Bioelectric neuromodulation for gastrointestinal disorders: effectiveness and mechanisms


The gastrointestinal tract has extensive, surgically accessible nerve connections with the central nervous system. This provides the opportunity to exploit rapidly advancing methods of nerve stimulation to treat gastrointestinal disorders. Bioelectric neuromodulation technology has considerably advanced in the past decade, but sacral nerve stimulation for faecal incontinence currently remains the only neuromodulation protocol in general use for a gastrointestinal disorder. Treatment of other conditions, such as IBD, obesity, nausea and gastroparesis, has had variable success. That nerves modulate inflammation in the intestine is well established, but the anti-inflammatory effects of vagal nerve stimulation have only recently been discovered, and positive effects of this approach were seen in only some patients with Crohn’s disease in a single trial. Pulses of high-frequency current applied to the vagus nerve have been used to block signalling from the stomach to the brain to reduce appetite with variable outcomes. Bioelectric neuromodulation has also been investigated for postoperative ileus, gastroparesis symptoms and constipation in animal models and some clinical trials. The clinical success of this bioelectric neuromodulation therapy might be enhanced through better knowledge of the targeted nerve pathways and their physiological and pathophysiological roles, optimizing stimulation protocols and determining which patients benefit most from this therapy.

Key points

  • The gastrointestinal tract has substantial two-way neural interactions with the central nervous system through the vagus nerve, thoracolumbar connections and sacral nerves, which provide opportunities for disease-modifying bioelectric neuromodulation therapy.

  • Sacral nerve stimulation (SNS) to treat faecal incontinence is the only neuromodulation protocol for a gastrointestinal disorder that is currently in general use; adapted SNS to selectively stimulate efferent pathways to treat constipation is not in general use.

  • Inhibition of gastrointestinal inflammation might be possible via vagal nerve stimulation (VNS) or sympathetic nerve stimulation, and limited clinical testing suggests effectiveness of cervical VNS.

  • The vagus nerve carries signals for feeding, whose block might reduce appetite and treat obesity; however, electrical block of vagal afferents had variable clinical success, whereas direct stimulation of afferent endings at the gastric surface reduced satiety in some studies.

  • Gastric electrical stimulation stimulates afferent endings at the gastric surface, which, in some studies, reduced postprandial nausea in patients with gastroparesis and reduced weight gain in patients with obesity.

  • Bioelectric neuromodulation might be a valuable treatment for several gastrointestinal disorders but further investigations into the underlying mechanisms, placement of stimulating electrodes, stimulus parameters and patient populations to optimize effectiveness are still required.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Sites of bioelectric neuromodulation to change gastrointestinal functions.
Fig. 2: The extrinsic innervation of the gastrointestinal tract.
Fig. 3: Gastric sites of bioelectric neuromodulation.
Fig. 4: Nerve pathways for voluntary control of defecation and faecal continence.


  1. 1.

    Chen, J. D., Yin, J. & Wei, W. Electrical therapies for gastrointestinal motility disorders. Expert Rev. Gastroenterol. Hepatol. 11, 407–418 (2017).

  2. 2.

    Bonaz, B., Sinniger, V. & Pellissier, S. Vagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease. J. Intern. Med. 282, 46–63 (2017).

  3. 3.

    de Lartigue, G. Role of the vagus nerve in the development and treatment of diet-induced obesity. J. Physiol. 594, 5791–5815 (2016).

  4. 4.

    Willemze, R. A., Luyer, M. D., Buurman, W. A. & de Jonge, W. J. Neural reflex pathways in intestinal inflammation: hypotheses to viable therapy. Nat. Rev. Gastroenterol. Hepatol. 12, 353–362 (2015).

  5. 5.

    Lee, P. C. & Dixon, J. Medical devices for the treatment of obesity. Nat. Rev. Gastroenterol. Hepatol. 14, 553–564 (2017).

  6. 6.

    Furness, J. B., Rivera, L. R., Cho, H.-J., Bravo, D. M. & Callaghan, B. The gut as a sensory organ. Nat. Rev. Gastroenterol. Hepatol. 10, 729–740 (2013).

  7. 7.

    Prechtl, J. C. & Powley, T. L. The fiber composition of the abdominal vagus of the rat. Anat. Embryol. (Berl.) 181, 101–115 (1990).

  8. 8.

    Kawagishi, K. et al. Tyrosine hydroxylase-immunoreactive fibers in the human vagus nerve. J. Clin. Neurosci. 15, 1023–1026 (2008).

  9. 9.

    Lundberg, J., Ahlman, H., Dahlstrom, A. & Kewenter, J. Catecholamine-containing nerve fibres in the human abdominal vagus. Gastroenterology 70, 472–474 (1976).

  10. 10.

    Ahlman, B. H. et al. Evidence for innervation of the small intestine from the cervical sympathetic ganglia. J. Surg. Res. 24, 142–149 (1978).

  11. 11.

    Brookes, S. J. H., Spencer, N. J., Costa, M. & Zagorodnyuk, V. P. Extrinsic primary afferent signalling in the gut. Nat. Rev. Gastroenterol. Hepatol. 10, 286–296 (2013).

  12. 12.

    Berthoud, H.-R. The vagus nerve, food intake and obesity. Regul. Pept. 149, 15–25 (2008).

  13. 13.

    Dockray, G. J. Enteroendocrine cell signalling via the vagus nerve. Curr. Opin. Pharmacol. 13, 1–5 (2013).

  14. 14.

    Powley, T. L. et al. Architecture of vagal motor units controlling striated muscle of esophagus: peripheral elements patterning peristalsis. Auton. Neurosci. 179, 90–98 (2013).

  15. 15.

    Furness, J. B., Callaghan, B., Rivera, L. R. & Cho, H. J. The enteric nervous system and gastrointestinal innervation: integrated local and central control. Adv. Exp. Med. Biol. 817, 39–71 (2014).

  16. 16.

    Furness, J. B. Integrated neural and endocrine control of gastrointestinal function. Adv. Exp. Med. Biol. 891, 159–173 (2016).

  17. 17.

    Ness, T. J. & Gebhart, G. F. Visceral pain: a review of experimental studies. Pain 41, 167–234 (1990).

  18. 18.

    Callaghan, B., Furness, J. B. & Pustovit, R. V. Neural pathways for colorectal control, relevance to spinal cord injury and treatment: a narrative review. Spinal Cord 56, 199–205 (2018).

  19. 19.

    Ananthakrishnan, A. N. Epidemiology and risk factors for IBD. Nat. Rev. Gastroenterol. Hepatol. 12, 205–217 (2015).

  20. 20.

    Thia, K. T., Loftus, E. V. Jr., Sandborn, W. J. & Yang, S. K. An update on the epidemiology of inflammatory bowel disease in Asia. Am. J. Gastroenterol. 103, 3167–3182 (2008).

  21. 21.

    Kaplan, G. G. The global burden of IBD: from 2015 to 2025. Nat. Rev. Gastroenterol. Hepatol. 12, 720–727 (2015).

  22. 22.

    Loftus, E. V. Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology 126, 1504–1517 (2004).

  23. 23.

    Cosnes, J., Gower-Rousseau, C., Seksik, P. & Cortot, A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 140, 1785–1794 (2011).

  24. 24.

    Tsianos, E. V. & Katsanos, K. Do we really understand what the immunological disturbances in inflammatory bowel disease mean? World J. Gastroenterol. 15, 521–525 (2009).

  25. 25.

    Mow, W. S. et al. Association of antibody responses to microbial antigens and complications of small bowel Crohn’s disease. Gastroenterology 126, 414–424 (2004).

  26. 26.

    Neurath, M. F. Cytokines in inflammatory bowel disease. Nat. Rev. Immunol. 14, 329–342 (2014).

  27. 27.

    Peyrin-Biroulet, L., Loftus, E. V. Jr, Colombel, J. F. & Sandborn, W. J. Long-term complications, extraintestinal manifestations, and mortality in adult Crohn’s disease in population-based cohorts. Inflamm. Bowel Dis. 17, 471–478 (2011).

  28. 28.

    De Cruz, P. et al. Postoperative recurrence of Crohn’s disease: impact of endoscopic monitoring and treatment step-up. Colorectal Dis. 15, 187–197 (2013).

  29. 29.

    Gisbert, J. P., Marin, A. C., McNicholl, A. G. & Chaparro, M. Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients with inflammatory bowel disease whose previous anti-TNF treatment has failed. Aliment. Pharmacol. Ther. 41, 613–623 (2015).

  30. 30.

    Ford, A. C. et al. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am. J. Gastroenterol. 106, 644–659 (2011).

  31. 31.

    Chaparro, M. et al. Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients. Inflamm. Bowel Dis. 19, 1404–1410 (2013).

  32. 32.

    De Cruz, P. et al. Crohn’s disease management after intestinal resection: a randomised trial. Lancet 385, 1406–1417 (2015).

  33. 33.

    Meregnani, J. et al. Anti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease. Auton. Neurosci. 160, 82–89 (2011).

  34. 34.

    Sun, P. et al. Involvement of MAPK/NF-kappaB signaling in the activation of the cholinergic anti-inflammatory pathway in experimental colitis by chronic vagus nerve stimulation. PLOS ONE 8, e69424 (2013).

  35. 35.

    Ghia, J. E., Blennerhassett, P., Kumar-Ondiveeran, H., Verdu, E. F. & Collins, S. M. The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology 131, 1122–1130 (2006).

  36. 36.

    Ji, H. et al. Central cholinergic activation of a vagus nerve-to-spleen circuit alleviates experimental colitis. Mucosal Immunol. 7, 335–347 (2014).

  37. 37.

    Willemze, R. A. et al. Neuronal control of experimental colitis occurs via sympathetic intestinal innervation. Neurogastroenterol. Motil. 30, e13163–e13177 (2017).

  38. 38.

    Pavlov, V. A. & Tracey, K. J. Neural regulation of immunity: molecular mechanisms and clinical translation. Nat. Neurosci. 20, 156–166 (2017).

  39. 39.

    Talbot, S., Foster, S. L. & Woolf, C. J. Neuroimmunity: physiology and pathology. Annu. Rev. Immunol. 34, 421–447 (2016).

  40. 40.

    Martelli, D., McKinley, M. J. & McAllen, R. M. The cholinergic anti-inflammatory pathway: a critical review. Auton. Neurosci. 182, 65–69 (2014).

  41. 41.

    Martelli, D., Yao, S. T., McKinley, M. J. & McAllen, R. M. Reflex control of inflammation by sympathetic nerves, not the vagus. J. Physiol. 592, 1677–1686 (2014).

  42. 42.

    Holzer, P. Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides. Neuroscience 24, 739–768 (1988).

  43. 43.

    Holzer, P. & Lippe, I. T. Stimulation of afferent nerve endings by intragastric capsaicin protects against ethanol-induced damage of gastric mucosa. Neuroscience 27, 981–987 (1988).

  44. 44.

    Holzer, P. & Lippe, I. T. Role of calcitonin gene-related peptide in gastrointestinal blood flow. Ann. NY Acad. Sci. 657, 228–239 (1992).

  45. 45.

    Jacobson, E. D. Vascular mediation of gastric mucosal damage and cytoprotection. Indian J. Physiol. Pharmacol. 34, 223–234 (1990).

  46. 46.

    Lambrecht, N., Burchert, M., Respondek, M., Muller, K. M. & Peskar, B. M. Role of calcitonin gene-related peptide and nitric oxide in the gastroprotective effect of capsaicin in the rat. Gastroenterology 104, 1371–1380 (1993).

  47. 47.

    Eysselein, V. E. et al. Calcitonin gene-related peptide in inflammatory bowel disease and experimentally induced colitis. Ann. NY Acad. Sci. 657, 319–327 (1992).

  48. 48.

    Mazelin, L., Theodorou, V., More, J., Fioramonti, J. & Bueno, L. Protective role of vagal afferents in experimentally-induced colitis in rats. J. Auton. Nerv. Syst. 73, 38–45 (1998).

  49. 49.

    Reinshagen, M. et al. Protective function of extrinsic sensory neurons in acute rabbit experimental colitis. Gastroenterology 106, 1208–1214 (1994).

  50. 50.

    Reinshagen, M. et al. Calcitonin gene-related peptide mediates the protective effect of sensory nerves in a model of colonic injury. J. Pharmacol. Exp. Ther. 286, 657–661 (1998).

  51. 51.

    Holzer, P. Role of visceral afferent neurons in mucosal inflammation and defense. Curr. Opin. Pharmacol. 7, 563–569 (2007).

  52. 52.

    Ritter, R. C. & Ladenheim, E. E. Capsaicin pretreatment attenuates suppression of food intake by cholecystokinin. Am. J. Physiol. 248, R501–R504 (1985).

  53. 53.

    de Jonge, W. J. et al. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat. Immunol. 6, 844–851 (2005).

  54. 54.

    Matteoli, G. et al. A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen. Gut 63, 938–948 (2014).

  55. 55.

    De Cruz, P., Kamm, M. A., Prideaux, L., Allen, P. B. & Desmond, P. V. Postoperative recurrent luminal Crohn’s disease: a systematic review. Inflamm. Bowel Dis. 18, 758–777 (2012).

  56. 56.

    Cervi, A. L., Lukewich, M. K. & Lomax, A. E. Neural regulation of gastrointestinal inflammation: role of the sympathetic nervous system. Auton. Neurosci. 182, 83–88 (2014).

  57. 57.

    Hirst, G. D. & McKirdy, H. C. Presynaptic inhibition at mammalian peripheral synapse? Nature 250, 430–431 (1974).

  58. 58.

    Stebbing, M., Johnson, P., Vremec, M. & Bornstein, J. Role of α2-adrenoceptors in the sympathetic inhibition of motility reflexes of guinea-pig ileum. J. Physiol. 534, 465–478 (2001).

  59. 59.

    Gabanyi, I. et al. Neuro-immune interactions drive tissue programming in intestinal macrophages. Cell 164, 378–391 (2016).

  60. 60.

    Vasina, V. et al. The β3-adrenoceptor agonist SR58611A ameliorates experimental colitis in rats. Neurogastroenterol. Motil. 20, 1030–1041 (2008).

  61. 61.

    De Winter, B. Y. et al. Effect of adrenergic and nitrergic blockade on experimental ileus in rats. Br. J. Pharmacol. 120, 464–468 (1997).

  62. 62.

    Fukuda, H. et al. Inhibition of sympathetic pathways restores postoperative ileus in the upper and lower gastrointestinal tract. J. Gastroenterol. Hepatol. 22, 1293–1299 (2007).

  63. 63.

    Willemze, R. A., Bakker, T., Pippias, M., Ponsioen, C. Y. & de Jonge, W. J. β-Blocker use is associated with a higher relapse risk of inflammatory bowel disease: a Dutch retrospective case-control study. Eur. J. Gastroenterol. Hepatol. 30, 161–166 (2018).

  64. 64.

    Bauer, A. J. Mentation on the immunological modulation of gastrointestinal motility. Neurogastroenterol. Motil. 20, 81–90 (2008).

  65. 65.

    Bonaz, B. et al. Chronic vagus nerve stimulation in Crohn’s disease: a 6-month follow-up pilot study. Neurogastroenterol. Motil. 28, 948–953 (2016).

  66. 66.

    US National Library of Medicine. (2017).

  67. 67.

    US National Library of Medicine. (2017).

  68. 68.

    Bregeon, J. et al. Improvement of refractory ulcerative proctitis with sacral nerve stimulation. J. Clin. Gastroenterol. 49, 853–857 (2015).

  69. 69.

    Guo, J. et al. Anti-inflammatory effects and mechanisms of sacral nerve stimulation on TNBS-induced ulcerative colitis in rats. Gastroenterology 150, S98–S99 (2016).

  70. 70.

    Luckey, A., Livingston, E. & Tache, Y. Mechanisms and treatment of postoperative ileus. Arch. Surg. 138, 206–214 (2003).

  71. 71.

    Stakenborg, N. et al. Abdominal vagus nerve stimulation as a new therapeutic approach to prevent postoperative ileus. Neurogastroenterol. Motil. 29, e13075–e13086 (2017).

  72. 72.

    Yuan, P. Q. & Tache, Y. Abdominal surgery induced gastric ileus and activation of M1-like macrophages in the gastric myenteric plexus: prevention by central vagal activation in rats. Am. J. Physiol. Gastrointest. Liver Physiol. 313, G320–G329 (2017).

  73. 73.

    Fang, J. F. et al. Electroacupuncture treatment partly promotes the recovery time of postoperative ileus by activating the vagus nerve but not regulating local inflammation. Scientif. Rep. 7, 39801–39815 (2017).

  74. 74.

    Inoue, T. et al. Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes. J. Clin. Invest. 126, 1939–1952 (2016).

  75. 75.

    Stevens, J., Oakkar, E. E., Cui, Z., Cai, J. & Truesdale, K. P. US adults recommended for weight reduction by 1998 and 2013 obesity guidelines, NHANES 2007–2012. Obes. (Silver Spring) 23, 527–531 (2015).

  76. 76.

    Kim, D. D. & Basu, A. Estimating the medical care costs of obesity in the United States: systematic review, meta-analysis, and empirical enalysis. Value Health 19, 602–613 (2016).

  77. 77.

    Leibel, R. L., Rosenbaum, M. & Hirsch, J. Changes in energy expenditure resulting from altered body weight. N. Engl. J. Med. 332, 621–628 (1995).

  78. 78.

    Sumithran, P. et al. Long-term persistence of hormonal adaptations to weight loss. N. Engl. J. Med. 365, 1597–1604 (2011).

  79. 79.

    Carvajal, R., Wadden, T. A., Tsai, A. G., Peck, K. & Moran, C. H. Managing obesity in primary care practice: a narrative review. Ann. NY Acad. Sci. 1281, 191–206 (2013).

  80. 80.

    Driscoll, S., Gregory, D. M., Fardy, J. M. & Twells, L. K. Long-term health-related quality of life in bariatric surgery patients: a systematic review and meta-analysis. Obes. (Silver Spring) 24, 60–70 (2016).

  81. 81.

    Hofmann, W., van Koningsbruggen, G. M., Stroebe, W., Ramanathan, S. & Aarts, H. As pleasure unfolds. Hedonic responses to tempting food. Psychol. Sci. 21, 1863–1870 (2010).

  82. 82.

    Miras, A. D. & le Roux, C. W. Mechanisms underlying weight loss after bariatric surgery. Nat. Rev. Gastroenterol. Hepatol. 10, 575–584 (2013).

  83. 83.

    Chang, S. H. et al. The effectiveness and risks of bariatric surgery: an updated systematic review and meta-analysis, 2003–2012. JAMA Surg. 149, 275–287 (2014).

  84. 84.

    Sanger, G. J., Broad, J., Callaghan, B. & Furness, J. B. Ghrelin and motilin control systems in GI physiology and therapeutics. Handb Exp. Pharmacol. 239, 379–416 (2017).

  85. 85.

    Meyer, J. H. in Gastrointestinal Disease: Pathophysiology, Diagnosis , Management (eds Sleisenger, M. H. & Fordtran, J. S.) 757–779 (W. B. Saunders Co., 1983).

  86. 86.

    Kral, J. G. & Gortz, L. Truncal vagotomy in morbid obesity. Int. J. Obes. 5, 431–435 (1981).

  87. 87.

    Furness, J. B. et al. Effects of vagal and splanchnic section on food intake, weight, serum leptin and hypothalamic neuropeptide Y in rat. Auton. Neurosci. 92, 28–36 (2001).

  88. 88.

    Camilleri, M. et al. Intra-abdominal vagal blocking (vBloc therapy): clinical results with a new implantable medical device. Surgery 143, 723–731 (2008).

  89. 89.

    Ikramuddin, S. et al. Effect of reversible intermittent intra-abdominal vagal nerve blockade on morbid obesity: the ReCharge randomized clinical trial. JAMA 312, 915–922 (2014).

  90. 90.

    Sarr, M. G. et al. The EMPOWER study: randomized, prospective, double-blind, multicenter trial of vagal blockade to induce weight loss in morbid obesity. Obes. Surg. 22, 1771–1782 (2012).

  91. 91.

    Shikora, S. A. et al. Sustained weight loss with vagal nerve blockade but not with sham: 18-month results of the ReCharge trial. J. Obes. 2015, 365604–365612 (2015).

  92. 92.

    Apovian, C. M. et al. Two-year outcomes of vagal nerve blocking (vBloc) for the treatment of obesity in the ReCharge trial. Obes. Surg. 27, 169–176 (2017).

  93. 93.

    Laskiewicz, J. et al. Effects of vagal neuromodulation and vagotomy on control of food intake and body weight in rats. J. Physiol. Pharmacol. 54, 603–610 (2003).

  94. 94.

    Roslin, M. & M, K. The use of electrical stimulation of the vagus nerve to treat morbid obesity. Epilepsy Behav. 2, 11–16 (2001).

  95. 95.

    Bugajski, A. J. et al. Effect of long-term vagal stimulation on food intake and body weight during diet induced obesity in rats. J. Physiol. Pharmacol. 58, 5–12 (2007).

  96. 96.

    Krolczyk, G. et al. The effects of baclofen on the feeding behaviour and body weight of vagally stimulated rats. J. Physiol. Pharmacol. 56, 121–131 (2005).

  97. 97.

    Laskiewicz, J., Krolczyk, G., Zurowski, D., Enck, P. & Thor, P. J. Capasaicin induced deafferentation enhances the effect of electrical vagal nerve stimulation on food intake and body mass. J. Physiol. Pharmacol. 55, 155–163 (2004).

  98. 98.

    Val-Laillet, D., Biraben, A., Randuineau, G. & Malbert, C. H. Chronic vagus nerve stimulation decreased weight gain, food consumption and sweet craving in adult obese minipigs. Appetite 55, 245–252 (2010).

  99. 99.

    Biraben, P. A., Guerin, S., Bobillier, É., Val-Laillet, D. & Malbert, C. H. Central activation after chronic vagus nerve stimualtion in pigs: contribution of functional imaging. Bull. l’Académie Vétérinaire France 161, 441–448 (2008).

  100. 100.

    Burneo, J. G., Faught, E., Knowlton, R., Morawetz, R. & Kuzniecky, R. Weight loss associated with vagus nerve stimulation. Neurology 59, 463–464 (2002).

  101. 101.

    Pardo, J. V. et al. Weight loss during chronic, cervical vagus nerve stimulation in depressed patients with obesity: an observation. Int. J. Obes. (Lond.) 31, 1756–1759 (2007).

  102. 102.

    Chuang, J. C. et al. Ghrelin mediates stress-induced food-reward behavior in mice. J. Clin. Invest. 121, 2684–2692 (2011).

  103. 103.

    Esser, N., Legrand-Poels, S., Piette, J., Scheen, A. J. & Paquot, N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res. Clin. Pract. 105, 141–150 (2014).

  104. 104.

    Wo, J. M., Nowak, T. V., Waseem, S. & Ward, M. P. Gastric electrical stimulation for gastroparesis and chronic unexplained nausea and vomiting. Curr. Treat. Opt. Gastroenterol. 14, 386–400 (2016).

  105. 105.

    Miras, M., Serrano, M., Duran, C., Valino, C. & Canton, S. Early experience with customized, meal-triggered gastric electrical stimulation in obese patients. Obes. Surg. 25, 174–179 (2015).

  106. 106.

    Shikora, S. A. et al. Implantable gastric stimulation for the treatment of clinically severe obesity: results of the SHAPE trial. Surg. Obes. Relat. Dis. 5, 31–37 (2009).

  107. 107.

    Lebovitz, H. E. et al. Fasting plasma triglycerides predict the glycaemic response to treatment of type 2 diabetes by gastric electrical stimulation. A novel lipotoxicity paradigm. Diabet Med. 30, 687–693 (2013).

  108. 108.

    Horbach, T. et al. abiliti® closed-loop gastric electrical stimulation system for treatment of obesity: clinical results with a 27-month follow-up. Obes. Surg. 25, 1779–1787 (2015).

  109. 109.

    Lebovitz, H. E. Interventional treatment of obesity and diabetes: an interim report on gastric electrical stimulation. Rev. Endocr. Metab. Disord. 17, 73–80 (2016).

  110. 110.

    Mizrahi, M., Ben Ya’acov, A. & Ilan, Y. Gastric stimulation for weight loss. World J. Gastroenterol. 18, 2309–2319 (2012).

  111. 111.

    Peles, S. et al. Enhancement of antral contractions and vagal afferent signaling with synchronized electrical stimulation. Am. J. Physiol. Gastrointest. Liver Physiol. 285, G577–G585 (2003).

  112. 112.

    D’Argent, J. Gastric electrical stimulation as therapy of morbid obesity: preliminary results from the French study. Obes. Surg. 12, S21–S25 (2002).

  113. 113.

    Cigaina, V. Gastric pacing as therapy for morbid obesity: preliminary results. Obes. Surg. 12, S12–S16 (2002).

  114. 114.

    Lebovitz, H. E. et al. Gastric electrical stimulation treatment of type 2diabetes: effects of implantation versus meal-mediated stimulation. A randomized blinded cross-over trial. Physiol. Rep. 3, e12456–e12464 (2015).

  115. 115.

    Lebovitz, H. E. et al. Treatment of patients with obese type 2 diabetes with Tantalus-DIAMOND(R) gastric electrical stimulation: normal triglycerides predict durable effects for at least 3 years. Horm. Metab. Res. 47, 456–462 (2015).

  116. 116.

    Horbach, T. et al. Closed-loop gastric electrical stimulation versus laparoscopic adjustable gastric band for the treatment of obesity: a randomized 12-month multicenter study. Int. J. Obes. (Lond.) 40, 1891–1898 (2016).

  117. 117.

    Levinthal, D. J. & Bielefeldt, K. Systematic review and meta-analysis: gastric electrical stimulation for gastroparesis. Auton. Neurosci. 202, 45–55 (2017).

  118. 118.

    Pasricha, P. J., Camilleri, M., Hasler, W. L. & Parkman, H. P. White Paper AGA: gastroparesis: clinical and regulatory insights for clinical trials. Clin. Gastroenterol. Hepatol. 15, 1184–1190 (2017).

  119. 119.

    Parkman, H. P. et al. Nausea and vomiting in gastroparesis: similarities and differences in idiopathic and diabetic gastroparesis. Neurogastroenterol. Motil. 28, 1902–1914 (2016).

  120. 120.

    Kelly, K. A. Gastric emptying of liquids and solids: roles of proximal and distal stomach. Am. J. Physiol. 239, G71–G76 (1980).

  121. 121.

    McCallum, R. W. et al. Gastric pacing improves emptying and symptoms in patients with gastroparesis. Gastroenterology 114, 456–461 (1998).

  122. 122.

    McCallum, R. W. et al. Gastric electrical stimulation with Enterra therapy improves symptoms from diabetic gastroparesis in a prospective study. Clin. Gastroenterol. Hepatol. 8, 947–954 (2010).

  123. 123.

    Asakawa, A. et al. Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology 120, 337–345 (2001).

  124. 124.

    le Roux, C. W. et al. Ghrelin does not stimulate food intake in patients with surgical procedures involving vagotomy. J. Clin. Endocr. Metab. 90, 4521–4524 (2005).

  125. 125.

    McCallum, R. W. et al. Gastric electrical stimulation with Enterra therapy improves symptoms of idiopathic gastroparesis. Neurogastroenterol. Motil. 25, 815–824 (2013).

  126. 126.

    Swenson, O. Hirschsprung’s disease: a review. Pediatrics 109, 914–918 (2002).

  127. 127.

    Furness, J. B. & Poole, D. P. Involvement of gut neural and endocrine systems in pathological disorders of the digestive tract. J. Anim. Sci. 90, 1203–1212 (2012).

  128. 128.

    Matsuda, N. M., Miller, S. M. & Evora, P. R. B. The chronic gastrointestinal manifestations of Chagas disease. Clinics 64, 1219–1224 (2009).

  129. 129.

    Glickman, S. & Kamm, M. A. Bowel dysfunction in spinal-cord-injury patients. Lancet 347, 1651–1653 (1996).

  130. 130.

    Lynch, A. C., Antony, A., Dobbs, B. R. & Frizelle, F. A. Bowel dysfunction following spinal cord injury. Spinal Cord 39, 193–203 (2001).

  131. 131.

    Lynch, A. C. & Frizelle, F. A. Colorectal motility and defecation after spinal cord injury in humans. Prog. Brain Res. 152, 335–343 (2006).

  132. 132.

    Ng, C. et al. Gastrointestinal symptoms in spinal cord inury: relationships with level of injury and psychologic factors. Dis. Colon Rectum 48, 1562–1568 (2005).

  133. 133.

    Snoek, G. J., Ijzerman, M. J., Hermens, H. J., Maxwell, D. & Biering-Sorensen, F. Survey of the needs of patients with spinal cord injury: impact and priority for improvement in hand function in tetraplegics. Spinal Cord 42, 526–532 (2004).

  134. 134.

    Krogh, K., Perkash, I., Stiens, S. A. & Biering-Sørensen, F. International bowel function extended spinal cord injury data set. Spinal Cord 47, 235–241 (2009).

  135. 135.

    Liu, C.-W. et al. Prediction of severe neurogenic bowel dysfunction in persons with spinal cord injury. Spinal Cord 48, 554–559 (2010).

  136. 136.

    Widerström-Noga, E. G., Felipe-Cuervo, E., Broton, J. G., Duncan, R. C. & Yezierski, R. P. Perceived difficulty in dealing with consequences of spinal cord injury. Arch. Phys. Med. Rehabil. 80, 580–586 (1999).

  137. 137.

    Fasano, A., Visanji, N. P., Liu, L. W. C., Lang, A. E. & Pfeiffer, R. F. Gastrointestinal dysfunction in Parkinson’s disease. Lancet Neurol. 14, 625–639 (2015).

  138. 138.

    Jost, W. H. Gastrointestinal dysfunction in Parkinson’s disease. J. Neurol. Sci. 289, 69–73 (2010).

  139. 139.

    Lin, C.-H., Lin, J.-W., Liu, Y.-C., Chang, C.-H. & Wu, R.-M. Risk of Parkinson’s disease following severe constipation: a nationwide population-based cohort study. Parkinsonism Relat. Disord. 20, 1371–1375 (2014).

  140. 140.

    Tariq, S. H. Constipation in long-term care. J. Am. Med. Dir. Assoc. 8, 209–218 (2007).

  141. 141.

    Auth, M. K. H., Vora, R., Farrelly, P. & Baillie, C. Childhood constipation. BMJ 345, e7390 (2012).

  142. 142.

    Shin, A. et al. Systematic review with meta-analysis: highly selective 5-HT4 agonists (prucalopride, velusetrag or naronapride) in chronic constipation. Aliment. Pharmacol. Ther. 39, 239–253 (2014).

  143. 143.

    Ford, A. C. & Talley, N. J. Laxatives for chronic constipation in adults. BMJ 345, 44–49 (2012).

  144. 144.

    Carrington, E. V. et al. A systematic review of sacral nerve stimulation mechanisms in the treatment of fecal incontinence and constipation. Neurogastroenterol. Motil. 26, 1222–1237 (2014).

  145. 145.

    Matzel, K. E., Stadelmaier, U., Hohenfellner, M. & Gall, F. P. Electrical stimulation of sacral spinal nerves for treatment of faecal incontinence. Lancet 346, 1124–1127 (1995).

  146. 146.

    Thin, N. N. et al. Systematic review of the clinical effectiveness of neuromodulation in the treatment of faecal incontinence. Br. J. Surg. 100, 1430–1447 (2013).

  147. 147.

    Tjandra, J. J., Chan, M. K., Yeh, C. H. & Murray-Green, C. Sacral nerve stimulation is more effective than optimal medical therapy for severe fecal incontinence: a randomized, controlled study. Dis. Colon Rectum 51, 494–502 (2008).

  148. 148.

    Duelund-Jakobsen, J. et al. Randomized double-blind crossover study of alternative stimulator settings in sacral nerve stimulation for faecal incontinence. Br. J. Surg. 99, 1445–1452 (2012).

  149. 149.

    Mitchell, P. J., Cattle, K., Saravanathan, S., Telford, K. J. & Kiff, E. S. Insertion under local anaesthetic of temporary electrodes for sacral nerve stimulation testing is reliable and cost effective. Colorectal Dis. 13, 445–448 (2011).

  150. 150.

    Govaert, B., Melenhorst, J., van Gemert, W. G. & Baeten, C. G. Can sensory and/or motor reactions during percutaneous nerve evaluation predict outcome of sacral nerve modulation? Dis. Colon Rectum 52, 1423–1426 (2009).

  151. 151.

    Varma, J. S., Binnie, N., Smith, A. N., Creasey, G. H. & Edmond, P. Differential effects of sacral anterior root stimulation on anal sphincter and colorectal motility in spinally injured man. Br. J. Surg. 73, 478–482 (1986).

  152. 152.

    Malouf, A. J., Wiesel, P. H., Nicholls, T., Nicholls, R. J. & Kamm, M. A. Short-term effects of sacral nerve stimulation for idiopathic slow transit constipation. World J. Surg. 26, 166–170 (2002).

  153. 153.

    Rasmussen, M. M. et al. Sacral anterior root stimulation improves bowel function in subjects with spinal cord injury. Spinal Cord 53, 297–301 (2015).

  154. 154.

    Zaer, H. et al. Effect of spinal anterior root stimulation and sacral deafferentation on bladder and sexual dysfunction in spinal cord injury. Acta Neurochir. (Wien) 160, 1377–1384 (2018).

  155. 155.

    Moore, J. S., Gibson, P. R. & Burgell, R. E. Neuromodulation via interferential electrical stimulation as a novel therapy in gastrointestinal motility disorders. J. Neurogastroenterol. Motil. 24, 19–29 (2018).

  156. 156.

    Palmer, S. T., Martin, D. J., Steedman, W. M. & Ravey, J. Alteration of interferential current and transcutaneous electrical nerve stimulation frequency: effects on nerve excitation. Arch. Phys. Med. Rehabil. 80, 1065–1071 (1999).

  157. 157.

    Johnson, M. I. Transcutaneous electrical nerve stimulation (TENS) as an adjunct for pain management in perioperative settings: a critical review. Expert Rev. Neurother. 17, 1013–1027 (2017).

  158. 158.

    Leong, L. C. et al. Long-term effects of transabdominal electrical stimulation in treating children with slow-transit constipation. J. Pediatr. Surg. 46, 2309–2312 (2011).

  159. 159.

    Clarke, M. C. et al. Transabdominal electrical stimulation increases colonic propagating pressure waves in paediatric slow transit constipation. J. Pediatr. Surg. 47, 2279–2284 (2012).

  160. 160.

    Loerwald, K. W. et al. Varying stimulation parameters to improve cortical plasticity generated by VNS-tone pairing. Neuroscience 388, 239–247 (2018).

  161. 161.

    Shepherd, R. K., Villalobos, J., Burns, O. & Nayagam, D. A. X. The development of neural stimulators: a review of preclinical safety and efficacy studies. J. Neural Eng. 15, 041004 (2018).

  162. 162.

    Abell, T. L. et al. A double-masked, randomized, placebo-controlled trial of temporary endoscopic mucosal gastric electrical stimulation for gastroparesis. Gastrointest. Endosc. 74, 496–503 (2011).

Download references


Work on bioelectric modulation for inflammatory bowel disease is supported by the Defense Advanced Research Projects Agency (DARPA) BTO through the Space and Naval Warfare Systems Center Contract No. N66001-15-2-4060 to J.B.F., and work on gastric disorders by NIH (SPARC) grant ID# OT2OD023847 to J.B.F., the National Institutes of Health (NIH) and the National Health and Medical Research Council of Australia. Billie Hunne is thanked for assistance in the preparation of illustrations.

Review criteria

Literature searches included publications in the past 10 years. Earlier publications have been sought if they were referenced in contemporary papers. Combinations of the following search terms were used: “vagus nerve”, “vagus nerve stimulation”, “gastric electrical stimulation”, “inflammatory bowel disease”, “sacral nerve stimulation”, “ileus”, “gastroparesis”, “faecal incontinence”, “constipation”, “appetite”, “satiety”, “nausea”. Searches were conducted in Google Scholar and PubMed.

Author information

All authors researched data for the article, made substantial contributions to discussion of the article content, wrote and reviewed/edited the manuscript before submission.

Correspondence to Sophie C. Payne.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Central nervous system

(CNS). The nervous system consisting of the brain and spinal cord.

Enteric nervous system

(ENS). The nervous system embedded in the wall of the gastrointestinal tract, in the gallbladder and the pancreas.


Refers to nerve pathways from the CNS and ENS to muscle, gland and epithelia.


Refers to nerve pathways that carry sensory information from tissues to the CNS and ENS.

Sympathetic postganglionic neurons

Neurons of sympathetic pathways whose cell bodies reside in ganglia outside the CNS and ENS.

Cervical sympathetic chain

The part of the chain of sympathetic ganglia in the neck.


Collections of the cell bodies of autonomic neurons.

C fibres

Axons that conduct at low speeds (approximately 1 m/s).

Enteroendocrine cells

Endocrine cells that are found in the lining of the gastrointestinal tract.

Autonomic and somatic efferents

Efferent neurons that belong to the autonomic nervous system and efferent neurons that are involved in somatic (skeletal muscle) control.


Antigens that cause nonspecific activation of T cells resulting in polyclonal T cell activation and massive cytokine release.

Oxidative burst

The rapid release of reactive oxygen species (superoxide radicals and hydrogen peroxide).

Cholinergic agents

Drugs whose action relies on the neurotransmitter acetylcholine.

Pathogen-associated molecular patterns

(PAMPs). Molecular motifs conserved within microorganisms that are recognized by cells of the innate immune system.


Refers to neurons that are activated by the capsaicin compound from red peppers, which in high enough concentrations causes the neurons to degenerate.

Myenteric plexus

A plexus of nerves and ganglia of the enteric nervous system, located within the external muscle of the gastrointestinal tract.

Tyrosine-hydroxylase-immunoreactive nerve endings

The endings of neurons that contain the enzyme tyrosine hydroxylase, which is necessary for the synthesis of adrenaline, dopamine and noradrenaline.

Colonic histological score

The score given by a histopathologist that quantifies damage to the colon.

Nicotinic receptors

A class of cell surface receptors that bind and mediate cellular effects of acetylcholine.

Excess weight loss

(EWL). A common metric for reporting loss of excess body weight, calculated as 100% × (weight loss / excess weight at beginning of treatment); excess weight is defined as the difference between the patient’s weight and the body weight if BMI were 25.

Hedonic eating

Eating for pleasure that is not necessarily associated with need for nutrient.

Slow waves

Slow oscillation in the membrane potentials of muscle cells that can lead to regular contractile activity.

Chagas disease

A disease caused by infection with the protist Trypanosoma cruzi that can result in degeneration of colonic enteric neurons.

Onuf’s nucleus

A gathering of nerve cells in the sacral spinal cord that innervate the pelvic floor, including the external anal sphincter.

Spinal cord injury

Injury to the spinal cord sufficient to cause clinically recognizable deficits of sensory or motor functions.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Payne, S.C., Furness, J.B. & Stebbing, M.J. Bioelectric neuromodulation for gastrointestinal disorders: effectiveness and mechanisms. Nat Rev Gastroenterol Hepatol 16, 89–105 (2019).

Download citation

Further reading