The bowel and beyond: the enteric nervous system in neurological disorders

Key Points

  • The enteric nervous system (ENS) is the largest component of the autonomic nervous system and is uniquely equipped with intrinsic microcircuits that enable it to orchestrate gastrointestinal function independently of central nervous system (CNS) input

  • Because many neurotransmitters, signalling pathways and anatomical properties are common to the ENS and CNS, pathophysiological processes that underlie CNS disease often have enteric manifestations

  • Neuronal connections and the immune system might provide conduits that allow diseases acquired in the gut to spread to the brain

  • Transmissible spongiform encephalopathies, autistic spectrum disorders, Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, and varicella zoster virus (VZV) infection are examples of disorders with both gastrointestinal and neurological consequences

  • VZV reactivations from latency in enteric and other autonomic neurons that lack cutaneous projections are occult causes of zoster without rash that lead to gastrointestinal disease, meningitis and strokes

  • Research on the gut–brain axis of disease is reasonably new, concepts are changing rapidly, and further investigation is much needed

Abstract

The enteric nervous system (ENS) is large, complex and uniquely able to orchestrate gastrointestinal behaviour independently of the central nervous system (CNS). An intact ENS is essential for life and ENS dysfunction is often linked to digestive disorders. The part the ENS plays in neurological disorders, as a portal or participant, has also become increasingly evident. ENS structure and neurochemistry resemble that of the CNS, therefore pathogenic mechanisms that give rise to CNS disorders might also lead to ENS dysfunction, and nerves that interconnect the ENS and CNS can be conduits for disease spread. We review evidence for ENS dysfunction in the aetiopathogenesis of autism spectrum disorder, amyotrophic lateral sclerosis, transmissible spongiform encephalopathies, Parkinson disease and Alzheimer disease. Animal models suggest that common pathophysiological mechanisms account for the frequency of gastrointestinal comorbidity in these conditions. Moreover, the neurotropic pathogen, varicella zoster virus (VZV), unexpectedly establishes latency in enteric and other autonomic neurons that do not innervate skin. VZV reactivation in these neurons produces no rash and is therefore a clandestine cause of gastrointestinal disease, meningitis and strokes. The gut–brain alliance has raised consciousness as a contributor to health, but a gut–brain axis that contributes to disease merits equal attention.

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Figure 1: Relationship between the ENS and components of the peripheral nervous system.
Figure 2: The ENS can regulate intestinal behaviours in the absence of CNS input.
Figure 3: Schematic of the peristaltic reflex microcircuit required for aboral propulsion of luminal contents.
Figure 4: Summary of primary disease interactions between the gut and brain.
Figure 5: Enteric manifestations of lytic VZV infection of the mucosa and latent VZV infection of the ENS.

References

  1. 1

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

    Google Scholar 

  2. 2

    Furness, J. B., Callaghan, B. P., 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).

    PubMed  Google Scholar 

  3. 3

    Clevers, H. The intestinal crypt, a prototype stem cell compartment. Cell 154, 274–284 (2013).

    CAS  PubMed  Google Scholar 

  4. 4

    Turner, J. R. Intestinal mucosal barrier function in health and disease. Nat. Rev. Immunol. 9, 799–809 (2009).

    CAS  PubMed  Google Scholar 

  5. 5

    Mowat, A. M. & Agace, W. W. Regional specialization within the intestinal immune system. Nat. Rev. Immunol. 14, 667–685 (2014).

    CAS  PubMed  Google Scholar 

  6. 6

    Langley, J. N. The Autonomic Nervous System, Part 1 [1921] (Cornell Univ. Library, 2010).

    Google Scholar 

  7. 7

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

    Google Scholar 

  8. 8

    Gershon, M. D. Developmental determinants of the independence and complexity of the enteric nervous system. Trends Neurosciences 33, 446–456 (2010).

    CAS  Google Scholar 

  9. 9

    Forsythe, P., Bienenstock, J. & Kunze, W. A. Vagal pathways for microbiome–brain–gut axis communication. Adv. Exp. Med. Biol. 817, 115–133 (2014).

    PubMed  Google Scholar 

  10. 10

    Rush, A. J. et al. Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study. Biol. Psychiatry 47, 276–286 (2000).

    CAS  PubMed  Google Scholar 

  11. 11

    George, M. S. et al. Vagus nerve stimulation: a new tool for brain research and therapy. Biol. Psychiatry 47, 287–295 (2000).

    CAS  PubMed  Google Scholar 

  12. 12

    Sampson, T. R. & Mazmanian, S. K. Control of brain development, function, and behavior by the microbiome. Cell Host Microbe 17, 565–576 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    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 

  14. 14

    Mayer, E. A., Knight, R., Mazmanian, S. K., Cryan, J. F. & Tillisch, K. Gut microbes and the brain: paradigm shift in neuroscience. J. Neurosci. 34, 15490–15496 (2014).

    PubMed  PubMed Central  Google Scholar 

  15. 15

    Tam, P. K. Hirschsprung's disease: a bridge for science and surgery. J. Pediatr. Surg. 51, 18–22 (2016).

    PubMed  Google Scholar 

  16. 16

    Heuckeroth, R. O. Hirschsprung's disease, Down syndrome, and missing heritability: too much collagen slows migration. J. Clin. Invest. 125, 4323–4326 (2015).

    PubMed  PubMed Central  Google Scholar 

  17. 17

    Amiel, J. & Lyonnet, S. Hirschsprung disease, associated syndromes, and genetics: a review. J. Med. Genet. 38, 729–739 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Bern, C. Chagas' disease. N. Engl. J. Med. 373, 1882 (2015).

    PubMed  Google Scholar 

  19. 19

    Avetisyan, M., Schill, E. M. & Heuckeroth, R. O. Building a second brain in the bowel. J. Clin. Invest. 125, 899–907 (2015).

    PubMed  PubMed Central  Google Scholar 

  20. 20

    Klingelhoefer, L. & Reichmann, H. Pathogenesis of Parkinson disease — the gut–brain axis and environmental factors. Nat. Rev. Neurol. 11, 625–636 (2015).

    CAS  PubMed  Google Scholar 

  21. 21

    Collins, S. J., Lawson, V. A. & Masters, C. L. Transmissible spongiform encephalopathies. Lancet 363, 51–61 (2004).

    CAS  PubMed  Google Scholar 

  22. 22

    Prusiner, S. B. Biology and genetics of prions causing neurodegeneration. Annu. Rev. Genet. 47, 601–623 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Aguzzi, A. Unraveling prion strains with cell biology and organic chemistry. Proc. Natl Acad. Sci. USA 105, 11–12 (2008).

    CAS  PubMed  Google Scholar 

  24. 24

    Cronier, S. et al. Endogenous prion protein conversion is required for prion-induced neuritic alterations and neuronal death. FASEB J. 26, 3854–3861 (2012).

    CAS  PubMed  Google Scholar 

  25. 25

    Ghosh, S. Mechanism of intestinal entry of infectious prion protein in the pathogenesis of variant Creutzfeldt–Jakob disease. Adv. Drug Deliv. Rev. 56, 915–920 (2004).

    CAS  PubMed  Google Scholar 

  26. 26

    Kujala, P. et al. Prion uptake in the gut: identification of the first uptake and replication sites. PLoS Pathog. 7, e1002449 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Chiocchetti, R. et al. Anatomical evidence for ileal Peyer's patches innervation by enteric nervous system: a potential route for prion neuroinvasion? Cell Tissue Res. 332, 185–194 (2008).

    PubMed  Google Scholar 

  28. 28

    Albanese, V. et al. Evidence for prion protein expression in enteroglial cells of the myenteric plexus of mouse intestine. Auton. Neurosci. 140, 17–23 (2008).

    CAS  PubMed  Google Scholar 

  29. 29

    Martin, G. R. et al. Endogenous cellular prion protein regulates contractility of the mouse ileum. Neurogastroenterol. Motil. 24, e412–424 (2012).

    CAS  PubMed  Google Scholar 

  30. 30

    Posar, A., Resca, F. & Visconti, P. Autism according to diagnostic and statistical manual of mental disorders 5th edition: the need for further improvements. J. Pediatr. Neurosci. 10, 146–148 (2015).

    PubMed  PubMed Central  Google Scholar 

  31. 31

    McElhanon, B. O., McCracken, C., Karpen, S. & Sharp, W. G. Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis. Pediatrics 133, 872–883 (2014).

    PubMed  Google Scholar 

  32. 32

    Halfon, N. & Kuo, A. A. What DSM-5 could mean to children with autism and their families. JAMA Pediatr. 167, 608–613 (2013).

    PubMed  Google Scholar 

  33. 33

    Betancur, C. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 1380, 42–77 (2011).

    CAS  PubMed  Google Scholar 

  34. 34

    Iossifov, I. et al. De novo gene disruptions in children on the autistic spectrum. Neuron 74, 285–299 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Neale, B. M. et al. Patterns and rates of exonic De novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    O'Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of De novo mutations. Nature 485, 246–250 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    O'Roak, B. J. et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338, 1619–1622 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Schulze, T. G. & McMahon, F. J. Defining the phenotype in human genetic studies: forward genetics and reverse phenotyping. Hum. Hered. 58, 131–138 (2004).

    PubMed  Google Scholar 

  39. 39

    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 

  40. 40

    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 

  41. 41

    Grubisic, V., Kennedy, A. J., Sweatt, J. D. & Parpura, V. Pitt–Hopkins mouse model has altered particular gastrointestinal transits in vivo. Autism Res. 8, 629–633 (2015).

    PubMed  PubMed Central  Google Scholar 

  42. 42

    Marler, S. et al. Brief report: whole blood serotonin levels and gastrointestinal symptoms in autism spectrum disorder. J. Autism Dev. Disord. 46, 1124–1130 (2016).

    PubMed  PubMed Central  Google Scholar 

  43. 43

    Matondo, R. B. et al. Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G963–G968 (2009).

    CAS  PubMed  Google Scholar 

  44. 44

    Morrissey, J. J., Walker, M. N. & Lovenberg, W. The absence of tryptophan hydroxylase activity in blood platelets. Proc. Soc. Exp. Biol. Med. 154, 496–499 (1977).

    CAS  PubMed  Google Scholar 

  45. 45

    Lesch, K. P., Wolozin, B. L., Murphy, D. L. & Riederer, P. Primary structure of the human platelet serotonin (5-HT) uptake site: identity with the brain 5-HT transporter. J. Neurochem. 60, 2319–2322 (1993).

    CAS  PubMed  Google Scholar 

  46. 46

    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 

  47. 47

    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 

  48. 48

    Bromley, R. L. et al. The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs. J. Neurol. Neurosurg. Psychiatry 84, 637–643 (2013).

    PubMed  PubMed Central  Google Scholar 

  49. 49

    Christensen, J. et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 309, 1696–1703 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Roullet, F. I., Lai, J. K. & Foster, J. A. In utero exposure to valproic acid and autism — a current review of clinical and animal studies. Neurotoxicol. Teratol. 36, 47–56 (2013).

    CAS  PubMed  Google Scholar 

  51. 51

    de Theije, C. G. et al. Intestinal inflammation in a murine model of autism spectrum disorders. Brain Behav. Immun. 37, 240–247 (2014).

    CAS  PubMed  Google Scholar 

  52. 52

    Ghia, J. E. et al. Serotonin has a key role in pathogenesis of experimental colitis. Gastroenterology 137, 1649–1660 (2009).

    CAS  PubMed  Google Scholar 

  53. 53

    Haub, S. et al. Enhancement of intestinal inflammation in mice lacking interleukin 10 by deletion of the serotonin reuptake transporter. Neurogastroenterol. Motil. 22, 826–e229 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Bischoff, S. C. et al. Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2,4,6-trinitrobenzene sulfonic acid colitis in mice. Am. J. Physiol. Gastrointest Liver Physiol. 296, G685–G695 (2009).

    CAS  PubMed  Google Scholar 

  55. 55

    Gershon, M. D. Serotonin is a sword and a shield of the bowel: serotonin plays offense and defense. Trans. Am. Clin. Climatol. Assoc. 123, 268–280; discussion 280 (2012).

    PubMed  PubMed Central  Google Scholar 

  56. 56

    Gershon, M. D. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr. Opin. Endocrinol. Diabetes Obes. 20, 14–21 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Liu, Z., Li, N. & Neu, J. Tight junctions, leaky intestines, and pediatric diseases. Acta Paediatr. 94, 386–393 (2005).

    CAS  PubMed  Google Scholar 

  58. 58

    D'Eufemia, P. et al. Abnormal intestinal permeability in children with autism. Acta Paediatr. 85, 1076–1079 (1996).

    CAS  PubMed  Google Scholar 

  59. 59

    Robertson, M. A. et al. Intestinal permeability and glucagon-like peptide-2 in children with autism: a controlled pilot study. J. Autism Dev. Disord. 38, 1066–1071 (2008).

    PubMed  Google Scholar 

  60. 60

    de Magistris, L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J. Pediatr. Gastroenterol. Nutr. 51, 418–424 (2010).

    PubMed  Google Scholar 

  61. 61

    Malkova, N. V., Yu, C. Z., Hsiao, E. Y., Moore, M. J. & Patterson, P. H. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav. Immun. 26, 607–616 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Hsiao, E. Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451–1463 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Neunlist, M. et al. The digestive neuronal–glial–epithelial unit: a new actor in gut health and disease. Nat. Rev. Gastroenterol. Hepatol. 10, 90–100 (2013).

    CAS  PubMed  Google Scholar 

  64. 64

    Jankovic, J. Parkinson's disease: clinical features and diagnosis. J. Neurol. Neurosurg. Psychiatry 79, 368–376 (2008).

    CAS  PubMed  Google Scholar 

  65. 65

    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 

  66. 66

    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 

  67. 67

    Wakabayashi, K., Takahashi, H., Takeda, S., Ohama, E. & Ikuta, F. Parkinson's disease: the presence of Lewy bodies in Auerbach's and Meissner's plexuses. Acta Neuropathol. (Berl.) 76, 217–221 (1988).

    CAS  Google Scholar 

  68. 68

    Wakabayashi, K., Takahashi, H., Ohama, E. & Ikuta, F. Tyrosine hydroxylase-immunoreactive intrinsic neurons in the Auerbach's and Meissner's plexuses of humans. Neurosci. Lett. 96, 259–263 (1989).

    CAS  PubMed  Google Scholar 

  69. 69

    Li, Z. S., Pham, T. D., Tamir, H., Chen, J. J. & Gershon, M. D. Enteric dopaminergic neurons: definition, developmental lineage, and effects of extrinsic denervation. J. Neurosci. 24, 1330–1339 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Li, Z. S., Schmauss, C., Cuenca, A., Ratcliffe, E. & Gershon, M. D. Physiological modulation of intestinal motility by enteric dopaminergic neurons and the D2 receptor: analysis of dopamine receptor expression, location, development, and function in wild-type and knock-out mice. J. Neurosci. 26, 2798–2807 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Tieu, K. A guide to neurotoxic animal models of Parkinson's disease. Cold Spring Harb. Perspect. Med. 1, a009316 (2011).

    PubMed  PubMed Central  Google Scholar 

  72. 72

    Anderson, G. et al. Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease. Exp. Neurol. 207, 4–12 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Chandra, S., Gallardo, G., Fernandez-Chacon, R., Schluter, O. M. & Sudhof, T. C. α-Synuclein cooperates with CSPα in preventing neurodegeneration. Cell 123, 383–396 (2005).

    CAS  PubMed  Google Scholar 

  74. 74

    Westphal, C. H. & Chandra, S. S. Monomeric synucleins generate membrane curvature. J. Biol. Chem. 288, 1829–1840 (2013).

    CAS  PubMed  Google Scholar 

  75. 75

    Vargas, K. J. et al. Synucleins regulate the kinetics of synaptic vesicle endocytosis. J. Neurosci. 34, 9364–9376 (2014).

    PubMed  PubMed Central  Google Scholar 

  76. 76

    Braak, H. & Braak, E. Pathoanatomy of Parkinson's disease. J. Neurol. 247 (Suppl. 2), II/3–II/10 (2000).

    Google Scholar 

  77. 77

    Preterre, C. et al. Optimizing Western Blots for the detection of endogenous α-synuclein in the enteric nervous system. J. Parkinsons Dis. 5, 765–772 (2015).

    CAS  PubMed  Google Scholar 

  78. 78

    Aldecoa, I. et al. Alpha-synuclein immunoreactivity patterns in the enteric nervous system. Neurosci. Lett. 602, 145–149 (2015).

    CAS  PubMed  Google Scholar 

  79. 79

    Miraglia, F., Betti, L., Palego, L. & Giannaccini, G. Parkinson's disease and alpha-synucleinopathies: from arising pathways to therapeutic challenge. Cent. Nerv. Syst. Agents Med. Chem. 15, 109–116 (2015).

    CAS  PubMed  Google Scholar 

  80. 80

    Hallett, P. J., McLean, J. R., Kartunen, A., Langston, J. W. & Isacson, O. Alpha-synuclein overexpressing transgenic mice show internal organ pathology and autonomic deficits. Neurobiol. Dis. 47, 258–267 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Wang, L., Fleming, S. M., Chesselet, M. F. & Tache, Y. Abnormal colonic motility in mice overexpressing human wild-type α-synuclein. Neuroreport 19, 873–876 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    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 

  83. 83

    Polymeropoulos, M. H. et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047 (1997).

    CAS  PubMed  Google Scholar 

  84. 84

    Kruger, R. et al. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease. Nat. Genet. 18, 106–108 (1998).

    CAS  PubMed  Google Scholar 

  85. 85

    Kuo, Y. M. et al. Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated α-synuclein gene mutations precede central nervous system changes. Hum. Mol. Genet. 19, 1633–1650 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Lebouvier, T. et al. Routine colonic biopsies as a new tool to study the enteric nervous system in living patients. Neurogastroenterol. Motil. 22, e11–e14 (2010).

    CAS  PubMed  Google Scholar 

  87. 87

    Gold, A., Turkalp, Z. T. & Munoz, D. G. Enteric alpha-synuclein expression is increased in Parkinson's disease but not Alzheimer's disease. Mov. Disord. 28, 237–240 (2013).

    CAS  PubMed  Google Scholar 

  88. 88

    US Preventive Services Task Force. Screening for colorectal cancer: U.S. Preventive Services Task Force recommendation statement. JAMA 315, 2564-2575 (2016).

  89. 89

    Hilton, D. et al. Accumulation of α-synuclein in the bowel of patients in the pre-clinical phase of Parkinson's disease. Acta Neuropathol. 127, 235–241 (2014).

    CAS  PubMed  Google Scholar 

  90. 90

    Shannon, K. M. et al. Alpha-synuclein in colonic submucosa in early untreated Parkinson's disease. Mov. Disord. 27, 709–715 (2012).

    PubMed  Google Scholar 

  91. 91

    Visanji, N. P. et al. Colonic mucosal α-synuclein lacks specificity as a biomarker for Parkinson disease. Neurology 84, 609–616 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Stokholm, M. G., Danielsen, E. H., Hamilton-Dutoit, S. J. & Borghammer, P. Pathological α-synuclein in gastrointestinal tissues from prodromal Parkinson disease patients. Ann. Neurol. 79, 940–949 (2016).

    CAS  PubMed  Google Scholar 

  93. 93

    Singaram, C. et al. Dopaminergic defect of enteric nervous system in Parkinson's disease patients with chronic constipation. Lancet 346, 861–864 (1995).

    CAS  PubMed  Google Scholar 

  94. 94

    Annerino, D. M. et al. Parkinson's disease is not associated with gastrointestinal myenteric ganglion neuron loss. Acta Neuropathol. 124, 665–680 (2012).

    PubMed  PubMed Central  Google Scholar 

  95. 95

    Pickel, V. M., Beckley, S. C., Joh, T. H. & Reis, D. J. Ultrastructural immunocytochemical localization of tyrosine hydroxylase in the neostriatum. Brain Res. 225, 373–385 (1981).

    CAS  PubMed  Google Scholar 

  96. 96

    Weiner, N. Regulation of norepinephrine biosynthesis. Annu. Rev. Pharmacol. 10, 273–290 (1970).

    CAS  PubMed  Google Scholar 

  97. 97

    Braak, E. et al. alpha-synuclein immunopositive Parkinson's disease-related inclusion bodies in lower brain stem nuclei. Acta Neuropathol. 101, 195–201 (2001).

    CAS  PubMed  Google Scholar 

  98. 98

    Del Tredici, K., Rub, U., De Vos, R. A., Bohl, J. R. & Braak, H. Where does parkinson disease pathology begin in the brain? J. Neuropathol. Exp. Neurol. 61, 413–426 (2002).

    PubMed  Google Scholar 

  99. 99

    Braak, H., Rub, U., Gai, W. P. & Del Tredici, K. Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J. Neural Transm. 110, 517–536 (2003).

    CAS  PubMed  Google Scholar 

  100. 100

    Del Tredici, K. & Duda, J. E. Peripheral Lewy body pathology in Parkinson's disease and incidental Lewy body disease: four cases. J. Neurol. Sci. 310, 100–106 (2011).

    PubMed  Google Scholar 

  101. 101

    Phillips, R. J., Walter, G. C., Wilder, S. L., Baronowsky, E. A. & Powley, T. L. Alpha-synuclein-immunopositive myenteric neurons and vagal preganglionic terminals: autonomic pathway implicated in Parkinson's disease? Neuroscience 153, 733–750 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Gorell, J. M., Johnson, C. C., Rybicki, B. A., Peterson, E. L. & Richardson, R. J. The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living. Neurology 50, 1346–1350 (1998).

    CAS  PubMed  Google Scholar 

  103. 103

    Pan-Montojo, F. et al. Progression of Parkinson's disease pathology is reproduced by intragastric administration of rotenone in mice. PLoS ONE 5, e8762 (2010).

    PubMed  PubMed Central  Google Scholar 

  104. 104

    Pan-Montojo, F. et al. Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci. Rep. 2, 898 (2012).

    PubMed  PubMed Central  Google Scholar 

  105. 105

    Ulusoy, A. et al. Caudo-rostral brain spreading of α-synuclein through vagal connections. EMBO Mol. Med. 5, 1051–1059 (2013).

    CAS  PubMed Central  Google Scholar 

  106. 106

    Holmqvist, S. et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 128, 805–820 (2014).

    PubMed  Google Scholar 

  107. 107

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

    PubMed  Google Scholar 

  108. 108

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

    PubMed  Google Scholar 

  109. 109

    Jellinger, K. A. A critical evaluation of current staging of α-synuclein pathology in Lewy body disorders. Biochim. Biophys. Acta 1792, 730–740 (2009).

    CAS  PubMed  Google Scholar 

  110. 110

    Kalaitzakis, M. E., Graeber, M. B., Gentleman, S. M. & Pearce, R. K. The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson's disease: a critical analysis of α-synuclein staging. Neuropathol. Appl. Neurobiol. 34, 284–295 (2008).

    CAS  PubMed  Google Scholar 

  111. 111

    Kingsbury, A. E. et al. Brain stem pathology in Parkinson's disease: an evaluation of the Braak staging model. Mov. Disord. 25, 2508–2515 (2010).

    PubMed  Google Scholar 

  112. 112

    Ubhi, K. & Masliah, E. Alzheimer's disease: recent advances and future perspectives. J. Alzheimers Dis. 33, S185–S194 (2013).

    PubMed  Google Scholar 

  113. 113

    Schliebs, R. Basal forebrain cholinergic dysfunction in Alzheimer's disease — interrelationship with beta-amyloid, inflammation and neurotrophin signaling. Neurochem. Res. 30, 895–908 (2005).

    CAS  PubMed  Google Scholar 

  114. 114

    Arai, H. et al. Expression patterns of beta-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 

  115. 115

    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 

  116. 116

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

    CAS  PubMed  Google Scholar 

  117. 117

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

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    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 

  119. 119

    Deguchi, E., Iwai, N., Goto, Y., Yanagihara, J. & Fushiki, S. An immunohistochemical study of neurofilament and microtubule-associated Tau protein in the enteric innervation in Hirschsprung's disease. J. Pediatr. Surg. 28, 886–890 (1993).

    CAS  PubMed  Google Scholar 

  120. 120

    Tam, P. K. & Owen, G. An immunohistochemical study of neuronal microtubule-associated proteins in Hirschsprung's disease. Hum. Pathol. 24, 424–431 (1993).

    CAS  PubMed  Google Scholar 

  121. 121

    Phillips, R. J., Walter, G. C., Ringer, B. E., Higgs, K. M. & Powley, T. L. Alpha-synuclein immunopositive aggregates in the myenteric plexus of the aging Fischer 344 rat. Exp. Neurol. 220, 109–119 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Shankle, W. R. et al. Studies of the enteric nervous system in Alzheimer disease and other dementias of the elderly: enteric neurons in Alzheimer disease. Mod. Pathol. 6, 10–14 (1993).

    CAS  PubMed  Google Scholar 

  123. 123

    Jovicic, A., Paul, J. W. 3rd & Gitler, A. D. Nuclear transport dysfunction: a common theme in amyotrophic lateral sclerosis and frontotemporal dementia. J. Neurochem. http://dx.doi.org/10.1111/jnc.13642 (2016).

  124. 124

    Geser, F., Martinez-Lage, M., Kwong, L. K., Lee, V. M. & Trojanowski, J. Q. Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases. J. Neurol. 256, 1205–1214 (2009).

    PubMed  PubMed Central  Google Scholar 

  125. 125

    Kabashi, E. et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 40, 572–574 (2008).

    CAS  PubMed  Google Scholar 

  126. 126

    Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668–1672 (2008).

    CAS  PubMed  Google Scholar 

  127. 127

    Chio, A. et al. Extensive genetics of ALS: a population-based study in Italy. Neurology 79, 1983–1989 (2012).

    PubMed  PubMed Central  Google Scholar 

  128. 128

    Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).

    CAS  PubMed  Google Scholar 

  129. 129

    Wegorzewska, I., Bell, S., Cairns, N. J., Miller, T. M. & Baloh, R. H. TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc. Natl Acad. Sci. USA 106, 18809–18814 (2009).

    CAS  PubMed  Google Scholar 

  130. 130

    Guo, Y. et al. HO-1 induction in motor cortex and intestinal dysfunction in TDP-43 A315T transgenic mice. Brain Res. 1460, 88–95 (2012).

    CAS  PubMed  Google Scholar 

  131. 131

    Esmaeili, M. A., Panahi, M., Yadav, S., Hennings, L. & Kiaei, M. Premature death of TDP-43 (A315T) transgenic mice due to gastrointestinal complications prior to development of full neurological symptoms of amyotrophic lateral sclerosis. Int. J. Exp. Pathol. 94, 56–64 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    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 

  133. 133

    Hatzipetros, T. et al. C57BL/6J congenic Prp-TDP43A315T mice develop progressive neurodegeneration in the myenteric plexus of the colon without exhibiting key features of ALS. Brain Res. 1584, 59–72 (2014).

    CAS  PubMed  Google Scholar 

  134. 134

    Kaur, S. J., McKeown, S. R. & Rashid, S. Mutant SOD1 mediated pathogenesis of amyotrophic lateral sclerosis. Gene 577, 109–118 (2016).

    CAS  PubMed  Google Scholar 

  135. 135

    Wu, S., Yi, J., Zhang, Y. G., Zhou, J. & Sun, J. Leaky intestine and impaired microbiome in an amyotrophic lateral sclerosis mouse model. Physiol. Rep. 3, e12356 (2015).

    PubMed  PubMed Central  Google Scholar 

  136. 136

    Gross, E. R., Gershon, M. D., Margolis, K. G., Gertsberg, Z. V. & Cowles, R. A. Neuronal serotonin regulates growth of the intestinal mucosa in mice. Gastroenterology 143, 408–417.e2 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    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 

  138. 138

    Colby, D. W. & Prusiner, S. B. Prions. Cold Spring Harb. Perspect. Biol. 3, a006833 (2011).

    PubMed  PubMed Central  Google Scholar 

  139. 139

    Pinkas, A. & Aschner, M. Advanced glycation end-products and their receptors: related pathologies, recent therapeutic strategies, and a potential model for future neurodegeneration studies. Chem. Res. Toxicol. 29, 707–714 (2016).

    CAS  PubMed  Google Scholar 

  140. 140

    Deng, H., Gao, K. & Jankovic, J. The role of FUS gene variants in neurodegenerative diseases. Nat. Rev. Neurol. 10, 337–348 (2014).

    CAS  PubMed  Google Scholar 

  141. 141

    Sharma, A. et al. ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function. Nat. Commun. 7, 10465 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Parakh, S. & Atkin, J. D. Protein folding alterations in amyotrophic lateral sclerosis. Brain Res. http://dx.doi.org/10.1016/j.brainres.2016.04.010 (2016).

  143. 143

    Gershon, A. A. et al. Varicella zoster virus infection. Nat. Rev. Dis. Primers 1, 15016 (2015).

    PubMed  PubMed Central  Google Scholar 

  144. 144

    Gershon, A. A., Chen, J. & Gershon, M. D. Use of saliva to identify varicella zoster virus infection of the gut. Clin. Infect. Dis. 61, 536–544 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Gershon, A. A. et al. Latency of varicella zoster virus in dorsal root, cranial, and enteric ganglia in vaccinated children. Trans. Am. Clin. Climatol. Assoc. 123, 17–33; discussion 33–35 (2012).

    PubMed  PubMed Central  Google Scholar 

  146. 146

    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 

  147. 147

    Levin, M. J. Varicella-zoster virus and virus DNA in the blood and oropharynx of people with latent or active varicella-zoster virus infections. J. Clin. Virol. 61, 487–495 (2014).

    CAS  PubMed  Google Scholar 

  148. 148

    Edelman, D. A. et al. Ogilvie syndrome and herpes zoster: case report and review of the literature. J. Emerg. Med. 39, 696–700 (2009).

    PubMed  Google Scholar 

  149. 149

    Mehta, S. K. et al. Varicella-zoster virus in the saliva of patients with herpes zoster. J. Infect. Dis. 197, 654–657 (2008).

    PubMed  PubMed Central  Google Scholar 

  150. 150

    Duncan, C. J. & Hambleton, S. Varicella zoster virus immunity: a primer. J. Infect. 71, S47–S53 (2015).

    PubMed  Google Scholar 

  151. 151

    Johnson, B. H. et al. Annual incidence rates of herpes zoster among an immunocompetent population in the United States. BMC Infect. Dis. 15, 502 (2015).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

M.R. receives research support from Ivan and Phyllis Seidenberg, the Paul Marks Scholars Program, and the American Gastroenterological Association – Takeda Pharmaceuticals International Research Scholar Award in Neurogastroenterology. M.D.G. is supported by grant NS15547 from the NIH and the Einhorn Family Charitable Trust.

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Rao, M., Gershon, M. The bowel and beyond: the enteric nervous system in neurological disorders. Nat Rev Gastroenterol Hepatol 13, 517–528 (2016). https://doi.org/10.1038/nrgastro.2016.107

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