When thinking about neurodegenerative diseases, the first symptoms that come to mind are loss of memory and learning capabilities, which all resemble hallmarks of manifestation of such diseases in the central nervous system (CNS). However, the gut comprises the largest nervous system outside the CNS that is autonomously active and in close interplay with its microbiota. Therefore, the enteric nervous system (ENS) might serve as an indicator of degenerative pathomechanisms that also affect the CNS. On the other hand, it might offer an entry point for devastating influences from the microbial community or – conversely – for therapeutic approaches via gut commensals. Within the last years, the ENS and gut microbiota therefore have sparked the interest of researchers of CNS diseases and we here report on recent findings and open questions, especially with regard to Alzheimer and Parkinson diseases.

Keywords:
Commensal microbiota, Enteric nervous system, Neurodegenerative diseases
1.
Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J, Deng Y, Blennerhassett P, Macri J, McCoy KD, Verdu EF, Collins SM: The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 2011; 141: 599–609, 609.e1–609e3.
2.
Clemente JC, Ursell LK, Parfrey LW, Knight R: The impact of the gut microbiota on human health: an integrative view. Cell 2012; 148: 1258–1270.
3.
Qu ZD, Thacker M, Castelucci P, Bagyanszki M, Epstein ML, Furness JB: Immunohistochemical analysis of neuron types in the mouse small intestine. Cell Tissue Res 2008; 334: 147–161.
4.
Timmermans JP, Scheuermann DW, Stach W, Adriaensen D, De Groodt-Lasseel MH: Distinct distribution of CGRP-, enkephalin-, galanin-, neuromedin U-, neuropeptide Y-, somatostatin-, substance P-, VIP- and serotonin-containing neurons in the two submucosal ganglionic neural networks of the porcine small intestine. Cell Tissue Res 1990; 260: 367–379.
5.
Timmermans MW, Scheuermann DW: Distributional pattern and targets of GABA-containing neurons in the porcine small and large intestine. Eur J Morphol 1998; 36: 133–142.
6.
Barrett E, Ross RP, O’Toole PW, Fitzgerald GF, Stanton C: Gamma-aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol 2012; 113: 411–417.
7.
Unger MM, Spiegel J, Dillmann KU, Grundmann D, Philippeit H, Burmann J, Fassbender K, Schwiertz A, Schafer KH: Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism Relat Disord 2016; 32: 66–72.
8.
Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, Nagler CR, Ismagilov RF, Mazmanian SK, Hsiao EY: Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 2015; 161: 264–276.
9.
Hyland NP, Cryan JF: A gut feeling about GABA: focus on GABA(B) receptors. Front Pharmacol 2010; 1: 124.
10.
Gershon MD, Tack J: The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 2007; 132: 397–414.
11.
Gershon MD, Rothman TP: Enteric glia. Glia 1991; 4: 195–204.
12.
Jessen KR, Mirsky R: Glial cells in the enteric nervous system contain glial fibrillary acidic protein. Nature 1980; 286: 736–737.
13.
von Boyen GB, Schulte N, Pfluger C, Spaniol U, Hartmann C, Steinkamp M: Distribution of enteric glia and GDNF during gut inflammation. BMC Gastroenterol 2011; 11: 3.
14.
Soret R, Coquenlorge S, Cossais F, Meurette G, Rolli-Derkinderen M, Neunlist M: Characterization of human, mouse, and rat cultures of enteric glial cells and their effect on intestinal epithelial cells. Neurogastroenterol Motil 2013; 25:e755–e764.
15.
Barajon I, Serrao G, Arnaboldi F, Opizzi E, Ripamonti G, Balsari A, Rumio C: Toll-like receptors 3, 4, and 7 are expressed in the enteric nervous system and dorsal root ganglia. J Histochem Cytochem 2009; 57: 1013–1023.
16.
Anitha M, Vijay-Kumar M, Sitaraman SV, Gewirtz AT, Srinivasan S: Gut microbial products regulate murine gastrointestinal motility via Toll-like receptor 4 signaling. Gastroenterology 2012; 143: 1006–1016.e14.
17.
Schuster A, Klotz M, Schwab T, Di Liddo R, Bertalot T, Schrenk S, Martin M, Nguyen TD, Nguyen TN, Gries M, Fassbender K, Conconi MT, Parnigotto PP, Schafer KH: Maintenance of the enteric stem cell niche by bacterial lipopolysaccharides? Evidence and perspectives. J Cell Mol Med 2014; 18: 1429–1443.
18.
Di Liddo R, Bertalot T, Schuster A, Schrenk S, Tasso A, Zanusso I, Conconi MT, Schafer KH: Anti-inflammatory activity of Wnt signaling in enteric nervous system: in vitro preliminary evidences in rat primary cultures. J Neuroinflammation 2015; 12: 23.
19.
Steinman L: Elaborate interactions between the immune and nervous systems. Nat Immunol 2004; 5: 575–581.
20.
Matteoli G, Gomez-Pinilla PJ, Nemethova A, Di Giovangiulio M, Cailotto C, van Bree SH, Michel K, Tracey KJ, Schemann M, Boesmans W, Vanden Berghe P, Boeckxstaens GE: A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen. Gut 2014; 63: 938–948.
21.
Man AL, Bertelli E, Rentini S, Regoli M, Briars G, Marini M, Watson AJ, Nicoletti C: Age-associated modifications of intestinal permeability and innate immunity in human small intestine. Clin Sci (Lond) 2015; 129: 515–527.
22.
Maidji E, Somsouk M, Rivera JM, Hunt PW, Stoddart CA: Replication of CMV in the gut of HIV-infected individuals and epithelial barrier dysfunction. PLoS Pathog 2017; 13: e1006202.
23.
Hagl CI, Klotz M, Wink E, Kranzle K, Holland-Cunz S, Gretz N, Diener M, Schafer KH: Temporal and regional morphological differences as a consequence of FGF-2 deficiency are mirrored in the myenteric proteome. Pediatr Surg Int 2008; 24: 49–60.
24.
West C, Wu RY, Wong A, Stanisz AM, Yan R, Min KK, Pasyk M, McVey Neufeld KA, Karamat MI, Foster JA, Bienenstock J, Forsythe P, Kunze WA: Lactobacillus rhamnosus strain JB-1 reverses restraint stress-induced gut dysmotility. Neurogastroenterol Motil 2017; 29.
25.
Muller PA, Koscso B, Rajani GM, Stevanovic K, Berres ML, Hashimoto D, Mortha A, Le­boeuf M, Li XM, Mucida D, Stanley ER, Dahan S, Margolis KG, Gershon MD, Merad M, Bogunovic M: Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 2014; 158: 300–313.
26.
Collins J, Borojevic R, Verdu EF, Huizinga JD, Ratcliffe EM: Intestinal microbiota influence the early postnatal development of the enteric nervous system. Neurogastroenterol Motil 2014; 26: 98–107.
27.
Kabouridis PS, Lasrado R, McCallum S, Chng SH, Snippert HJ, Clevers H, Pettersson S, Pachnis V: Microbiota controls the homeostasis of glial cells in the gut lamina propria. Neuron 2015; 85: 289–295.
28.
Grundmann D, Markwart F, Scheller A, Kirchhoff F, Schafer KH: Phenotype and distribution pattern of nestin-GFP-expressing cells in murine myenteric plexus. Cell Tissue Res 2016; 366: 573–586.
29.
Klingelhoefer L, Reichmann H: The gut and nonmotor symptoms in Parkinson’s disease. Int Rev Neurobiol 2017; 134: 787–809.
30.
Goldblum JR, Whyte RI, Orringer MB, Appelman HD: Achalasia: a morphologic study of 42 resected specimens. Am J Surg Pathol 1994; 18: 327–337.
31.
Badner JA, Sieber WK, Garver KL, Chakravarti A: A genetic study of Hirschsprung disease. Am J Hum Genet 1990; 46: 568–580.
32.
Spouge D, Baird PA: Hirschsprung disease in a large birth cohort. Teratology 1985; 32: 171–177.
33.
Bodian M, Stephens FD, Ward BC: Hirschsprung’s disease and idiopathic megacolon. Lancet 1949; 1: 6–11.
34.
Bondurand N, Southard-Smith EM: Mouse models of Hirschsprung disease and other developmental disorders of the enteric nervous system: old and new players. Dev Biol 2016; 417: 139–157.
35.
Li Y, Poroyko V, Yan Z, Pan L, Feng Y, Zhao P, Xie Z, Hong L: Characterization of Intestinal microbiomes of Hirschsprung’s disease patients with or without enterocolitis using Illumina-MiSeq high-throughput sequencing. PLoS One 2016; 11:e0162079.
36.
Heckert J, Thomas RM, Parkman HP: Gastric neuromuscular histology in patients with refractory gastroparesis: relationships to etiology, gastric emptying, and response to gastric electric stimulation. Neurogastroenterol Motil 2017; 29.
37.
Banerji NK, Hurwitz LJ: Neurological manifestations in adult steatorrhoea (probable gluten enteropathy). J Neurol Sci 1971; 14: 125–141.
38.
Lossos A, River Y, Eliakim A, Steiner I: Neurologic aspects of inflammatory bowel disease. Neurology 1995; 45: 416–421.
39.
Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG: The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord 2008; 23: 837–844.
40.
Mertsalmi TH, Aho VTE, Pereira PAB, Paulin L, Pekkonen E, Auvinen P, Scheperjans F: More than constipation – bowel symptoms in Parkinson’s disease and their connection to gut microbiota. Eur J Neurol 2017; 24: 1375–1383.
41.
Xie X, Luo X, Xie M: Association between Parkinson’s disease and risk of colorectal cancer. Parkinsonism Relat Disord 2017; 35: 42–47.
42.
Boursi B, Mamtani R, Haynes K, Yang YX: Parkinson’s disease and colorectal cancer risk: a nested case control study. Cancer Epidemiol 2016; 43: 9–14.
43.
Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafshede P, Knight R, Mazmanian SK: Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 2016; 167: 1469–1480 e1412.
44.
Scheperjans F, Aho V, Pereira PA, Koskinen K, Paulin L, Pekkonen E, Haapaniemi E, Kaakkola S, Eerola-Rautio J, Pohja M, Kinnunen E, Murros K, Auvinen P: Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord 2015; 30: 350–358.
45.
Hopfner F, Kunstner A, Muller SH, Kunzel S, Zeuner KE, Margraf NG, Deuschl G, Baines JF, Kuhlenbaumer G: Gut microbiota in Parkinson disease in a northern German cohort. Brain Res 2017; 1667: 41–45.
46.
Hill-Burns EM, Debelius JW, Morton JT, Wissemann WT, Lewis MR, Wallen ZD, Peddada SD, Factor SA, Molho E, Zabetian CP, Knight R, Payami H: Parkinson’s disease and Parkinson’s disease medications have distinct signatures of the gut microbiome. Mov Disord 2017; 32: 739–749.
47.
Pereira PAB, Aho VTE, Paulin L, Pekkonen E, Auvinen P, Scheperjans F: Oral and nasal microbiota in Parkinson’s disease. Parkinsonism Relat Disord 2017; 38: 61–67.
48.
Scott LV, Clarke G, Dinan TG: The brain-gut axis: a target for treating stress-related disorders. Mod Trends Pharmacopsychiatry 2013; 28: 90–99.
49.
Wang L, Fleming SM, Chesselet MF, Tache Y: Abnormal colonic motility in mice overexpressing human wild-type alpha-synuclein. Neuroreport 2008; 19: 873–876.
50.
Hallett PJ, McLean JR, Kartunen A, Langston JW, Isacson O: Alpha-synuclein overexpressing transgenic mice show internal organ pathology and autonomic deficits. Neurobiol Dis 2012; 47: 258–267.
51.
Shannon KM, Keshavarzian A, Mutlu E, Dodiya HB, Daian D, Jaglin JA, Kordower JH: Alpha-synuclein in colonic submucosa in early untreated Parkinson’s disease. Mov Disord 2012; 27: 709–715.
52.
Barrenschee M, Zorenkov D, Bottner M, Lange C, Cossais F, Scharf AB, Deuschl G, Schneider SA, Ellrichmann M, Fritscher-Ravens A, Wedel T: Distinct pattern of enteric phospho-alpha-synuclein aggregates and gene expression profiles in patients with Parkinson’s disease. Acta Neuropathol Commun 2017; 5: 1.
53.
Forsyth CB, Shannon KM, Kordower JH, Voigt RM, Shaikh M, Jaglin JA, Estes JD, Dodiya HB, Keshavarzian A: Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS One 2011; 6:e28032.
54.
Goldman SM, Kamel F, Ross GW, Jewell SA, Marras C, Hoppin JA, Umbach DM, Bhudhikanok GS, Meng C, Korell M, Comyns K, Hauser RA, Jankovic J, Factor SA, Bressman S, Lyons KE, Sandler DP, Langston JW, Tanner CM: Peptidoglycan recognition protein genes and risk of Parkinson’s disease. Mov Disord 2014; 29: 1171–1180.
55.
Kelly LP, Carvey PM, Keshavarzian A, Shannon KM, Shaikh M, Bakay RA, Kordower JH: Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson’s disease. Mov Disord 2014; 29: 999–1009.
56.
Nourhashemi F, Deschamps V, Larrieu S, Letenneur L, Dartigues JF, Barberger-Gateau P, PAQUID Study: Body mass index and incidence of dementia: the PAQUID study. Neurology 2003; 60: 117–119.
57.
Chen CH, Lin CL, Kao CH: Irritable bowel syndrome is associated with an increased risk of dementia: a nationwide population-based study. PLoS One 2016; 11:e0144589.
58.
Joachim CL, Mori H, Selkoe DJ: Amyloid beta-protein deposition in tissues other than brain in Alzheimer’s disease. Nature 1989; 341: 226–230.
59.
Brandscheid C, Schuck F, Reinhardt S, Schafer KH, Pietrzik CU, Grimm M, Hartmann T, Schwiertz A, Endres K: Altered gut microbiome composition and tryptic activity of the 5xFAD Alzheimer’s mouse model. J Alzhei­mers Dis 2017; 56: 775–788.
60.
Semar S, Klotz M, Letiembre M, Van Ginneken C, Braun A, Jost V, Bischof M, Lammers WJ, Liu Y, Fassbender K, Wyss-Coray T, Kirchhoff F, Schafer KH: Changes of the enteric nervous system in amyloid-beta protein precursor transgenic mice correlate with disease progression. J Alzheimers Dis 2013; 36: 7–20.
61.
Cattaneo A, Cattane N, Galluzzi S, Provasi S, Lopizzo N, Festari C, Ferrari C, Guerra UP, Paghera B, Muscio C, Bianchetti A, Volta GD, Turla M, Cotelli MS, Gennuso M, Prelle A, Zanetti O, Lussignoli G, Mirabile D, Bellandi D, Gentile S, Belotti G, Villani D, Harach T, Bolmont T, Padovani A, Boccardi M, Frisoni GB, INDIA-FBP Group: Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging 2017; 49: 60–68.
62.
Emery DC, Shoemark DK, Batstone TE, Waterfall CM, Coghill JA, Cerajewska TL, Davies M, West NX, Allen SJ: 16S rRNA next generation sequencing analysis shows bacteria in Alzheimer’s post-mortem brain. Front Aging Neurosci 2017; 9: 195.
63.
Zhao Y, Jaber V, Lukiw WJ: Secretory products of the human GI tract microbiome and their potential impact on Alzheimer’s disease (AD): detection of lipopolysaccharide (LPS) in AD hippocampus. Front Cell Infect Microbiol 2017; 7: 318.
64.
Noble JM, Scarmeas N, Celenti RS, Elkind MS, Wright CB, Schupf N, Papapanou PN: Serum IgG antibody levels to periodontal microbiota are associated with incident Alz­heimer disease. PLoS One 2014; 9:e114959.
65.
Negi S, Singh H, Mukhopadhyay A: Gut bacterial peptides with autoimmunity potential as environmental trigger for late onset complex diseases: in-silico study. PLoS One 2017; 12:e0180518.
66.
Harach T, Marungruang N, Duthilleul N, Cheatham V, Mc Coy KD, Frisoni G, Neher JJ, Fak F, Jucker M, Lasser T, Bolmont T: Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep 2017; 7: 41802.
67.
Fransen F, van Beek AA, Borghuis T, Aidy SE, Hugenholtz F, van der Gaast-de Jongh C, Savelkoul HFJ, De Jonge MI, Boekschoten MV, Smidt H, Faas MM, de Vos P: Aged gut microbiota contributes to systemical inflammaging after transfer to germ-free mice. Front Immunol 2017; 8: 1385.
68.
Evrensel A, Ceylan ME: Fecal microbiota transplantation and its usage in neuropsychiatric disorders. Clin Psychopharmacol Neurosci 2016; 14: 231–237.
69.
Yuan T, Ma H, Liu W, Niesen DB, Shah N, Crews R, Rose KN, Vattem DA, Seeram NP: Pomegranate’s neuroprotective effects against Alzheimer’s disease are mediated by urolithins, its ellagitannin-gut microbial derived metabolites. ACS Chem Neurosci 2016; 7: 26–33.
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