Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Disorders of the enteric nervous system — a holistic view

Abstract

The enteric nervous system (ENS) is the largest division of the peripheral nervous system and closely resembles components and functions of the central nervous system. Although the central role of the ENS in congenital enteric neuropathic disorders, including Hirschsprung disease and inflammatory and functional bowel diseases, is well acknowledged, its role in systemic diseases is less understood. Evidence of a disordered ENS has accumulated in neurodegenerative diseases ranging from amyotrophic lateral sclerosis, Alzheimer disease and multiple sclerosis to Parkinson disease as well as neurodevelopmental disorders such as autism. The ENS is a key modulator of gut barrier function and a regulator of enteric homeostasis. A ‘leaky gut’ represents the gateway for bacterial and toxin translocation that might initiate downstream processes. Data indicate that changes in the gut microbiome acting in concert with the individual genetic background can modify the ENS, central nervous system and the immune system, impair barrier function, and contribute to various disorders such as irritable bowel syndrome, inflammatory bowel disease or neurodegeneration. Here, we summarize the current knowledge on the role of the ENS in gastrointestinal and systemic diseases, highlighting its interaction with various key players involved in shaping the phenotypes. Finally, current flaws and pitfalls related to ENS research in addition to future perspectives are also addressed.

Key points

  • As a potent modulator of gut barrier function and enteric homeostasis, the enteric nervous system (ENS) is a key player in disease pathogenesis.

  • The role of the ENS in human health and disease has largely been neglected and gastrointestinal symptoms have been overlooked.

  • In addition to a role in classical enteric neuropathies, evidence has accumulated regarding the importance of the ENS in cancer, diabetes mellitus, neurodevelopmental disorders and neurodegenerative diseases.

  • Considering ENS-related gastrointestinal symptoms is crucial in the early detection of different diseases, for example Parkinson disease, and early targeted intervention might improve symptoms or even prevent disease.

  • More research applying state of the art tools is needed for a better understanding of ENS-related pathomechanisms.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Organization of the ENS in health and disease.
Fig. 2: Extrinsic and intrinsic factors shaping ENS structure and function.
Fig. 3: The ENS and cancer.
Fig. 4: Studying ENS in neurodegeneration/neurodevelopmental disorders.

References

  1. 1.

    Furness, J. B. The Enteric Nervous System. (Blackwell, 2006).

  2. 2.

    Gershon, M. D. The Second Brain. (Harper Collins, 1998).

  3. 3.

    Furness, J. B. & Stebbing, M. J. The first brain: Species comparisons and evolutionary implications for the enteric and central nervous systems. Neurogastroenterol. Motil. https://doi.org/10.1111/nmo.13234 (2018).

  4. 4.

    Wedel, T. et al. Organization of the enteric nervous system in the human colon demonstrated by wholemount immunohistochemistry with special reference to the submucous plexus. Ann. Anat. 181, 327–337 (1999).

    CAS  PubMed  Google Scholar 

  5. 5.

    Timmermans, J.-P., Hens, J. & Adriaensen, D. Outer submucous plexus: an intrinsic nerve network involved in both secretory and motility processes in the intestine of large mammals and humans. Anat. Rec. 262, 71–78 (2001).

    CAS  PubMed  Google Scholar 

  6. 6.

    Sharkey, K. A. Emerging roles for enteric glia in gastrointestinal disorders. J. Clin. Invest. 125, 918–925 (2015).

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Grubišić, V. & Gulbransen, B. D. Enteric glia: the most alimentary of all glia. J. Physiol. 595, 557–570 (2017).

    PubMed  Google Scholar 

  8. 8.

    Gulbransen, B. D. & Sharkey, K. A. Novel functional roles for enteric glia in the gastrointestinal tract. Nat. Rev. Gastroenterol. Hepatol. 9, 625–632 (2012).

    CAS  PubMed  Google Scholar 

  9. 9.

    Grundmann, D. et al. Enteric glia: S100, GFAP, and beyond. Anat. Rec. 302, 1333–1344 (2019).

    CAS  Google Scholar 

  10. 10.

    Uesaka, T., Young, H. M., Pachnis, V. & Enomoto, H. Development of the intrinsic and extrinsic innervation of the gut. Dev. Biol. 417, 158–167 (2016).

    CAS  PubMed  Google Scholar 

  11. 11.

    De Giorgio, R. et al. Enteric neuropathies: yesterday, today and tomorrow. Adv. Exp. Med. Biol. 891, 123–133 (2016).

    PubMed  Google Scholar 

  12. 12.

    Heanue, T. A. & Pachnis, V. Enteric nervous system development and Hirschsprung’s disease: advances in genetic and stem cell studies. Nat. Rev. Neurosci. 8, 466–479 (2007).

    CAS  PubMed  Google Scholar 

  13. 13.

    Sanchez, M. P. et al. Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382, 70–73 (1996).

    CAS  PubMed  Google Scholar 

  14. 14.

    Moore, M. W. et al. Renal and neuronal abnormalities in mice lacking GDNF. Nature 382, 76–79 (1996).

    CAS  PubMed  Google Scholar 

  15. 15.

    Pichel, J. G. et al. Defects in enteric innervation and kidney development in mice lacking GDNF. Nature 382, 73–76 (1996).

    CAS  PubMed  Google Scholar 

  16. 16.

    Young, H. M. et al. GDNF is a chemoattractant for enteric neural cells. Dev. Biol. 229, 503–516 (2001).

    CAS  PubMed  Google Scholar 

  17. 17.

    Mwizerwa, O. et al. Gdnf is mitogenic, neurotrophic, and chemoattractive to enteric neural crest cells in the embryonic colon. Dev. Dyn. 240, 1402–1411 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Gianino, S., Grider, J. R., Cresswell, J., Enomoto, H. & Heuckeroth, R. O. GDNF availability determines enteric neuron number by controlling precursor proliferation. Development 130, 2187–2198 (2003).

    CAS  PubMed  Google Scholar 

  19. 19.

    Young, H. M., Turner, K. N. & Bergner, A. J. The location and phenotype of proliferating neural-crest-derived cells in the developing mouse gut. Cell Tissue Res. 320, 1–9 (2005).

    CAS  PubMed  Google Scholar 

  20. 20.

    Fu, M., Lui, V. C., Sham, M. H., Cheung, A. N. & Tam, P. K. HOXB5 expression is spatially and temporarily regulated in human embryonic gut during neural crest cell colonization and differentiation of enteric neuroblasts. Dev. Dyn. 228, 1–10 (2003).

    CAS  PubMed  Google Scholar 

  21. 21.

    Bergner, A. J. et al. Birthdating of myenteric neuron subtypes in the small intestine of the mouse. J. Comp. Neurol. 522, 514–527 (2014).

    CAS  PubMed  Google Scholar 

  22. 22.

    Erickson, C. S. et al. Appearance of cholinergic myenteric neurons during enteric nervous system development: comparison of different ChAT fluorescent mouse reporter lines. Neurogastroenterol. Motil. 26, 874–884 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Pham, T. D., Gershon, M. D. & Rothman, T. P. Time of origin of neurons in the murine enteric nervous system: sequence in relation to phenotype. J. Comp. Neurol. 314, 789–798 (1991).

    CAS  PubMed  Google Scholar 

  24. 24.

    Liu, M. T., Kuan, Y. H., Wang, J., Hen, R. & Gershon, M. D. 5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice. J. Neurosci. 29, 9683–9699 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Belkind-Gerson, J. et al. Nestin-expressing cells in the gut give rise to enteric neurons and glial cells. Neurogastroenterol. Motil. 25, 61–69 e67 (2013).

    CAS  PubMed  Google Scholar 

  26. 26.

    Grundmann, D., Markwart, F., Scheller, A., Kirchhoff, F. & Schafer, K. H. Phenotype and distribution pattern of nestin-GFP-expressing cells in murine myenteric plexus. Cell Tissue Res. 366, 573–586 (2016).

    CAS  PubMed  Google Scholar 

  27. 27.

    Cavallucci, V., Fidaleo, M. & Pani, G. Nutrients and neurogenesis: the emerging role of autophagy and gut microbiota. Curr. Opin. Pharmacol. 50, 46–52 (2019).

    PubMed  Google Scholar 

  28. 28.

    Kruger, G. M. et al. Neural crest stem cells persist in the adult gut but undergo changes in self-renewal, neuronal subtype potential, and factor responsiveness. Neuron 35, 657–669 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Grundmann, D., Klotz, M., Rabe, H., Glanemann, M. & Schafer, K. H. Isolation of high-purity myenteric plexus from adult human and mouse gastrointestinal tract. Sci. Rep. 5, 9226 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Kulkarni, S. et al. Adult enteric nervous system in health is maintained by a dynamic balance between neuronal apoptosis and neurogenesis. Proc. Natl Acad. Sci. USA 114, E3709–E3718 (2017).

    CAS  PubMed  Google Scholar 

  31. 31.

    Joseph, N. M. et al. Enteric glia are multipotent in culture but primarily form glia in the adult rodent gut. J. Clin. Invest. 121, 3398–3411 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Laranjeira, C. et al. Glial cells in the mouse enteric nervous system can undergo neurogenesis in response to injury. J. Clin. Invest. 121, 3412–3424 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Delalande, J. M. et al. Vascularisation is not necessary for gut colonisation by enteric neural crest cells. Dev. Biol. 385, 220–229 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Schrenk, S. et al. Vascular and neural stem cells in the gut: do they need each other? Histochem. Cell Biol. 143, 397–410 (2015).

    CAS  PubMed  Google Scholar 

  35. 35.

    Garcia, S. B., Stopper, H. & Kannen, V. The contribution of neuronal-glial-endothelial-epithelial interactions to colon carcinogenesis. Cell. Mol. Life Sci. 71, 3191–3197 (2014).

    CAS  PubMed  Google Scholar 

  36. 36.

    Heuckeroth, R. O. & Schafer, K. H. Gene-environment interactions and the enteric nervous system: neural plasticity and Hirschsprung disease prevention. Dev. Biol. 417, 188–197 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Odenwald, M. A. & Turner, J. R. The intestinal epithelial barrier: a therapeutic target? Nat. Rev. Gastroenterol. Hepatol. 14, 9–21 (2017).

    CAS  PubMed  Google Scholar 

  38. 38.

    France, M. M. & Turner, J. R. The mucosal barrier at a glance. J. Cell Sci. 130, 307–314 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Bellono, N. W. et al. Enterochromaffin cells are gut chemosensors that couple to sensory neural pathways. Cell 170, 185–198 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Bohorquez, D. V. et al. Neuroepithelial circuit formed by innervation of sensory enteroendocrine cells. J. Clin. Invest. 125, 782–786 (2015).

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Muller, P. A. et al. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 158, 1210 (2014).

    CAS  PubMed  Google Scholar 

  42. 42.

    Sovran, B. et al. Age-associated impairment of the mucus barrier function is associated with profound changes in microbiota and immunity. Sci. Rep. 9, 1437 (2019).

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Clark, R. I. et al. Distinct shifts in microbiota composition during drosophila aging impair intestinal function and drive mortality. Cell Rep. 12, 1656–1667 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Ferrari, M. L. et al. Shigella promotes major alteration of gut epithelial physiology and tissue invasion by shutting off host intracellular transport. Proc. Natl Acad. Sci. USA 116, 13582–13591 (2019).

    CAS  PubMed  Google Scholar 

  45. 45.

    Camilleri, M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut 68, 1516–1526 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Nyavor, Y. et al. Intestinal nerve cell injury occurs prior to insulin resistance in female mice ingesting a high-fat diet. Cell Tissue Res. 376, 325–340 (2019).

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Forsyth, C. B. et al. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS ONE 6, e28032 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Schwiertz, A. et al. Fecal markers of intestinal inflammation and intestinal permeability are elevated in Parkinson’s disease. Parkinsonism Relat. Disord. 50, 104–107 (2018).

    PubMed  Google Scholar 

  49. 49.

    Savidge, T. C., Sofroniew, M. V. & Neunlist, M. Starring roles for astroglia in barrier pathologies of gut and brain. Lab. Invest. 87, 731–736 (2007).

    PubMed  Google Scholar 

  50. 50.

    Rao, M. et al. Enteric glia regulate gastrointestinal motility but are not required for maintenance of the epithelium in mice. Gastroenterology 153, 1068–1081 (2017).

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Spreadbury, I. et al. Concurrent psychological stress and infectious colitis is key to sustaining enhanced peripheral sensory signaling. Neurogastroenterol. Motil. 27, 347–355 (2015).

    CAS  PubMed  Google Scholar 

  52. 52.

    Neunlist, M. et al. Enteric glial cells: recent developments and future directions. Gastroenterology 147, 1230–1237 (2014).

    CAS  PubMed  Google Scholar 

  53. 53.

    Ibiza, S. et al. Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Nature 535, 440–443 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Burns, A. J. et al. White paper on guidelines concerning enteric nervous system stem cell therapy for enteric neuropathies. Dev. Biol. 417, 229–251 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Vaezi, M. F. et al. Achalasia: from diagnosis to management. Ann. NY Acad. Sci. 1381, 34–44 (2016).

    PubMed  Google Scholar 

  56. 56.

    Heuckeroth, R. O. Hirschsprung disease - integrating basic science and clinical medicine to improve outcomes. Nat. Rev. Gastroenterol. Hepatol. 15, 152–167 (2018).

    PubMed  Google Scholar 

  57. 57.

    Furuzawa-Carballeda, J. et al. New insights into the pathophysiology of achalasia and implications for future treatment. World J. Gastroenterol. 22, 7892–7907 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Knowles, C. H., Lindberg, G., Panza, E. & Giorgio, R. D. New perspectives in the diagnosis and management of enteric neuropathies. Nat. Rev. Gastroenterol. Hepatol. 10, 206–218 (2013).

    CAS  PubMed  Google Scholar 

  59. 59.

    Rao, M. & Gershon, M. D. The bowel and beyond: the enteric nervous system in neurological disorders. Nat. Rev. Gastroenterol. Hepatol. 13, 517–528 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Goldstein, A. M., Thapar, N., Karunaratne, T. B. & De Giorgio, R. Clinical aspects of neurointestinal disease: Pathophysiology, diagnosis, and treatment. Dev. Biol. 417, 217–228 (2016).

    CAS  PubMed  Google Scholar 

  61. 61.

    Gunnarsson, J. & Simren, M. Peripheral factors in the pathophysiology of irritable bowel syndrome. Dig. Liver Dis. 41, 788–793 (2009).

    CAS  PubMed  Google Scholar 

  62. 62.

    Manabe, N. et al. Lower functional gastrointestinal disorders: evidence of abnormal colonic transit in a 287 patient cohort. Neurogastroenterol. Motil. 22, 293-e82 (2010).

    PubMed  Google Scholar 

  63. 63.

    Ng, C. et al. Attenuation of the colorectal tonic reflex in female patients with irritable bowel syndrome. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G489–G494 (2005).

    CAS  PubMed  Google Scholar 

  64. 64.

    Fukudo, S. et al. Exaggerated motility of the descending colon with repetitive distention of the sigmoid colon in patients with irritable bowel syndrome. J. Gastroenterol. 37, 145–150 (2002).

    PubMed  Google Scholar 

  65. 65.

    van der Veek, P. P. et al. Recto-colonic reflex is impaired in patients with irritable bowel syndrome. Neurogastroenterol. Motil. 19, 653–659 (2007).

    PubMed  Google Scholar 

  66. 66.

    Mertz, H., Naliboff, B., Munakata, J., Niazi, N. & Mayer, E. A. Altered rectal perception is a biological marker of patients with irritable bowel syndrome. Gastroenterology 109, 40–52 (1995).

    CAS  PubMed  Google Scholar 

  67. 67.

    Hughes, P. A. et al. Sensory neuro-immune interactions differ between irritable bowel syndrome subtypes. Gut 62, 1456–1465 (2013).

    CAS  PubMed  Google Scholar 

  68. 68.

    Gershon, M. D. Nerves, reflexes, and the enteric nervous system: pathogenesis of the irritable bowel syndrome. J. Clin. Gastroenterol. 39, S184–S193 (2005).

    PubMed  Google Scholar 

  69. 69.

    Scanzi, J. et al. Colonic overexpression of the T-type calcium channel Cav 3.2 in a mouse model of visceral hypersensitivity and in irritable bowel syndrome patients. Neurogastroenterol. Motil. 28, 1632–1640 (2016).

    CAS  PubMed  Google Scholar 

  70. 70.

    Akbar, A. et al. Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain. Gut 57, 923–929 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    van Wanrooij, S. J. et al. Sensitivity testing in irritable bowel syndrome with rectal capsaicin stimulations: role of TRPV1 upregulation and sensitization in visceral hypersensitivity? Am. J. Gastroenterol. 109, 99–109 (2014).

    PubMed  Google Scholar 

  72. 72.

    Palsson, O. S. et al. Elevated vasoactive intestinal peptide concentrations in patients with irritable bowel syndrome. Dig. Dis. Sci. 49, 1236–1243 (2004).

    CAS  PubMed  Google Scholar 

  73. 73.

    Dothel, G. et al. Nerve fiber outgrowth is increased in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology 148, 1002–1011 (2015).

    CAS  Google Scholar 

  74. 74.

    Xu, X. J., Zhang, Y. L., Liu, L., Pan, L. & Yao, S. K. Increased expression of nerve growth factor correlates with visceral hypersensitivity and impaired gut barrier function in diarrhoea-predominant irritable bowel syndrome: a preliminary explorative study. Aliment. Pharmacol. Ther. 45, 100–114 (2017).

    CAS  PubMed  Google Scholar 

  75. 75.

    Tornblom, H. et al. Autoantibodies in patients with gut motility disorders and enteric neuropathy. Scand. J. Gastroenterol. 42, 1289–1293 (2007).

    PubMed  Google Scholar 

  76. 76.

    Buhner, S. et al. Activation of human enteric neurons by supernatants of colonic biopsy specimens from patients with irritable bowel syndrome. Gastroenterology 137, 1425–1434 (2009).

    CAS  PubMed  Google Scholar 

  77. 77.

    Buhner, S. et al. Neuronal activation by mucosal biopsy supernatants from irritable bowel syndrome patients is linked to visceral sensitivity. Exp. Physiol. 99, 1299–1311 (2014).

    PubMed  Google Scholar 

  78. 78.

    Farthing, M. J. & Lennard-jones, J. E. Sensibility of the rectum to distension and the anorectal distension reflex in ulcerative colitis. Gut 19, 64–69 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Kern, F. Jr., Almy, T. P., Abbot, F. K. & Bogdonoff, M. D. The motility of the distal colon in nonspecific ulcerative colitis. Gastroenterology 19, 492–503 (1951).

    PubMed  Google Scholar 

  80. 80.

    Reddy, S. N. et al. Colonic motility and transit in health and ulcerative colitis. Gastroenterology 101, 1289–1297 (1991).

    CAS  PubMed  Google Scholar 

  81. 81.

    Geboes, K. & Collins, S. Structural abnormalities of the nervous system in Crohn’s disease and ulcerative colitis. Neurogastroenterol. Motil. 10, 189–202 (1998).

    CAS  PubMed  Google Scholar 

  82. 82.

    Villanacci, V. et al. Enteric nervous system abnormalities in inflammatory bowel diseases. Neurogastroenterol. Motil. 20, 1009–1016 (2008).

    CAS  PubMed  Google Scholar 

  83. 83.

    Akbar, A. et al. Expression of the TRPV1 receptor differs in quiescent inflammatory bowel disease with or without abdominal pain. Gut 59, 767–774 (2010).

    PubMed  Google Scholar 

  84. 84.

    Brierley, S. M. & Linden, D. R. Neuroplasticity and dysfunction after gastrointestinal inflammation. Nat. Rev. Gastroenterol. Hepatol. 11, 611–627 (2014).

    PubMed  Google Scholar 

  85. 85.

    Tilghman, J. M. et al. Molecular genetic anatomy and risk profile of Hirschsprung’s disease. N. Engl. J. Med. 380, 1421–1432 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Tang, C. S. et al. Identification of genes associated with Hirschsprung disease, based on whole-genome sequence analysis, and potential effects on enteric nervous system development. Gastroenterology 155, 1908–1922 (2018).

    CAS  PubMed  Google Scholar 

  87. 87.

    Luzon-Toro, B. et al. Exome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease. Sci. Rep. 5, 16473 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Gui, H. et al. Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes. Genome Biol. 18, 48 (2017).

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Sergi, C. M., Caluseriu, O., McColl, H. & Eisenstat, D. D. Hirschsprung’s disease: clinical dysmorphology, genes, micro-RNAs, and future perspectives. Pediatr. Res. 81, 177–191 (2017).

    PubMed  Google Scholar 

  90. 90.

    Fernández, R. M. et al. Pathways systematically associated to Hirschsprung’s disease. Orphanet J. Rare Dis. 8, 187 (2013).

    PubMed  PubMed Central  Google Scholar 

  91. 91.

    Yang, D. et al. Effects of RET, NRG1 and NRG3 polymorphisms in a Chinese population with Hirschsprung disease. Sci. Rep. 7, 43222 (2017).

    PubMed  PubMed Central  Google Scholar 

  92. 92.

    Amiel, J. et al. Hirschsprung disease, associated syndromes and genetics: a review. J. Med. Genet. 45, 1–14 (2008).

    CAS  PubMed  Google Scholar 

  93. 93.

    Serra, A. et al. Analysis of RET, ZEB2, EDN3 and GDNF genomic rearrangements in 80 patients with Hirschsprung disease (using multiplex ligation-dependent probe amplification). Ann. Hum. Genet. 73, 147–151 (2009).

    CAS  PubMed  Google Scholar 

  94. 94.

    Bahrami, A. et al. Genetic background of hirschsprung disease: a bridge between basic science and clinical application. J. Cell. Biochem. 119, 28–33 (2018).

    CAS  PubMed  Google Scholar 

  95. 95.

    Brosens, E. et al. Genetics of enteric neuropathies. Dev. Biol. 417, 198–208 (2016).

    CAS  PubMed  Google Scholar 

  96. 96.

    Schill, E. M. et al. Ibuprofen slows migration and inhibits bowel colonization by enteric nervous system precursors in zebrafish, chick and mouse. Dev. Biol. 409, 473–488 (2016).

    CAS  PubMed  Google Scholar 

  97. 97.

    Nielsen, S. W., Ljungdalh, P. M., Nielsen, J., Nørgård, B. M. & Qvist, N. Maternal use of selective serotonin reuptake inhibitors during pregnancy is associated with Hirschsprung’s disease in newborns – a nationwide cohort study. Orphanet J. Rare Dis. 12, 116 (2017).

    PubMed  PubMed Central  Google Scholar 

  98. 98.

    Fu, M. et al. Vitamin A facilitates enteric nervous system precursor migration by reducing Pten accumulation. Development 137, 631–640 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Torroglosa, A. et al. Epigenetic mechanisms in Hirschsprung disease. Int. J. Mol. Sci. 20, 3123 (2019).

    CAS  PubMed Central  Google Scholar 

  100. 100.

    Gockel, H. R. et al. Etiopathological aspects of achalasia: lessons learned with Hirschsprung’s disease. Dis. Esophagus 25, 566–572 (2012).

    CAS  PubMed  Google Scholar 

  101. 101.

    Koehler, K. et al. Mutations in GMPPA cause a glycosylation disorder characterized by intellectual disability and autonomic dysfunction. Am. J. Hum. Genet. 93, 727–734 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Tullio-Pelet, A. et al. Mutant WD-repeat protein in triple-A syndrome. Nat. Genet. 26, 332–335 (2000).

    CAS  PubMed  Google Scholar 

  103. 103.

    Wallace, S. et al. Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension. Clin. Genet. 90, 351–360 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Shteyer, E. et al. Truncating mutation in the nitric oxide synthase 1 gene is associated with infantile achalasia. Gastroenterology 148, 533–536 e534 (2015).

    CAS  PubMed  Google Scholar 

  105. 105.

    Sivarao, D. V., Mashimo, H. L., Thatte, H. S. & Goyal, R. K. Lower esophageal sphincter is achalasic in nNOS-/- and hypotensive in W/W(v) mutant mice. Gastroenterology 121, 34–42 (2001).

    CAS  PubMed  Google Scholar 

  106. 106.

    Gockel, I. et al. Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia. Nat. Genet. 46, 901–904 (2014).

    CAS  PubMed  Google Scholar 

  107. 107.

    Fröhlich, H. et al. Gastrointestinal dysfunction in autism: altered motility and achalasia in Foxp1+/- mice. Proc. Natl Acad. Sci. USA 116, 22237–22245 (2019).

    PubMed  Google Scholar 

  108. 108.

    Gazouli, M. et al. Lessons learned – resolving the enigma of genetic factors in IBS. Nat. Rev. Gastroenterol. Hepatol. 13, 77–87 (2016).

    CAS  PubMed  Google Scholar 

  109. 109.

    Mohr, S. et al. A functional variant in the alternative serotonin transporter gene SLC6A4 promoter P2 has a potential impact on irritable bowel syndrome. Neurogastroenterol. Motil. 28, 14 (2016).

    Google Scholar 

  110. 110.

    Niesler, B. et al. The Serotonin receptor 3E subunit variant HTR3E c.*76G> A is confirmed as a risk factor for IBS-D in females. Neurogastroenterol. Motil. 30, Abstract 031 (2018).

  111. 111.

    Henstrom, M. et al. Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome. Gut 67, 263–270 (2018).

    PubMed  Google Scholar 

  112. 112.

    Henstrom, M. et al. TRPM8 polymorphisms associated with increased risk of IBS-C and IBS-M. Gut 66, 1725–1727 (2017).

    PubMed  Google Scholar 

  113. 113.

    Wohlfarth, C. et al. miR-16 and miR-103 impact 5-HT4 receptor signalling and correlate with symptom profile in irritable bowel syndrome. Sci. Rep. 7, 14680 (2017).

    PubMed  PubMed Central  Google Scholar 

  114. 114.

    Bonfiglio, F. et al. Female-specific association between variants on chromosome 9 and self-reported diagnosis of irritable bowel syndrome. Gastroenterology 155, 168–179 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Ek, W. E. et al. Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts. Gut 64, 1774–1782 (2015).

    CAS  PubMed  Google Scholar 

  116. 116.

    Holliday, E. G. et al. Genome-wide association study identifies two novel genomic regions in irritable bowel syndrome. Am. J. Gastroenterol. 109, 770–772 (2014).

    CAS  PubMed  Google Scholar 

  117. 117.

    Bonfiglio, F. et al. A GWAS meta-analysis from 5 population-based cohorts implicates ion channel genes in the pathogenesis of irritable bowel syndrome. Neurogastroenterol. Motil. 30, e13358 (2018).

    CAS  PubMed  Google Scholar 

  118. 118.

    Annese, V. Genetics and epigenetics of IBD. Pharmacol. Res. 159, 104892 (2020).

    CAS  PubMed  Google Scholar 

  119. 119.

    Lake, J. I. & Heuckeroth, R. O. Enteric nervous system development: migration, differentiation, and disease. Am. J. Physiol. Gastrointest. Liver Physiol. 305, G1–G24 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Niesler, B. & Rappold, G. A. Emerging evidence for gene mutations driving both brain and gut dysfunction in autism spectrum disorder. Mol. Psychiatry https://doi.org/10.1038/s41380-020-0778-5 (2020).

  121. 121.

    Bernier, R. et al. Disruptive CHD8 mutations define a subtype of autism early in development. Cell 158, 263–276 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Sweetser, D. A. et al. In GeneReviews (eds. Adam, M. P. et al.) (University of Washington, 1993).

  123. 123.

    Sweatt, J. D. Pitt-Hopkins syndrome: intellectual disability due to loss of TCF4-regulated gene transcription. Exp. Mol. Med. 45, e21 (2013).

    PubMed  PubMed Central  Google Scholar 

  124. 124.

    Veenstra-VanderWeele, J. et al. Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior. Proc. Natl Acad. Sci. USA 109, 5469–5474 (2012).

    CAS  PubMed  Google Scholar 

  125. 125.

    Margolis, K. G. et al. Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function. J. Clin. Invest. 126, 2221–2235 (2016).

    PubMed  PubMed Central  Google Scholar 

  126. 126.

    James, D. M. et al. Intestinal dysmotility in a zebrafish (Danio rerio) shank3a;shank3b mutant model of autism. Mol. Autism 10, 3 (2019).

    PubMed  PubMed Central  Google Scholar 

  127. 127.

    Hosie, S. et al. Gastrointestinal dysfunction in patients and mice expressing the autism-associated R451C mutation in neuroligin-3. Autism Res. 12, 1043–1056 (2019).

    PubMed  PubMed Central  Google Scholar 

  128. 128.

    Hofer, D., Asan, E. & Drenckhahn, D. Chemosensory perception in the gut. N. Physiol. Sci. 14, 18–23 (1999).

    CAS  Google Scholar 

  129. 129.

    Kaelberer, M. M. et al. A gut-brain neural circuit for nutrient sensory transduction. Science 361, eaat5236 (2018).

    PubMed  PubMed Central  Google Scholar 

  130. 130.

    Bohorquez, D. V. & Liddle, R. A. The gut connectome: making sense of what you eat. J. Clin. Invest. 125, 888–890 (2015).

    PubMed  PubMed Central  Google Scholar 

  131. 131.

    Caputi, V. et al. Antibiotic-induced dysbiosis of the microbiota impairs gut neuromuscular function in juvenile mice. Br. J. Pharmacol. 174, 3623–3639 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Collins, J., Borojevic, R., Verdu, E. F., Huizinga, J. D. & Ratcliffe, E. M. Intestinal microbiota influence the early postnatal development of the enteric nervous system. Neurogastroenterol. Motil. 26, 98–107 (2014).

    CAS  PubMed  Google Scholar 

  133. 133.

    Rolig, A. S. et al. The enteric nervous system promotes intestinal health by constraining microbiota composition. PLoS Biol. 15, e2000689 (2017).

    PubMed  PubMed Central  Google Scholar 

  134. 134.

    Toure, A. M., Landry, M., Souchkova, O., Kembel, S. W. & Pilon, N. Gut microbiota-mediated Gene-Environment interaction in the TashT mouse model of Hirschsprung disease. Sci. Rep. 9, 492 (2019).

    PubMed  PubMed Central  Google Scholar 

  135. 135.

    Yano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264–276 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Li, Y. et al. Characterization of intestinal microbiomes of Hirschsprung’s disease patients with or without enterocolitis using Illumina-miSeq high-throughput sequencing. PLoS ONE 11, e0162079 (2016).

    PubMed  PubMed Central  Google Scholar 

  137. 137.

    Gosain, A. & Brinkman, A. S. Hirschsprung’s associated enterocolitis. Curr. Opin. Pediatr. 27, 364–369 (2015).

    PubMed  PubMed Central  Google Scholar 

  138. 138.

    Frykman, P. K. et al. Characterization of bacterial and fungal microbiome in children with Hirschsprung disease with and without a history of enterocolitis: a multicenter study. PLoS ONE 10, e0124172 (2015).

    PubMed  PubMed Central  Google Scholar 

  139. 139.

    Srikantha, P. & Mohajeri, M. H. The possible role of the microbiota-gut-brain-axis in autism spectrum disorder. Int. J. Mol. Sci. 20, 2115 (2019).

    CAS  PubMed Central  Google Scholar 

  140. 140.

    Liu, F. et al. Altered composition and function of intestinal microbiota in autism spectrum disorders: a systematic review. Transl Psychiatry 9, 43 (2019).

    PubMed  PubMed Central  Google Scholar 

  141. 141.

    Genedi, M., Janmaat, I. E., Haarman, B. & Sommer, I. E. C. Dysregulation of the gut-brain axis in schizophrenia and bipolar disorder: probiotic supplementation as a supportive treatment in psychiatric disorders. Curr. Opin. Psychiatry 32, 185–195 (2019).

    PubMed  Google Scholar 

  142. 142.

    Endres, K. & Schafer, K. H. Influence of commensal microbiota on the enteric nervous system and its role in neurodegenerative diseases. J. Innate Immun. 10, 172–180 (2018).

    PubMed  PubMed Central  Google Scholar 

  143. 143.

    Unger, M. M. et al. Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism Relat. Disord. 32, 66–72 (2016).

    PubMed  Google Scholar 

  144. 144.

    Hirschberg, S., Gisevius, B., Duscha, A. & Haghikia, A. Implications of diet and the gut microbiome in neuroinflammatory and neurodegenerative diseases. Int. J. Mol. Sci. 20, 3109 (2019).

    CAS  PubMed Central  Google Scholar 

  145. 145.

    Cirstea, M. S. et al. Microbiota composition and metabolism are associated with gut function in Parkinson’s disease. Mov. Disord. 35, 1208–1217 (2020).

    CAS  PubMed  Google Scholar 

  146. 146.

    Haschke, G., Schafer, H. & Diener, M. Effect of butyrate on membrane potential, ionic currents and intracellular Ca2+ concentration in cultured rat myenteric neurones. Neurogastroenterol. Motil. 14, 133–142 (2002).

    CAS  PubMed  Google Scholar 

  147. 147.

    Soret, R. et al. Short-chain fatty acids regulate the enteric neurons and control gastrointestinal motility in rats. Gastroenterology 138, 1772–1782 (2010).

    CAS  PubMed  Google Scholar 

  148. 148.

    Cossais, F. et al. Postnatal development of the myenteric glial network and its modulation by butyrate. Am. J. Physiol. Gastrointest. Liver Physiol. 310, G941–G951 (2016).

    PubMed  Google Scholar 

  149. 149.

    Beumer, J. & Clevers, H. How the gut feels, smells, and talks. Cell 170, 10–11 (2017).

    CAS  PubMed  Google Scholar 

  150. 150.

    Wood, J. D. Effects of bacteria on the enteric nervous system: implications for the irritable bowel syndrome. J. Clin. Gastroenterol. 41 (Suppl. 1), S7–S19 (2007).

    PubMed  Google Scholar 

  151. 151.

    Stefanis, L. Synuclein in Parkinson’s disease. Cold Spring Harb. Perspect. Med. 2, a009399 (2012).

    PubMed  PubMed Central  Google Scholar 

  152. 152.

    Chen, S. G. et al. Exposure to the functional bacterial amyloid protein curli enhances alpha-synuclein aggregation in aged Fischer 344 rats and Caenorhabditis elegans. Sci. Rep. 6, 34477 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Mou, L., Ding, W. & Fernandez-Funez, P. Open questions on the nature of Parkinson’s disease: from triggers to spreading pathology. J. Med. Genet. 57, 73–81 (2020).

    CAS  PubMed  Google Scholar 

  154. 154.

    Sampson, T. R. et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469–1480 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    Gershon, M. & Gershon, A. Varicella-zoster virus and the enteric nervous system. J. Infect. Dis. 218, S113–S119 (2018).

    PubMed  PubMed Central  Google Scholar 

  156. 156.

    Holland-Cunz, S. et al. Acquired intestinal aganglionosis after a lytic infection with varicella-zoster virus. J. Pediatr. Surg. 41, e29–e31 (2006).

    PubMed  Google Scholar 

  157. 157.

    Pui, J. C., Furth, E. E., Minda, J. & Montone, K. T. Demonstration of varicella-zoster virus infection in the muscularis propria and myenteric plexi of the colon in an HIV-positive patient with herpes zoster and small bowel pseudo-obstruction (Ogilvie’s syndrome). Am. J. Gastroenterol. 96, 1627–1630 (2001).

    CAS  PubMed  Google Scholar 

  158. 158.

    de Oliveira, J. A. et al. 5-HT3A serotonin receptor in the gastrointestinal tract: the link between immune system and enteric nervous system in the digestive form of Chagas disease. Parasitol. Res. 118, 1325–1329 (2019).

    PubMed  Google Scholar 

  159. 159.

    Trevizan, A. R. et al. Acute Toxoplasma gondii infection alters the number of neurons and the proportion of enteric glial cells in the duodenum in Wistar rats. Neurogastroenterol. Motil. 31, e13523 (2019).

    PubMed  Google Scholar 

  160. 160.

    Maizels, R. M. Regulation of immunity and allergy by helminth parasites. Allergy 75, 524–534 (2020).

    PubMed  Google Scholar 

  161. 161.

    Gutin, L. et al. Fecal microbiota transplant for Crohn disease: a study evaluating safety, efficacy, and microbiome profile. United Eur. Gastroenterol. J. 7, 807–814 (2019).

    Google Scholar 

  162. 162.

    Abdoli, A. Therapeutic potential of helminths and helminth-derived antigens for resolution of inflammation in inflammatory bowel disease. Arch. Med. Res. 50, 58–59 (2019).

    CAS  PubMed  Google Scholar 

  163. 163.

    Aryal, B. & Lee, Y. Disease model organism for Parkinson disease: Drosophila melanogaster. BMB Rep. 52, 250–258 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Betarbet, R. et al. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat. Neurosci. 3, 1301–1306 (2000).

    CAS  PubMed  Google Scholar 

  165. 165.

    Cirilo, C. P. et al. Dietary restriction interferes with oxidative status and intrinsic intestinal innervation in aging rats. Nutrition 29, 673–680 (2013).

    CAS  PubMed  Google Scholar 

  166. 166.

    Cowen, T., Johnson, R. J., Soubeyre, V. & Santer, R. M. Restricted diet rescues rat enteric motor neurones from age related cell death. Gut 47, 653–660 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Evangelakou, Z., Manola, M., Gumeni, S. & Trougakos, I. P. Nutrigenomics as a tool to study the impact of diet on aging and age-related diseases: the Drosophila approach. Genes Nutr. 14, 12 (2019).

    PubMed  PubMed Central  Google Scholar 

  168. 168.

    Scalabrino, G. Vitamin-regulated cytokines and growth factors in the CNS and elsewhere. J. Neurochem. 111, 1309–1326 (2009).

    CAS  PubMed  Google Scholar 

  169. 169.

    Voss, U., Sand, E., Olde, B. & Ekblad, E. Enteric neuropathy can be induced by high fat diet in vivo and palmitic acid exposure in vitro. PLoS ONE 8, e81413 (2013).

    PubMed  PubMed Central  Google Scholar 

  170. 170.

    Nezami, B. G. et al. MicroRNA 375 mediates palmitate-induced enteric neuronal damage and high-fat diet-induced delayed intestinal transit in mice. Gastroenterology 146, 473–483 (2014).

    CAS  PubMed  Google Scholar 

  171. 171.

    Rusek, M., Pluta, R., Ulamek-Koziol, M. & Czuczwar, S. J. Ketogenic diet in Alzheimer’s disease. Int. J. Mol. Sci. 20, 3892 (2019).

    CAS  PubMed Central  Google Scholar 

  172. 172.

    Larsson, S. & Voss, U. Neuroprotective effects of vitamin D on high fat diet- and palmitic acid-induced enteric neuronal loss in mice. BMC Gastroenterol. 18, 175 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Kabouridis, P. S. et al. Microbiota controls the homeostasis of glial cells in the gut lamina propria. Neuron 85, 289–295 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Panpetch, W. et al. Lactobacillus rhamnosus L34 attenuates gut translocation-induced bacterial sepsis in murine models of leaky gut. Infect. Immun. 86, e00700–17 (2017).

    PubMed  PubMed Central  Google Scholar 

  175. 175.

    Broad, J. et al. Changes in neuromuscular structure and functions of human colon during ageing are region-dependent. Gut 68, 1210–1223 (2019).

    CAS  PubMed  Google Scholar 

  176. 176.

    Ranson, R. N. & Saffrey, M. J. Neurogenic mechanisms in bladder and bowel ageing. Biogerontology 16, 265–284 (2015).

    PubMed  PubMed Central  Google Scholar 

  177. 177.

    Hetz, S. et al. Age-related gene expression analysis in enteric ganglia of human colon after laser microdissection. Front. Aging Neurosci. 6, 276 (2014).

    PubMed  PubMed Central  Google Scholar 

  178. 178.

    Phillips, R. J., Kieffer, E. J. & Powley, T. L. Aging of the myenteric plexus: neuronal loss is specific to cholinergic neurons. Auton. Neurosci. 106, 69–83 (2003).

    PubMed  Google Scholar 

  179. 179.

    Cheng, X. et al. Galectin-3 causes enteric neuronal loss in mice after left sided permanent middle cerebral artery occlusion, a model of stroke. Sci. Rep. 6, 32893 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180.

    Stanley, D. et al. Translocation and dissemination of commensal bacteria in post-stroke infection. Nat. Med. 22, 1277–1284 (2016).

    CAS  PubMed  Google Scholar 

  181. 181.

    Stephenson, J., Nutma, E., van der Valk, P. & Amor, S. Inflammation in CNS neurodegenerative diseases. Immunology 154, 204–219 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    Prasad, A., Bharathi, V., Sivalingam, V., Girdhar, A. & Patel, B. K. Molecular mechanisms of TDP-43 misfolding and pathology in amyotrophic lateral sclerosis. Front. Mol. Neurosci. 12, 25 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183.

    Natale, G., Pasquali, L., Paparelli, A. & Fornai, F. Parallel manifestations of neuropathologies in the enteric and central nervous systems. Neurogastroenterol. Motil. 23, 1056–1065 (2011).

    CAS  PubMed  Google Scholar 

  184. 184.

    Herdewyn, S. et al. Prevention of intestinal obstruction reveals progressive neurodegeneration in mutant TDP-43 (A315T) mice. Mol. Neurodegener. 9, 24 (2014).

    PubMed  PubMed Central  Google Scholar 

  185. 185.

    Pokrishevsky, E., Grad, L. I. & Cashman, N. R. TDP-43 or FUS-induced misfolded human wild-type SOD1 can propagate intercellularly in a prion-like fashion. Sci. Rep. 6, 22155 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186.

    Shindo, K. et al. Chronological changes of sympathetic outflow to muscles in amyotrophic lateral sclerosis. J. Neurol. Sci. 227, 79–84 (2004).

    PubMed  Google Scholar 

  187. 187.

    Wingate, D. Gastrointestinal dysfunction in ALS. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 1, 2 (1999).

    CAS  PubMed  Google Scholar 

  188. 188.

    Toepfer, M. et al. Gastrointestinal dysfunction in amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 1, 15–19 (1999).

    CAS  PubMed  Google Scholar 

  189. 189.

    Jiang, C., Li, G., Huang, P., Liu, Z. & Zhao, B. The gut microbiota and Alzheimer’s disease. J. Alzheimers Dis. 58, 1–15 (2017).

    PubMed  Google Scholar 

  190. 190.

    Nourhashemi, F. et al. Body mass index and incidence of dementia: the PAQUID study. Neurology 60, 117–119 (2003).

    CAS  PubMed  Google Scholar 

  191. 191.

    Murphy, M. P. & LeVine, H. 3rd Alzheimer’s disease and the amyloid-beta peptide. J. Alzheimers Dis. 19, 311–323 (2010).

    PubMed  PubMed Central  Google Scholar 

  192. 192.

    Jouanne, M., Rault, S. & Voisin-Chiret, A. S. Tau protein aggregation in Alzheimer’s disease: an attractive target for the development of novel therapeutic agents. Eur. J. Med. Chem. 139, 153–167 (2017).

    CAS  PubMed  Google Scholar 

  193. 193.

    Agostinho, P., Cunha, R. A. & Oliveira, C. Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer’s disease. Curr. Pharm. Des. 16, 2766–2778 (2010).

    CAS  PubMed  Google Scholar 

  194. 194.

    Joachim, C. L., Mori, H. & Selkoe, D. J. Amyloid β-protein deposition in tissues other than brain in Alzheimer’s disease. Nature 341, 226–230 (1989).

    CAS  PubMed  Google Scholar 

  195. 195.

    Puig, K. L., Swigost, A. J., Zhou, X., Sens, M. A. & Combs, C. K. Amyloid precursor protein expression modulates intestine immune phenotype. J. Neuroimmune Pharmacol. 7, 215–230 (2012).

    PubMed  Google Scholar 

  196. 196.

    Chalazonitis, A. & Rao, M. Enteric nervous system manifestations of neurodegenerative disease. Brain Res. 1693, 207–213 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. 197.

    Semar, S. et al. Changes of the enteric nervous system in amyloid-beta protein precursor transgenic mice correlate with disease progression. J. Alzheimers Dis. 36, 7–20 (2013).

    CAS  PubMed  Google Scholar 

  198. 198.

    Brandscheid, C. et al. Altered gut microbiome composition and tryptic activity of the 5xFAD Alzheimer’s mouse model. J. Alzheimers Dis. 56, 775–788 (2017).

    CAS  PubMed  Google Scholar 

  199. 199.

    Mancuso, C. & Santangelo, R. Alzheimer’s disease and gut microbiota modifications: The long way between preclinical studies and clinical evidence. Pharmacol. Res. 129, 329–336 (2018).

    CAS  PubMed  Google Scholar 

  200. 200.

    Jain, N. & Chapman, M. R. Bacterial functional amyloids: order from disorder. Biochim. Biophys. Acta Proteins Proteom. 1867, 954–960 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. 201.

    Dugger, B. N. et al. The presence of select tau species in human peripheral tissues and their relation to Alzheimer’s disease. J. Alzheimers Dis. 54, 1249 (2016).

    PubMed  Google Scholar 

  202. 202.

    Lionnet, A. et al. Characterisation of tau in the human and rodent enteric nervous system under physiological conditions and in tauopathy. Acta Neuropathol. Commun. 6, 65 (2018).

    PubMed  PubMed Central  Google Scholar 

  203. 203.

    Dugger, B. N. et al. Tau immunoreactivity in peripheral tissues of human aging and select tauopathies. Neurosci. Lett. 696, 132–139 (2019).

    CAS  PubMed  Google Scholar 

  204. 204.

    Malek, N. & Newman, E. J. Hereditary chorea - what else to consider when the Huntington’s disease genetics test is negative? Acta Neurol. Scand. 135, 25–33 (2017).

    CAS  PubMed  Google Scholar 

  205. 205.

    Saffert, P., Adamla, F., Schieweck, R., Atkins, J. F. & Ignatova, Z. An expanded CAG repeat in Huntingtin causes +1 frameshifting. J. Biol. Chem. 291, 18505–18513 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. 206.

    Aziz, N. A. et al. Weight loss in Huntington disease increases with higher CAG repeat number. Neurology 71, 1506–1513 (2008).

    CAS  PubMed  Google Scholar 

  207. 207.

    Djousse, L. et al. Weight loss in early stage of Huntington’s disease. Neurology 59, 1325–1330 (2002).

    CAS  PubMed  Google Scholar 

  208. 208.

    Lanska, D. J., Lanska, M. J., Lavine, L. & Schoenberg, B. S. Conditions associated with Huntington’s disease at death. A case-control study. Arch. Neurol. 45, 878–880 (1988).

    CAS  PubMed  Google Scholar 

  209. 209.

    Moffitt, H., McPhail, G. D., Woodman, B., Hobbs, C. & Bates, G. P. Formation of polyglutamine inclusions in a wide range of non-CNS tissues in the HdhQ150 knock-in mouse model of Huntington’s disease. PLoS ONE 4, e8025 (2009).

    PubMed  PubMed Central  Google Scholar 

  210. 210.

    McCourt, A. C. et al. Characterization of gastric mucosa biopsies reveals alterations in Huntington’s disease. PLoS Curr. https://doi.org/10.1371/currents.hd.858b4cc7f235df068387e9c20c436a79 (2015).

  211. 211.

    Haschka, D. et al. Expansion of neutrophils and classical and nonclassical monocytes as a hallmark in relapsing-remitting multiple sclerosis. Front. Immunol. 11, 594 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. 212.

    Frohlich, K. et al. Brain MRI lesions are related to bowel incontinence in multiple sclerosis. J. Neuroimaging 29, 211–217 (2019).

    PubMed  Google Scholar 

  213. 213.

    Tornic, J. & Panicker, J. N. The management of lower urinary tract dysfunction in multiple sclerosis. Curr. Neurol. Neurosci. Rep. 18, 54 (2018).

    PubMed  PubMed Central  Google Scholar 

  214. 214.

    Valencia-Sanchez, C., Goodman, B. P., Carter, J. L. & Wingerchuk, D. M. The spectrum of acute cardiopulmonary events associated with multiple sclerosis exacerbations. Mult. Scler. 25, 758–765 (2019).

    PubMed  Google Scholar 

  215. 215.

    Chu, F. et al. Gut microbiota in multiple sclerosis and experimental autoimmune encephalomyelitis: current applications and future perspectives. Mediators Inflamm. 2018, 8168717 (2018).

    PubMed  PubMed Central  Google Scholar 

  216. 216.

    Berer, K. et al. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proc. Natl Acad. Sci. USA 114, 10719–10724 (2017).

    CAS  PubMed  Google Scholar 

  217. 217.

    Berer, K. et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538–541 (2011).

    CAS  PubMed  Google Scholar 

  218. 218.

    Spear, E. T. et al. Altered gastrointestinal motility involving autoantibodies in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Neurogastroenterol. Motil. 30, e13349 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. 219.

    Wunsch, M. et al. The enteric nervous system is a potential autoimmune target in multiple sclerosis. Acta Neuropathol. 134, 281–295 (2017).

    CAS  PubMed  Google Scholar 

  220. 220.

    Esposito, S., Bonavita, S., Sparaco, M., Gallo, A. & Tedeschi, G. The role of diet in multiple sclerosis: a review. Nutr. Neurosci. 21, 377–390 (2018).

    CAS  PubMed  Google Scholar 

  221. 221.

    Parkinson, J. An essay on the shaking palsy. 1817. J. Neuropsychiatry Clin. Neurosci. 14, 223–236 (2002).

    PubMed  Google Scholar 

  222. 222.

    Pfeiffer, F. R. Gastrointestinal dysfunction in Parkinson’s disease. Curr. Treat. Options Neurol. 20, 54 (2018).

    PubMed  Google Scholar 

  223. 223.

    Qualman, S. J., Haupt, H. M., Yang, P. & Hamilton, S. R. Esophageal Lewy bodies associated with ganglion cell loss in achalasia. Similarity to Parkinson’s disease. Gastroenterology 87, 848–856 (1984).

    CAS  PubMed  Google Scholar 

  224. 224.

    Kupsky, W. J., Grimes, M. M., Sweeting, J., Bertsch, R. & Cote, L. J. Parkinson’s disease and megacolon: concentric hyaline inclusions (Lewy bodies) in enteric ganglion cells. Neurology 37, 1253–1255 (1987).

    CAS  PubMed  Google Scholar 

  225. 225.

    Wakabayashi, K., Takahashi, H., Ohama, E. & Ikuta, F. Parkinson’s disease: an immunohistochemical study of Lewy body-containing neurons in the enteric nervous system. Acta Neuropathol. 79, 581–583 (1990).

    CAS  PubMed  Google Scholar 

  226. 226.

    Braak, H., de Vos, R. A. I., Bohl, J. & Del Tredici, K. 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 (2006).

    CAS  PubMed  Google Scholar 

  227. 227.

    Abbott, R. D. et al. Frequency of bowl movements and the future risk of Parkinson’s disease. Neurology 57, 456–623 (2001).

    CAS  PubMed  Google Scholar 

  228. 228.

    Ueki, A. & Otsuka, M. Life style risks of Parkinson’s disease: association between decreased water intake and constipation. J. Neurol. 251 (Suppl. 7), vII18–23 (2004).

    Google Scholar 

  229. 229.

    Svensson, E. et al. Vagotomy and subsequent risk of Parkinson’s disease. Ann. Neurol. 78, 522–529 (2015).

    PubMed  Google Scholar 

  230. 230.

    Tysnes, O. B. et al. Does vagotomy reduce the risk of Parkinson’s disease? Ann. Neurol. 78, 1011–1012 (2015).

    PubMed  Google Scholar 

  231. 231.

    Liu, B. et al. Vagotomy and Parkinson disease: a Swedish register-based matched-cohort study. Neurology 88, 1996–2002 (2017).

    PubMed  PubMed Central  Google Scholar 

  232. 232.

    Lionett, A. et al. Does Parkinson’s disease start in the gut? Acta Neuropathol. 135, 1–12 (2018).

    Google Scholar 

  233. 233.

    Borghammer, P. How does Parkinson’s disease begin? Perspectives on neuroanatomical pathways, prions and histology. Mov. Disord. 33, 48–57 (2018).

    PubMed  Google Scholar 

  234. 234.

    Kim, S. et al. Transneuronal propagation of pathologic alpha-synuclein from the gut to the brain models Parkinson’s disease. Neuron 103, 627–641 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. 235.

    Killinger, B. A. et al. The vermiform appendix impacts the risk of developing Parkinson’s disease. Sci. Transl Med. 10, eaar5280 (2018).

    PubMed  PubMed Central  Google Scholar 

  236. 236.

    Zauszkiewicz-Pawlak, A., Godlewski, J., Kwiatkowski, P. & Kmiec, Z. Ultrastructural characteristics of myenteric plexus in patients with colorectal cancer. Folia Histochem. Cytobiol. 55, 6–10 (2017).

    CAS  PubMed  Google Scholar 

  237. 237.

    Kozlowska, A. et al. Myenteric plexuses atrophy in the vicinity of colorectal cancer tissue is not caused by apoptosis or necrosis. Folia Histochem. Cytobiol. 54, 99–107 (2016).

    CAS  PubMed  Google Scholar 

  238. 238.

    Godlewski, J. Morphological changes in the enteric nervous system caused by carcinoma of the human large intestine. Folia Histochem. Cytobiol. 48, 157–162 (2010).

    PubMed  Google Scholar 

  239. 239.

    Godlewski, J. & Lakomy, I. M. Changes in vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide and neuropeptide Y-ergic structures of the enteric nervous system in the carcinoma of the human large intestine. Folia Histochem. Cytobiol. 48, 208–216 (2010).

    PubMed  Google Scholar 

  240. 240.

    Jeppsson, S., Srinivasan, S. & Chandrasekharan, B. Neuropeptide Y (NPY) promotes inflammation-induced tumorigenesis by enhancing epithelial cell proliferation. Am. J. Physiol. Gastrointest. Liver Physiol. 312, G103–G111 (2017).

    PubMed  Google Scholar 

  241. 241.

    Ogasawara, M., Murata, J., Ayukawa, K. & Saimi, I. Differential effect of intestinal neuropeptides on invasion and migration of colon carcinoma cells in vitro. Cancer Lett. 116, 111–116 (1997).

    CAS  PubMed  Google Scholar 

  242. 242.

    Alleaume, C., Eychene, A., Caigneaux, E., Muller, J. M. & Philippe, M. Vasoactive intestinal peptide stimulates proliferation in HT29 human colonic adenocarcinoma cells: concomitant activation of Ras/Rap1-B-Raf-ERK signalling pathway. Neuropeptides 37, 98–104 (2003).

    CAS  PubMed  Google Scholar 

  243. 243.

    Dufes, C., Alleaume, C., Montoni, A., Olivier, J. C. & Muller, J. M. Effects of the vasoactive intestinal peptide (VIP) and related peptides on glioblastoma cell growth in vitro. J. Mol. Neurosci. 21, 91–102 (2003).

    CAS  PubMed  Google Scholar 

  244. 244.

    Schonhuber, N. et al. A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer. Nat. Med. 20, 1340–1347 (2014).

    PubMed  PubMed Central  Google Scholar 

  245. 245.

    Duchalais, E. et al. Colorectal Cancer Cells Adhere to and Migrate Along the Neurons of the Enteric Nervous System. Cell Mol. Gastroenterol. Hepatol. 5, 31–49 (2018).

    PubMed  Google Scholar 

  246. 246.

    Ceyhan, G. O. et al. Neural invasion in pancreatic cancer: a mutual tropism between neurons and cancer cells. Biochem. Biophys. Res. Commun. 374, 442–447 (2008).

    CAS  PubMed  Google Scholar 

  247. 247.

    Deborde, S. et al. Schwann cells induce cancer cell dispersion and invasion. J. Clin. Invest. 126, 1538–1554 (2016).

    PubMed  PubMed Central  Google Scholar 

  248. 248.

    Demir, I. E. et al. The microenvironment in chronic pancreatitis and pancreatic cancer induces neuronal plasticity. Neurogastroenterol. Motil. 22, 480–490 (2010).

    CAS  PubMed  Google Scholar 

  249. 249.

    Albo, D. et al. Neurogenesis in colorectal cancer is a marker of aggressive tumor behavior and poor outcomes. Cancer 117, 4834–4845 (2011).

    CAS  PubMed  Google Scholar 

  250. 250.

    Liebl, F. et al. The impact of neural invasion severity in gastrointestinal malignancies: a clinicopathological study. Ann. Surg. 260, 900–907 (2014).

    PubMed  Google Scholar 

  251. 251.

    Schorn, S. et al. The influence of neural invasion on survival and tumor recurrence in pancreatic ductal adenocarcinoma-a systematic review and meta-analysis. Surg. Oncol. 26, 105–115 (2017).

    PubMed  Google Scholar 

  252. 252.

    Hayakawa, Y. et al. Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling. Cancer Cell 31, 21–34 (2017).

    CAS  PubMed  Google Scholar 

  253. 253.

    Renz, B. W. et al. 2 adrenergic-neurotrophin feedforward loop promotes pancreatic cancer. Cancer Cell 33, 75–90 (2018).

    CAS  PubMed  Google Scholar 

  254. 254.

    Partecke, L. I. et al. Subdiaphragmatic vagotomy promotes tumor growth and reduces survival via TNFalpha in a murine pancreatic cancer model. Oncotarget 8, 22501–22512 (2017).

    PubMed  PubMed Central  Google Scholar 

  255. 255.

    Renz, B. W. et al. Cholinergic signaling via muscarinic receptors directly and indirectly suppresses pancreatic tumorigenesis and cancer stemness. Cancer Discov. 8, 1458–1473 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. 256.

    Demir, I. E. et al. Investigation of Schwann cells at neoplastic cell sites before the onset of cancer invasion. J. Natl. Cancer Inst. 106, dju184 (2014).

    PubMed  Google Scholar 

  257. 257.

    Stopczynski, R. E. et al. Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma. Cancer Res. 74, 1718–1727 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  258. 258.

    Saloman, J. L. et al. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer. Proc. Natl Acad. Sci. USA 113, 3078–3083 (2016).

    CAS  PubMed  Google Scholar 

  259. 259.

    Demir, I. E. et al. Early pancreatic cancer lesions suppress pain through CXCL12-mediated chemoattraction of Schwann cells. Proc. Natl Acad. Sci. USA 114, E85–E94 (2017).

    CAS  PubMed  Google Scholar 

  260. 260.

    Demir, I. E. et al. Activated Schwann cells in pancreatic cancer are linked to analgesia via suppression of spinal astroglia and microglia. Gut 65, 1001–1014 (2016).

    CAS  PubMed  Google Scholar 

  261. 261.

    Schafer, K. H. et al. IgG-mediated cytotoxicity to myenteric plexus cultures in patients with paraneoplastic neurological syndromes. J. Autoimmun. 15, 479–484 (2000).

    CAS  PubMed  Google Scholar 

  262. 262.

    Stojanovska, V., Sakkal, S. & Nurgali, K. Platinum-based chemotherapy: gastrointestinal immunomodulation and enteric nervous system toxicity. Am. J. Physiol. Gastrointest. Liver Physiol. 308, G223–G232 (2015).

    CAS  PubMed  Google Scholar 

  263. 263.

    Vera, G. et al. Enteric neuropathy evoked by repeated cisplatin in the rat. Neurogastroenterol. Motil. 23, 370–378 (2011).

    CAS  PubMed  Google Scholar 

  264. 264.

    Kirchgessner, A. L., Liu, M. T. & Gershon, M. D. In situ identification and visualization of neurons that mediate enteric and enteropancreatic reflexes. J. Comp. Neurol. 371, 270–286 (1996).

    CAS  PubMed  Google Scholar 

  265. 265.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  266. 266.

    Cognigni, P., Bailey, A. P. & Miguel-Aliaga, I. Enteric neurons and systemic signals couple nutritional and reproductive status with intestinal homeostasis. Cell Metab. 13, 92–104 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  267. 267.

    Chandrasekharan, B. & Srinivasan, S. Diabetes and the enteric nervous system. Neurogastroenterol. Motil. 19, 951–960 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  268. 268.

    Stenkamp-Strahm, C. M., Kappmeyer, A. J., Schmalz, J. T., Gericke, M. & Balemba, O. High-fat diet ingestion correlates with neuropathy in the duodenum myenteric plexus of obese mice with symptoms of type 2 diabetes. Cell Tissue Res. 354, 381–394 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  269. 269.

    He, C. L. et al. Loss of interstitial cells of cajal and inhibitory innervation in insulin-dependent diabetes. Gastroenterology 121, 427–434 (2001).

    CAS  PubMed  Google Scholar 

  270. 270.

    Iwasaki, H. et al. A deficiency of gastric interstitial cells of Cajal accompanied by decreased expression of neuronal nitric oxide synthase and substance P in patients with type 2 diabetes mellitus. J. Gastroenterol. 41, 1076–1087 (2006).

    CAS  PubMed  Google Scholar 

  271. 271.

    Du, F., Wang, L., Qian, W. & Liu, S. Loss of enteric neurons accompanied by decreased expression of GDNF and PI3K/Akt pathway in diabetic rats. Neurogastroenterol. Motil. 21, 1229–e114 (2009).

    CAS  PubMed  Google Scholar 

  272. 272.

    Pasricha, P. J. et al. Changes in the gastric enteric nervous system and muscle: a case report on two patients with diabetic gastroparesis. BMC Gastroenterol. 8, 21 (2008).

    PubMed  PubMed Central  Google Scholar 

  273. 273.

    Grover, M., Farrugia, G. & Stanghellini, V. Gastroparesis: a turning point in understanding and treatment. Gut 68, 2238–2250 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  274. 274.

    Meldgaard, T. et al. Diabetic enteropathy: from molecule to mechanism-based treatment. J. Diabetes Res. 2018, 3827301 (2018).

    PubMed  PubMed Central  Google Scholar 

  275. 275.

    Farmer, A. D. et al. Gastrointestinal motility in people with type 1 diabetes and peripheral neuropathy. Reply to Marathe CS, Rayner CK, Jones KL, et al [letter]. Diabetologia 60, 2314–2315 (2017).

    PubMed  Google Scholar 

  276. 276.

    Marathe, C. S., Rayner, C. K., Jones, K. L. & Horowitz, M. Gastrointestinal motility in people with type 1 diabetes and peripheral neuropathy. Diabetologia 60, 2312–2313 (2017).

    CAS  PubMed  Google Scholar 

  277. 277.

    Farrugia, G. Histologic changes in diabetic gastroparesis. Gastroenterol. Clin. North Am. 44, 31–38 (2015).

    PubMed  Google Scholar 

  278. 278.

    Marathe, C. S., Rayner, C. K., Wu, T., Jones, K. L. & Horowitz, M. Gastrointestinal disorders in diabetes. (eds Feingold, K. R. et al.) Endotext [online] https://www.ncbi.nlm.nih.gov/books/NBK553219/ (2000).

  279. 279.

    Bodi, N. et al. Gut region-specific diabetic damage to the capillary endothelium adjacent to the myenteric plexus. Microcirculation 19, 316–326 (2012).

    CAS  PubMed  Google Scholar 

  280. 280.

    Gershon, M. D. & Bursztajn, S. Properties of the enteric nervous system: limitation of access of intravascular macromolecules to the myenteric plexus and muscularis externa. J. Comp. Neurol. 180, 467–488 (1978).

    CAS  PubMed  Google Scholar 

  281. 281.

    Nekrep, N., Wang, J., Miyatsuka, T. & German, M. S. Signals from the neural crest regulate beta-cell mass in the pancreas. Development 135, 2151–2160 (2008).

    CAS  PubMed  Google Scholar 

  282. 282.

    Garcia de Souza, S. R. et al. Antioxidant effects of the quercetin in the jejunal myenteric innervation of diabetic rats. Front. Med. 4, 8 (2017).

    Google Scholar 

  283. 283.

    Eriksson, D., Schneck, M., Schneider, A., Coulon, P. & Diester, I. A starting kit for training and establishing in vivo electrophysiology, intracranial pharmacology, and optogenetics. J. Neurosci. Methods 336, 108636 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  284. 284.

    Hibberd, T. J. et al. Optogenetic induction of colonic motility in mice. Gastroenterology 155, 514–528 (2018).

    PubMed  PubMed Central  Google Scholar 

  285. 285.

    Smith-Edwards, K. M. et al. Extrinsic primary afferent neurons link visceral pain to colon motility through a spinal reflex in mice. Gastroenterology 157, 522–536 (2019).

    PubMed  PubMed Central  Google Scholar 

  286. 286.

    Schäfer, I. et al. Conditional deletion of LRP1 leads to progressive loss of recombined NG2-expressing oligodendrocyte precursor cells in a novel mouse model. Cells 8, 1550 (2019).

    PubMed Central  Google Scholar 

  287. 287.

    De Schepper, S. et al. Self-maintaining gut macrophages are essential for intestinal homeostasis. Cell 175, 400–415 (2018).

    PubMed  Google Scholar 

  288. 288.

    1000 Genomes Project Consortium. et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

    Google Scholar 

  289. 289.

    Rollo, B. N. et al. Enteric neural cells from Hirschsprung disease patients form ganglia in autologous aneuronal colon. Cell Mol. Gastroenterol. Hepatol. 2, 92–109 (2016).

    PubMed  Google Scholar 

  290. 290.

    Fattahi, F. et al. Deriving human ENS lineages for cell therapy and drug discovery in Hirschsprung disease. Nature 531, 105–109 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  291. 291.

    Lai, F. P. et al. Correction of Hirschsprung-associated mutations in human induced pluripotent stem cells via clustered regularly interspaced short palindromic repeats/Cas9, restores neural crest cell function. Gastroenterology 153, 139–153 (2017).

    CAS  PubMed  Google Scholar 

  292. 292.

    Workman, M. J. et al. Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Nat. Med. 23, 49–59 (2017).

    CAS  PubMed  Google Scholar 

  293. 293.

    Wang, Y. et al. Establishment of an induced pluripotent stem cell model of Hirschsrpung disease, a congenital condition of the enteric nervous system, from a patient carrying a novel RET mutation. Neuroreport 29, 975–980 (2018).

    CAS  PubMed  Google Scholar 

  294. 294.

    Obermayr, F. & Seitz, G. Recent developments in cell-based ENS regeneration – a short review. Innov. Surg. Sci. 3, 93–99 (2018).

    PubMed  PubMed Central  Google Scholar 

  295. 295.

    Schmitteckert, S. et al. Postnatal human enteric neurospheres show a remarkable molecular complexity. Neurogastroenterol. Motil. 31, e13674 (2019).

    PubMed  Google Scholar 

  296. 296.

    Boesmans, W., Hao, M. M. & Vanden Berghe, P. Optical tools to investigate cellular activity in the intestinal wall. J. Neurogastroenterol. Motil. 21, 337–351 (2015).

    PubMed  PubMed Central  Google Scholar 

  297. 297.

    Lichtman, J. W., Pfister, H. & Shavit, N. The big data challenges of connectomics. Nat. Neurosci. 17, 1448–1454 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  298. 298.

    Zhao, J. et al. Simultaneous inhibition of hedgehog signaling and tumor proliferation remodels stroma and enhances pancreatic cancer therapy. Biomaterials 159, 215–228 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  299. 299.

    Kapeller, J. et al. First evidence for an association of a functional variant in the microRNA-510 target site of the serotonin receptor-type 3E gene with diarrhea predominant irritable bowel syndrome. Hum. Mol. Genet. 17, 2967–2977 (2008).

    CAS  PubMed  Google Scholar 

  300. 300.

    Snape, W. J. Jr. The role of a colonic motility disturbance in ulcerative colitis. Keio J. Med. 40, 6–8 (1991).

    PubMed  Google Scholar 

  301. 301.

    Annese, V. et al. Gastrointestinal motility disorders in patients with inactive Crohn’s disease. Scand. J. Gastroenterol. 32, 1107–1117 (1997).

    CAS  PubMed  Google Scholar 

  302. 302.

    Rao, S. S. & Read, N. W. Gastrointestinal motility in patients with ulcerative colitis. Scand. J. Gastroenterol. Suppl. 172, 22–28 (1990).

    CAS  PubMed  Google Scholar 

  303. 303.

    Van Ginneken, C., Schafer, K. H., Van Dam, D., Huygelen, V. & De Deyn, P. P. Morphological changes in the enteric nervous system of aging and APP23 transgenic mice. Brain Res. 1378, 43–53 (2011).

    PubMed  Google Scholar 

  304. 304.

    Cabal, A. et al. Amyloid precursor protein (βAPP) in human gut with special reference to the enteric nervous system. Brain Res. Bull. 38, 417–423 (1995).

    CAS  PubMed  Google Scholar 

  305. 305.

    Arai, H. et al. Expression patterns of β-amyloid precursor protein (β-APP) in neural and nonneural human tissues from Alzheimer’s disease and control subjects. Ann. Neurol. 30, 686–693 (1991).

    CAS  PubMed  Google Scholar 

  306. 306.

    Puig, K. L. et al. Overexpression of mutant amyloid-beta protein precursor and presenilin 1 modulates enteric nervous system. J. Alzheimers Dis. 44, 1263–1278 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  307. 307.

    Idiaquez, J. & Roman, G. C. Autonomic dysfunction in neurodegenerative dementias. J. Neurol. Sci. 305, 22–27 (2011).

    PubMed  Google Scholar 

  308. 308.

    Wang, L. et al. Mice overexpressing wild-type human α-synuclein display alterations in colonic myenteric ganglia and defecation. Neurogastroenterol. Motil. 24, e425–e436 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  309. 309.

    Braak, H., de Vos, R. A. I., Bohl, J. & Del Tredici, K. Gastric alpha-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 (2006).

    CAS  PubMed  Google Scholar 

  310. 310.

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

    CAS  PubMed  Google Scholar 

  311. 311.

    Sathasivam, K. et al. Formation of polyglutamine inclusions in non-CNS tissue. Hum. Mol. Genet. 8, 813–822 (1999).

    CAS  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

B.N. and K.-H.S. developed the concept, designed, wrote, assembled input data and edited the manuscript. B.N., I.E.D. and K.-H.S. created and revised the figures. B.N., S.K., I.E.D. and K.-H.S. reviewed the literature, selected the data and wrote the manuscript, and prepared Table 1. All authors discussed the results and implications and commented on the manuscript at all stages.

Corresponding authors

Correspondence to Beate Niesler or Karl-Herbert Schäfer.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Gastroenterology & Hepatology thanks P. Derkinderen, K. Nurgali and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Niesler, B., Kuerten, S., Demir, I.E. et al. Disorders of the enteric nervous system — a holistic view. Nat Rev Gastroenterol Hepatol 18, 393–410 (2021). https://doi.org/10.1038/s41575-020-00385-2

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing