. M., Escardo, J., Lynn, R. B., Miselis, R. R. (1993) The central organization of the vagus nerve innervating the colon of the rat. Gastroenterology, vol. 104, no. 2, pp. 502–509. DOI: 10.1016/0016-5085(93)90419-d (In English)

Badran, B. W., Dowdle, L. T., Mithoefer, O. J. et al. (2018) Neurophysiologic effects of transcutaneous auricular vagus nerve stimulation (taVNS) via electrical stimulation of the tragus: A concurrent taVNS/fMRI study and review. Brain Stimulation, vol. 11, no. 3, pp. 492–500. DOI: 10.1016/j.brs.2017.12.009 (In English)

Benarroch, E. E. (1993) The central autonomic network: Functional organization, dysfunction, and perspective. Mayo Clinic Proceedings, vol. 68, no. 10, pp. 988–1001. DOI: 10.1016/s0025-6196(12)62272-1 (In English)

Bernik, T. R., Friedman, S. G., Ochani, M. et al. (2002) Cholinergic anti-inflammatory pathway inhibition of tumor necrosis factor during ischemia reperfusion. Journal of Vascular Surgery, vol. 36, no. 6, pp. 1231–1236. DOI: 10.1067/mva.2002.129643 (In English)

Berthoud, H. R., Carlson, N. R., Powley, T. L. (1991) Topography of efferent vagal innervation of the rat gastrointestinal tract. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, vol. 260, no. 1, pp. R200–R207. DOI: 10.1152/ajpregu.1991.260.1.R200 (In English)

Bonaz, B. (2020) Parameters matter: Modulating cytokines using nerve stimulation. Bioelectronic Medicine, vol. 6, article 12. DOI: 10.1186/s42234-020-00049-1 (In English)

Bonaz, B., Bazin, T., Pellissier, S. (2018) The vagus nerve at the interface of the microbiota-gut-brain axis. Frontiers in Neuroscience, vol. 12, article 49. DOI: 10.3389/fnins.2018.00049 (In English)

Bonaz, B. L., Bernstein, C. N. (2013) Brain–gut interactions in inflammatory bowel disease. Gastroenterology, vol. 144, no. 1, pp. 36–49. DOI: 10.1053/j.gastro.2012.10.003 (In English)

Bonaz, B., Lane, R. D., Oshinsky, M. L. (2020) Diseases, disorders, and comorbidities of interoception. Trends in Neurosciences. (In press). (In English)

Bonaz, B., Sinniger, V., Hoffmann, D. et al. (2013) Vagus nerve stimulation: From epilepsy to the cholinergic anti-inflammatory pathway. Journal of Neurogastroenterology and Motility, vol. 25, no. 3, pp. 208–221. DOI: 10.1111/nmo.12076 (In English)

Bonaz, B., Sinniger, V., Hoffmann, D. et al. (2016) Chronic vagus nerve stimulation in Crohn’s disease: A 6-month follow-up pilot study. Journal of Neurogastroenterology and Motility, vol. 28, no. 6, pp. 948–953. DOI: 10.1111/nmo.12792 (In English)

Bonaz, B., Sinniger, V., Pellissier, S. (2017) The vagus nerve in the neuro-immune axis: Implications in the pathology of the gastrointestinal tract. Frontiers in Immunology, vol. 8, article 1452. DOI: 10.3389/fimmu.2017.01452 (In English)

Bonaz, B., Sinniger, V., Pellissier, S. (2019) Vagus nerve stimulation at the interface of brain-gut interactions. Cold Spring Harbor Perspectives in Medicine, vol. 9, no. 8, article a034199. DOI: 10.1101/cshperspect.a034199 (In English)

Borovikova, L. V., Ivanova, S., Zhang, M. et al. (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature, vol. 405, no. 6785, pp. 458–462. DOI: 10.1038/35013070 (In English)

Buller, K. M. (2001) Role of circumventricular organs in pro-inflammatory cytokine-induced activation of the hypothalamic–pituitary–adrenal axis. Clinical and Experimental Pharmacology and Physiology, vol. 28, no. 7, pp. 581–589. DOI: 10.1046/j.1440-1681.2001.03490.x (In English)

Cailotto, C., Gomez-Pinilla, P. J., Costes, L. M. et al. (2014) Neuro-anatomical evidence indicating indirect modulation of macrophages by vagal efferents in the intestine but not in the spleen. PLoS One, vol. 9, no. 1, article e87785. DOI: 10.1371/journal.pone.0087785 (In English)

Cechetto, D. F. (1987) Central representation of visceral function. Federation Proceedings, vol. 46, no. 1, pp. 17–23. PMID: 3542576. (In English)

Chan, W., Chen, A., Tiao, D. et al. (2017) Medication adherence in inflammatory bowel disease. Intestinal Research, vol. 15, no. 4, pp. 434–445. DOI: 10.5217/ir.2017.15.4.434 (In English)

Click, B., Regueiro, M. (2019) Managing risks with biologics. Current Gastroenterology Reports, vol. 21, no. 2, article 1. DOI: 10.1007/s11894-019-0669-6 (In English)

De Jonge, W. J., van den Wijngaard, R. M., The, F. O. et al. (2003) Postoperative ileus is maintained by intestinal immune infiltrates that activate inhibitory neural pathways in mice. Gastroenterology, vol. 125, no. 4, pp. 1137–1147. DOI: 10.1016/s0016-5085(03)01197-1 (In English)

De Jonge, W. J., van der Zanden, E. P., The, F. O. et al. (2005) Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nature Immunology, vol. 6, no. 8, pp. 844–851. DOI: 10.1038/ni1229 (In English)

Delmas, J., Laux, G. (1933) Anatomie médico-chirurgicale du système nerveux végétatif: sympathique & parasympathique [Medical-surgical anatomy of the vegetative nervous system: sympathetic and parasympathetic]. Paris: Masson, 266 p. (In French)

D’Haens, G. R., Cabrijan, Z., Eberhardson, M. (2018) The effects of vagus nerve stimulation in biologic-refractory Crohn’s disease: A prospective clinical trial. Journal of Crohn’s and Colitis, vol. 12, no. 1, pp. S397–S398. DOI: 10.1093/ecco-jcc/jjx180.701 (In English)

Englot, D. J., Chang, E. F., Auguste, K. I. (2011) Vagus nerve stimulation for epilepsy: A meta-analysis of efficacy and predictors of response. Journal of Neurosurgery, vol. 115, no. 6, pp. 1248–1255. DOI: 10.3171/2011.7.JNS11977 (In English)

Fournier, A., Mondillon, L., Luminet, O. et al. (2020) Interoceptive abilities in inflammatory bowel diseases and irritable bowel syndrome. Frontiers in Psychiatry, vol. 11, article 229. DOI: 10.3389/fpsyt.2020.00229 (In English)

Ghia, J. E., Blennerhassett, P., Kumar-Ondiveeran, H. et al. (2006) The vagus nerve: A tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology, vol. 131, no. 4, pp. 1122–1130. DOI: 10.1053/j.gastro.2006.08.016 (In English)

Kibleur, A., Pellissier, S., Sinniger, V. et al. (2018) Electroencephalographic correlates of low-frequency vagus nerve stimulation therapy for Crohn’s disease. Clinical Neurophysiology, vol. 129, no. 5, pp. 1041–1046. DOI: 10.1016/j.clinph.2018.02.127 (In English)

Koopman, F. A., Chavan, S. S., Miljko, S. et al. (2016) Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proceedings of the National Academy of Sciences of USA, vol. 113, no. 29, pp. 8284–8289. DOI: 10.1073/pnas.1605635113 (In English)

Koopman, F. A., Schuurman, P. R., Vervoordeldonk, M. J., Tak, P. P. (2014) Vagus nerve stimulation: A new bioelectronics approach to treat rheumatoid arthritis? Best Practice & Research Clinical Rheumatology, vol. 28, no. 4, pp. 625–635. DOI: 10.1016/j.berh.2014.10.015 (In English)

Krahl, S. E., Senanayake, S. S., Handforth, A. (2001) Destruction of peripheral C-fibers does not alter subsequent vagus nerve stimulation-induced seizure suppression in rats. Epilepsia, vol. 42, no. 5, pp. 586–589. DOI: 10.1046/j.1528-1157.2001.09700.x (In English)

Martelli, D., McKinley, M. J., McAllen, R. M. (2014) The cholinergic anti-inflammatory pathway: A critical review. Autonomic Neuroscience: Basic & Clinical, vol. 182, pp. 65–69. DOI: 10.1016/j.autneu.2013.12.007 (In English)

Meregnani, J., Clarencon, D., Vivier, M. et al. (2011) Anti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease. Autonomic Neuroscience: Basic & Clinical, vol. 160, no. 1–2, pp. 82–89. DOI: 10.1016/j.autneu.2010.10.007 (In English)

Mion, F., Pellissier, S., Garros, A. et al. (2020) Transcutaneous auricular vagus nerve stimulation for the treatment of irritable bowel syndrome: A pilot, open-label study. Neuromodulation. (In press). (In English)

Morris, G. L., Mueller, W. M., The Vagus Nerve Stimulation Study Group E01-E05. (1999) Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. Neurology, vol. 53, no. 8, pp. 1731–1735. DOI: 10.1212/wnl.53.8.1731 (In English)

Mwamburi, M., Liebler, E. J., Staats, P. S. (2020) Patient experience with non-invasive vagus nerve stimulator: GammaCore patient registry. American Journal of Managed Care, vol. 26, no. 1, pp. S15–S19. DOI: 10.37765/ajmc.2020.42545 (In English)

Netter, F. H., Colacino, S. (1989) Atlas of human anatomy. Summit: Ciba-Geigy Corporation, 550 p. (In English)

Olofsson, P. S., Katz, D. A., Rosas-Ballina, M. et al. (2012) α-7-Nicotinic acetylcholine receptor (α7nAChR) expression in bone marrow-derived non-T cells is required for the inflammatory reflex. Molecular Medicine, vol. 18, pp. 539–543. DOI: 10.2119/molmed.2011.00405 (In English)

Pellissier, S., Dantzer, C., Canini, F. et al. (2010) Psychological adjustment and autonomic disturbances in inflammatory bowel diseases and irritable bowel syndrome. Psychoneuroendocrinology, vol. 35, no. 5, pp. 653–662. DOI: 10.1016/j.psyneuen.2009.10.004 (In English)

Pellissier, S., Dantzer, C., Mondillon, L. et al. (2014) Relationship between vagal tone, cortisol, TNF-alpha, epinephrine and negative affects in Crohn’s disease and irritable bowel syndrome. PLoS One, vol. 9, no. 9, article e105328. DOI: 10.1371/journal.pone.0105328 (In English)

Peuker, E. T., Filler, T. J. (2002) The nerve supply of the human auricle. Clinical Anatomy, vol. 15, no. 1, pp. 35–37. DOI: 10.1002/ca.1089 (In English)

Reyt, S., Picq, C., Sinniger, V. et al. (2010) Dynamic causal modelling and physiological confounds: A functional MRI study of vagus nerve stimulation. Neuroimage, vol. 52, no. 4, pp. 1456–1464. DOI: 10.1016/j.neuroimage.2010.05.021 (In English)

Ricardo, J. A., Koh, E. T. (1978) Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat. Brain Research, vol. 153, no. 1, pp. 1–26. DOI: 10.1016/0006-8993(78)91125-3 (In English)

Rosas-Ballina, M., Ochani, M., Parrish, W. R. et al. (2008) Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. Proceedings of the National Academy of Sciences of USA, vol. 105, no. 31, pp. 11008–11013. DOI: 10.1073/pnas.0803237105 (In English)

Sinniger, V., Pellissier, S., Fauvelle, F. et al. (2020) A 12-month pilot study outcomes of vagus nerve stimulation in Crohn’s disease. Neurogastroenterology & Motility, vol. 32, no. 10, article e13911. DOI: 10.1111/nmo.13911 (In English)

Stakenborg, N., Gomez-Pinilla, P. J., Boeckxstaens, G. E. (2017a) Postoperative ileus: Pathophysiology, current therapeutic approaches. Gastrointestinal Pharmacology. Handbook of Experimental Pharmacology, vol. 239, pp. 39–57. DOI: 10.1007/164_2016_108 (In English)

Stakenborg, N., Wolthuis, A. M., Gomez-Pinilla, P. J. et al. (2017b) Abdominal vagus nerve stimulation as a new therapeutic approach to prevent postoperative ileus. Neurogastroenterology & Motility, vol. 29, no. 9, article e13075. DOI: 10.1111/nmo.13075 (In English)

Stefan, H., Kreiselmeyer, G., Kerling, F. et al. (2012) Transcutaneous vagus nerve stimulation (t-VNS) in pharmacoresistant epilepsies: A proof of concept trial. Epilepsia, vol. 53, no. 7, pp. e115–e118. DOI: 10.1111/j.1528-1167.2012.03492.x (In English)

Strack, A. M., Sawyer, W. B., Platt, K. B., Loewy, A. D. (1989) CNS cell groups regulating the sympathetic outflow to adrenal gland as revealed by transneuronal cell body labelling with pseudorabies virus. Brain Research, vol. 491, no. 2, pp. 274–296. DOI: 10.1016/0006-8993(89)90063-2 (In English)

Targownik, L. E., Benchimol, E. I., Witt, J. et al. (2019) The effect of initiation of anti-TNF therapy on the subsequent direct health care costs of inflammatory Bowel disease. Inflammatory Bowel Diseases, vol. 25, no. 10, pp. 1718-1728. DOI: 10.1093/ibd/izz063 (In English)

Torres, J., Ellul, P., Langhorst, J. et al. (2019) European Crohn’s and colitis organisation topical review on complementary medicine and psychotherapy in inflammatory Bowel disease. Journal of Crohn’s and Colitis, vol. 13, no. 6, pp. 673–685e. DOI: 10.1093/ecco-jcc/jjz051 (In English)

Wang, H., Liao, H., Ochani, M. et al. (2004) Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nature Medicine, vol. 10, no. 11, pp. 1216–1221. DOI: 10.1038/nm1124 (In English)

Wang, H., Yu, M., Ochani, M. et al. (2003) Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature, vol. 421, no. 6921, pp. 384–388. DOI: 10.1038/nature01339 (In English)

Werner, M. F. P., Fraga, D., Melo, M. C. C. et al. (2003) Importance of the vagus nerve for fever and neutrophil migration induced by intraperitoneal LPS injection. Inflammation Research, vol. 52, no. 7, pp. 291–296. DOI: 10.1007/s00011-003-1174-8 (In English)

Zagon, A. (2001) Does the vagus nerve mediate the sixth sense? Trends in Neurosciences, vol. 24, no. 11, pp. 671–673. DOI: 10.1016/s0166-2236(00)01929-9 (In English)