Accessible Requires Authentication Published by De Gruyter January 11, 2020

The enteric nervous system: “A little brain in the gut”

Anita Annahazi and Michael Schemann
From the journal Neuroforum


The gut’s own autonomous nervous system, the enteric nervous system (ENS), has fascinated scientists for more than 100 years. It functions, in the true sense of the word, autonomously, by performing complex tasks and controlling vital functions independently of extrinsic inputs. At the same time, the ENS is bombarded with signals from other cells in the gut wall and lumen and has to integrate all of these inputs. We describe the main functions of the ENS under physiological conditions and give a few examples of its role in gut diseases. The ENS has received increasing attention recently as scientists outside the field of Neurogastroenterology realize its important role in the pathogenesis of Parkinson’s, autism and multiple sclerosis.


Darmfunktionen werden durch das autonom agierende enterische Nervensystem (ENS) reguliert. Es kontrolliert vitale Funktionen des Darms unabhängig von extrinsischen Einflüssen. Das ENS muss eine Fülle von Signalen anderer Zellen in der Darmwand oder Faktoren im Darmlumen integrieren. In diesem Artikel beschreiben wir die wesentlichen Funktionen des ENS und erläutern Beispiele aus der klinischen Neurogastroenterologie. Darüber hinaus eröffnen sich neue Aspekte für das Verständnis systemischer neurologischer Erkrankungen wie Parkinson, Autismus oder Multipler Sklerose, bei denen die Rolle des Darms und des ENS immer offensichtlicher wird.


Adams, J.B., Johansen, L.J., Powell, L.D., Quig, D., and Rubin, R.A. (2011). Gastrointestinal flora and gastrointestinal status in children with autism – comparisons to typical children and correlation with autism severity. BMC Gastroenterol. 11, 22. Search in Google Scholar

Anitha, M., Joseph, I., Ding, X., Torre, E.R., Sawchuk, M.A., Mwangi, S., … Srinivasan, S. (2008). Characterization of Fetal and Postnatal Enteric Neuronal Cell Lines With Improvement in Intestinal Neural Function. Gastroenterology 134, 1424–1435. Search in Google Scholar

Annaházi, A., Ferrier, L., Bézirard, V., Lévêque, M., Eutamène, H., Ait-Belgnaoui, A., … Bueno, L. (2013). Luminal Cysteine-Proteases Degrade Colonic Tight Junction Structure and Are Responsible for Abdominal Pain in Constipation-Predominant IBS. Am. J. Gastroenterol. 108, 1322–1331. Search in Google Scholar

Barbara, G., Stanghellini, V., De Giorgio, R., Cremon, C., Cottrell, G.S., Santini, … Corinaldesi, R. (2004). Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 126, 693–702. Search in Google Scholar

Bayliss, W.M., and Starling, E.H. (1899). The movements and innervation of the small intestine. J. Physiol. 24, 99–143. Search in Google Scholar

Bertrand, P.P., Kunze, W.A., Bornstein, J.C., Furness, J.B., and Smith, M.L. (1997). Analysis of the responses of myenteric neurons in the small intestine to chemical stimulation of the mucosa. Am. J. Physiol.: Gastrointest. Liver Physiol. 273, G422–G435. Search in Google Scholar

Bialecka, M., Kurzawski, M., Klodowska-Duda, G., Opala, G., Juzwiak, S., Kurzawski, G., Tan, E.-K., and Drozdzik, M. (2007). CARD15 variants in patients with sporadic Parkinson’s disease. Neurosci. Res. 57, 473–476. Search in Google Scholar

Blackshaw, L.A., Brookes, S.J.H., Grundy, D., and Schemann, M. (2007). Sensory transmission in the gastrointestinal tract. Neurogastroenterol. Motil. 19, 1–19. Search in Google Scholar

Braak, H., de Vos, R.A.I., Bohl, J., and Del Tredici, K. (2006). Gastric α-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci. Lett. 396, 67–72. Search in Google Scholar

Buhner, S., Li, Q., Vignali, S., Barbara, G., De Giorgio, R., Stanghellini, V. … Schemann, M. (2009). Activation of Human Enteric Neurons by Supernatants of Colonic Biopsy Specimens From Patients With Irritable Bowel Syndrome. Gastroenterology 137, 1425–1434. Search in Google Scholar

Buhner, S., Li, Q., Berger, T., Vignali, S., Barbara, G., De Giorgio, R., Stanghellini, V., and Schemann, M. (2012). Submucous rather than myenteric neurons are activated by mucosal biopsy supernatants from irritable bowel syndrome patients: Enteric plexuses and IBS supernatants. Neurogastroenterol. Motil. 24, 1134-e572. Search in Google Scholar

Buhner, S., Braak, B., Li, Q., Kugler, E.M., Klooker, T., Wouters, M., … Schemann, M. (2014). Neuronal activation by mucosal biopsy supernatants from irritable bowel syndrome patients is linked to visceral sensitivity: Neuronal activation in irritable bowel syndrome. Exp. Physiol. 99, 1299–1311. Search in Google Scholar

Butler Tjaden, N.E., and Trainor, P.A. (2013). The developmental etiology and pathogenesis of Hirschsprung disease. Transl. Res. 162, 1–15. Search in Google Scholar

Cenac, N., Andrews, C.N., Holzhausen, M., Chapman, K., Cottrell, G., Andrade-Gordon, P., … Vergnole, N. (2007). Role for protease activity in visceral pain in irritable bowel syndrome. J. Clin. Invest. 117, 636–647. Search in Google Scholar

Chapelet, G., Leclair-Visonneau, L., Clairembault, T., Neunlist, M., and Derkinderen, P. (2019). Can the gut be the missing piece in uncovering PD pathogenesis? Parkinsonism Relat. Disord. 59, 26–31. Search in Google Scholar

Chen, S.G., Stribinskis, V., Rane, M.J., Demuth, D.R., Gozal, E., Roberts, A.M., … Friedland, R.P. (2016). Exposure to the Functional Bacterial Amyloid Protein Curli Enhances Alpha-Synuclein Aggregation in Aged Fischer 344 Rats and Caenorhabditis elegans. Sci. Rep. 6, 34477. Search in Google Scholar

Choi, J.G., Kim, N., Ju, I.G., Eo, H., Lim, S.-M., Jang, S.-E., Kim, D.-H., and Oh, M.S. (2018). Oral administration of Proteus mirabilis damages dopaminergic neurons and motor functions in mice. Sci. Rep. 8, 1275. Search in Google Scholar

Clairembault, T., Leclair-Visonneau, L., Coron, E., Bourreille, A., Le Dily, S., Vavasseur, F., … Derkinderen, P. (2015). Structural alterations of the intestinal epithelial barrier in Parkinson’s disease. Acta Neuropathol. Commun. 3, 12. Search in Google Scholar

Davies, K.N., King, D., Billington, D., and Barrett, J.A. (1996). Intestinal permeability and orocaecal transit time in elderly patients with Parkinson’s disease. Postgrad. Med. J. 72, 164–167. Search in Google Scholar

Deisseroth, K., Feng, G., Majewska, A.K., Miesenbock, G., Ting, A., and Schnitzer, M.J. (2006). Next-Generation Optical Technologies for Illuminating Genetically Targeted Brain Circuits. J. Neurosci. 26, 10380–10386. Search in Google Scholar

Devos, D., Lebouvier, T., Lardeux, B., Biraud, M., Rouaud, T., Pouclet, … Derkinderen, P. (2013). Colonic inflammation in Parkinson’s disease. Neurobiol. Dis. 50, 42–48. Search in Google Scholar

Drossman, D.A. (2016). Functional Gastrointestinal Disorders: History, Pathophysiology, Clinical Features, and Rome IV. Gastroenterology 150, 1262–1279.e2. Search in Google Scholar

Enck, P., Aziz, Q., Barbara, G., Farmer, A. D., Fukudo, S., Mayer, E.A., … Spiller, R.C. (2016). Irritable bowel syndrome. Nat. Rev. Dis. Primers 2, 16014. Search in Google Scholar

Fan, W., Fei, G., Li, X., Wang, X., Hu, C., Xin, H., … Fang, X. (2018). Sera with anti-enteric neuronal antibodies from patients with irritable bowel syndrome promote apoptosis in myenteric neurons of guinea pigs and human SH-Sy5Y cells. Neurogastroenterol. Motil. 30, e13457. Search in Google Scholar

Friedland, R.P., and Chapman, M.R. (2017). The role of microbial amyloid in neurodegeneration. PLoS Pathog. 13, e1006654. Search in Google Scholar

Furness, J.B. (2006). The enteric nervous system (Malden, Mass: Blackwell Pub). Search in Google Scholar

Furness, J.B., and Stebbing, M.J. (2018). The first brain: Species comparisons and evolutionary implications for the enteric and central nervous systems. Neurogastroenterol. Motil. 30, e13234. Search in Google Scholar

Furness, J.B., Callaghan, B.P., Rivera, L.R., and Cho, H.-J. (2014). The Enteric Nervous System and Gastrointestinal Innervation: Integrated Local and Central Control. In Microbial Endocrinology: The Microbiota-Gut-Brain Axis in Health and Disease. M. Lyte and J.F. Cryan, eds. (New York, NY: Springer New York), pp. 39–71. Search in Google Scholar

Gecse, K., Roka, R., Ferrier, L., Leveque, M., Eutamene, H., Cartier, C., … Bueno, L. (2008). Increased faecal serine protease activity in diarrhoeic IBS patients: a colonic lumenal factor impairing colonic permeability and sensitivity. Gut 57, 591–599. Search in Google Scholar

Grubišić, V., and Parpura, V. (2015). The second brain in autism spectrum disorder: could connexin 43 expressed in enteric glial cells play a role? Front. Cell. Neurosci. 9, 242. Search in Google Scholar

Gustafson, E., Larsson, T., and Danielson, J. (2019). Controlled outcome of Hirschsprung’s disease beyond adolescence: a single center experience. Pediatr. Surg. Int. 35, 181–185. Search in Google Scholar

Hirschsprung, H. (1888). Stuhlträgheit Neugeborener in Folge von Dilatation und Hypertrophie des Colons. In Jahrbuch Für Kinderheilkunde Und Physische Erziehung, 27: pp. 1–7. Search in Google Scholar

Hsiao, E.Y., McBride, S.W., Hsien, S., Sharon, G., Hyde, E.R., McCue, T., … Mazmanian S.K. (2013). Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders. Cell 155, 1451–1463. Search in Google Scholar

Hui, K.Y., Fernandez-Hernandez, H., Hu, J., Schaffner, A., Pankratz, N., Hsu, N.-Y., … Peter, I. (2018). Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease. Sci. Transl. Med. 10, eaai7795. Search in Google Scholar

Huizinga, J.D., and Lammers, W.J.E.P. (2009). Gut peristalsis is governed by a multitude of cooperating mechanisms. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G1–G8. Search in Google Scholar

Israelyan, N., and Margolis, K.G. (2019). Reprint of: Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders. Pharmacol. Res. 140, 115–120. Search in Google Scholar

Jahng, J., and Kim, Y.S. (2016). Irritable Bowel Syndrome: Is It Really a Functional Disorder? A New Perspective on Alteration of Enteric Nervous System. Neurogastroenterol. Motil. 22, 163–165. Search in Google Scholar

Kugler, E.M., Michel, K., Zeller, F., Demir, I. E., Ceyhan, G.O., Schemann, M., and Mazzuoli-Weber, G. (2015). Mechanical stress activates neurites and somata of myenteric neurons. Front. Cell. Neurosci. 9, 342. Search in Google Scholar

Latorre, R., Sternini, C., De Giorgio, R., and Greenwood-Van Meerveld, B. (2016). Enteroendocrine cells: a review of their role in brain-gut communication. Neurogastroenterol. Motil. 28, 620–630. Search in Google Scholar

Levinthal, D.J., Rahman, A., Nusrat, S., O’Leary, M., Heyman, R., and Bielefeldt, K. (2013). Adding to the Burden: Gastrointestinal Symptoms and Syndromes in Multiple Sclerosis. Mult. Scler. Int. 2013, 1–9. Search in Google Scholar

Li, Q., Michel, K., Annahazi, A., Demir, I. E., Ceyhan, G.O., Zeller, F., … Schemann, M. (2016a). Anti-Hu antibodies activate enteric and sensory neurons. Sci. Rep. 6, 38216. Search in Google Scholar

Li, S., Fei, G., Fang, X., Yang, X., Sun, X., Qian, J., Wood, J.D., and Ke, M. (2016b). Changes in Enteric Neurons of Small Intestine in a Rat Model of Irritable Bowel Syndrome with Diarrhea. Neurogastroenterol. Motil. 22, 310–320. Search in Google Scholar

Lionnet, A., Leclair-Visonneau, L., Neunlist, M., Murayama, S., Takao, M., Adler, C.H., Derkinderen, P., and Beach, T.G. (2018). Does Parkinson’s disease start in the gut? Acta Neuropathol. 135, 1–12. Search in Google Scholar

Liu, M., Seino, S., and Kirchgessner, A.L. (1999). Identification and characterization of glucoresponsive neurons in the enteric nervous system. J. Neurosci. 19, 10305–10317. Search in Google Scholar

Liu, V., Dietrich, A., Kasparek, M.S., Benhaqi, P., Schneider, M.R., Schemann, M., Seeliger, H., and Kreis, M. E. (2015). Extrinsic intestinal denervation modulates tumor development in the small intestine of ApcMin/+ mice. J. Exp. Clin. Cancer Res. 34, 39. Search in Google Scholar

Lüderitz, C. (1890). Experimentelle Untersuchungen über die Entstehung der Darmperistaltik. Archiv f. pathol. Anat. 122, 1–28. Search in Google Scholar

Margolis, K.G., Li, Z., Stevanovic, K., Saurman, V., Israelyan, N., Anderson, G.M., … Gershon, M.D. (2016). Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function. J. Clin. Invest. 126, 2221–2235. Search in Google Scholar

Mayer, E.A. (2011). Gut feelings: the emerging biology of gut–brain communication. Nat. Rev. Neurosci. 12, 453–466. Search in Google Scholar

Mazzuoli-Weber, G., and Schemann, M. (2015). Mechanosensitivity in the enteric nervous system. Front. Cell. Neurosci. 9, 408. Search in Google Scholar

Moloney, R.D., O’Mahony, S.M., Dinan, T.G., and Cryan, J.F. (2015). Stress-Induced Visceral Pain: Toward Animal Models of Irritable-Bowel Syndrome and Associated Comorbidities. Front. Psychiatry 6, 15. Search in Google Scholar

Neunlist, M., Michel, K., Reiche, D., Dobreva, G., Huber, K., and Schemann, M. (2001). Glycine activates myenteric neurones in adult guinea-pigs. J. Physiol. 536, 727–739. Search in Google Scholar

Ostertag, D., Buhner, S., Michel, K., Pehl, C., Kurjak, M., Götzberger, M., … Schemann, M. (2015). Reduced Responses of Submucous Neurons from Irritable Bowel Syndrome Patients to a Cocktail Containing Histamine, Serotonin, TNFα, and Tryptase (IBS-Cocktail). Front. in Neurosci. 9, 465. Search in Google Scholar

O’Sullivan, M., Clayton, N., Breslin, N.P., Harman, I., Bountra, C., McLaren, A., and O’Morain, C.A. (2000). Increased mast cells in the irritable bowel syndrome. Neurogastroenterol. Motil. 12, 449–457. Search in Google Scholar

Pan, W.K., Zheng, B.J., Gao, Y., Qin, H., and Liu, Y. (2011). Transplantation of Neonatal Gut Neural Crest Progenitors Reconstructs Ganglionic Function in Benzalkonium Chloride-Treated Homogenic Rat Colon. J. Surg. Res. 167, e221–e230. Search in Google Scholar

Ro, S., Hwang, S.J., Muto, M., Jewett, W.K., and Spencer, N.J. (2006). Anatomic modifications in the enteric nervous system of piebald mice and physiological consequences to colonic motor activity. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G710–718. Search in Google Scholar

Róka, R., Rosztóczy, A., Leveque, M., Izbéki, F., Nagy, F., Molnár, T., … Bueno, L. (2007). A Pilot Study of Fecal Serine-Protease Activity: A Pathophysiologic Factor in Diarrhea-Predominant Irritable Bowel Syndrome. Clin. Gastroenterol. Hepatol. 5, 550–555. Search in Google Scholar

Sampson, T.R., Debelius, J.W., Thron, T., Janssen, S., Shastri, G.G., Ilhan, Z.E., … Mazmanian, S.K. (2016). Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease. Cell 167, 1469–1480.e12. Search in Google Scholar

Schemann, M., and Grundy, D. (1992). Electrophysiological identification of vagally innervated enteric neurons in guinea pig stomach. Am. J. Physiol. Gastrointest. Liver Physiol. 263, G709–G718. Search in Google Scholar

Schemann, M., Frieling, T., and Enck, P. (2019). To learn, to remember, to forget—How smart is the gut? Acta Physiol. e13296. Search in Google Scholar

Sergi, C. (2015). Hirschsprung’s disease: Historical notes and pathological diagnosis on the occasion of the 100th anniversary of Dr. Harald Hirschsprung’s death. World J. Clin. Pediatr. 4, 120. Search in Google Scholar

Shimizu, H., Koizumi, O., and Fujisawa, T. (2004). Three digestive movements in Hydra regulated by the diffuse nerve net in the body column. J. Comp. Physiol. A 190. Search in Google Scholar

Smith, T.K., Spencer, N.J., Hennig, G.W., and Dickson, E.J. (2007). Recent advances in enteric neurobiology: mechanosensitive interneurons. Neurogastroenterol. Motil. 19, 869–878. Search in Google Scholar

Spear, E.T., Holt, E.A., Joyce, E.J., Haag, M.M., Mawe, S.M., Hennig, G.W., Lavoie, B., Applebee, A.M., Teuscher, C., and Mawe, G.M. (2018). Altered gastrointestinal motility involving autoantibodies in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Neurogastroenterol. Motil. 30, e13349. Search in Google Scholar

Stamp, L.A. (2017). Cell therapy for GI motility disorders: comparison of cell sources and proposed steps for treating Hirschsprung disease. Am. J. Physiol. Gastrointest. Liver Physiol. 312, G348–G354. Search in Google Scholar

Stamp, L.A., Gwynne, R.M., Foong, J.P.P., Lomax, A.E., Hao, M.M., Kaplan, D. I., … Young, H.M. (2017). Optogenetic Demonstration of Functional Innervation of Mouse Colon by Neurons Derived From Transplanted Neural Cells. Gastroenterology 152, 1407–1418. Search in Google Scholar

Svensson, E., Horváth-Puhó, E., Thomsen, R.W., Djurhuus, J.C., Pedersen, L., Borghammer, P., and Sørensen, H.T. (2015). Vagotomy and subsequent risk of Parkinson’s disease: Vagotomy and Risk of PD. Ann. Neurol. 78, 522–529. Search in Google Scholar

Tittel, K. (1901). Ueber eine angeborene Missbildung des Dickdarmes. Wien. klin. Wchnschr. 903–907. Search in Google Scholar

Traini, C., Evangelista, S., Girod, V., Faussone-Pellegrini, M.S., and Vannucchi, M.G. (2016). Changes of excitatory and inhibitory neurotransmitters in the colon of rats underwent to the wrap partial restraint stress. Neurogastroenterol. Motil. 28, 1172–1185. Search in Google Scholar

Wang, W. (2018). Optogenetic manipulation of ENS – The brain in the gut. Life Sci. 192, 18–25. Search in Google Scholar

Wood, J.D., Liu, S., Drossman, D.A., Ringel, Y., and Whitehead, W.E. (2012). Anti-Enteric Neuronal Antibodies and the Irritable Bowel Syndrome. Neurogastroenterol. Motil. 18, 78–85. Search in Google Scholar

Wunsch, M., Jabari, S., Voussen, B., Enders, M., Srinivasan, S., Cossais, F., … Kuerten, S. (2017). The enteric nervous system is a potential autoimmune target in multiple sclerosis. Acta Neuropathol. 134, 281–295. Search in Google Scholar

Zhang, L., Song, J., and Hou, X. (2016). Mast Cells and Irritable Bowel Syndrome: From the Bench to the Bedside. Neurogastroenterol. Motil. 22, 181–192. Search in Google Scholar

Published Online: 2020-01-11
Published in Print: 2020-02-25

© 2020 Walter de Gruyter GmbH, Berlin/Boston