https://doi.org/10.4081/ejh.2021.3278
From the intestinal mucosal barrier to the enteric neuromuscular compartment: an integrated overview on the morphological changes in Parkinson’s disease
Submitted: 21 May 2021
Accepted: 20 October 2021
Published: 22 November 2021
Accepted: 20 October 2021
Abstract Views: 1004
PDF: 620
HTML: 29
HTML: 29
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Gastrointestinal dysfunctions represent the most common non-motor symptoms in Parkinson’s disease (PD). Of note, changes in gut microbiota, impairments of intestinal epithelial barrier (IEB), bowel inflammation and neuroplastic rearrangements of the enteric nervous system (ENS) could be involved in the pathophysiology of the intestinal disturbances in PD. In this context, although several review articles have pooled together evidence on the alterations of enteric bacteria-neuro-immune network in PD, a revision of the literature on the specific morphological changes occurring in the intestinal mucosal barrier, the ENS and enteric muscular layers in PD, is lacking. The present review provides a complete appraisal of the available knowledge on the morphological alterations of intestinal mucosal barrier, with particular focus on IEB, ENS and enteric muscular layers in PD. In particular, our intent was to critically discuss whether, based on evidence from translational studies and pre-clinical models, morphological changes in the intestinal barrier and enteric neuromuscular compartment contribute to the pathophysiology of intestinal dysfunctions occurring in PD.
Pellegrini C, Antonioli L, Colucci R, Blandizzi C, Fornai M. Interplay among gut microbiota, intestinal mucosal barrier and enteric neuro-immune system: a common path to neurodegenerative diseases? Acta Neuropathol 2018;136:345-61.
DOI: https://doi.org/10.1007/s00401-018-1856-5
Perez-Pardo P, Dodiya HB, Engen PA, Forsyth CB, Huschens AM, Shaikh M, et al. Role of TLR4 in the gut-brain axis in Parkinson's disease: a translational study from men to mice. Gut 2019;68:829-43.
DOI: https://doi.org/10.1136/gutjnl-2018-316844
Fasano A, Visanji NP, Liu LW, Lang AE, Pfeiffer RF. Gastrointestinal dysfunction in Parkinson's disease. Lancet Neurol 2015;14:625-39.
DOI: https://doi.org/10.1016/S1474-4422(15)00007-1
Pfeiffer RF. Gastrointestinal dysfunction in Parkinson's disease. Curr Treat Options Neurol 2018;20:54.
DOI: https://doi.org/10.1007/s11940-018-0539-9
D'Antongiovanni V, Pellegrini C, Fornai M, Colucci R, Blandizzi C, Antonioli L, Bernardini N. Intestinal epithelial barrier and neuromuscular compartment in health and disease. World J Gastroenterol 2020;26:1564-79.
DOI: https://doi.org/10.3748/wjg.v26.i14.1564
Keshavarzian A, Green SJ, Engen PA, et al. Colonic bacterial composition in Parkinson's disease. Mov Disord 2015;30:1351-60.
DOI: https://doi.org/10.1002/mds.26307
Rutsch A, Kantsjo JB, Ronchi F. The gut-brain axis: How microbiota and host inflammasome influence brain physiology and pathology. Front Immunol 2020;11:604179.
DOI: https://doi.org/10.3389/fimmu.2020.604179
Spencer NJ, Hu H. Enteric nervous system: sensory transduction, neural circuits and gastrointestinal motility. Nat Rev Gastroenterol Hepatol 2020;17:338-51.
DOI: https://doi.org/10.1038/s41575-020-0271-2
Sanders KM, Koh SD, Ro S, Ward SM. Regulation of gastrointestinal motility--insights from smooth muscle biology. Nat Rev Gastroenterol Hepatol 2012;9:633-45.
DOI: https://doi.org/10.1038/nrgastro.2012.168
Chelakkot C, Ghim J, Ryu SH. Mechanisms regulating intestinal barrier integrity and its pathological implications. Exp Mol Med 2018;50:103.
DOI: https://doi.org/10.1038/s12276-018-0126-x
Salvo Romero E, Alonso Cotoner C, Pardo Camacho C, Casado Bedmar M, Vicario M. The intestinal barrier function and its involvement in digestive disease. Rev Esp Enferm Dig 2015;107:686-96.
DOI: https://doi.org/10.17235/reed.2015.3846/2015
Kim YS, Ho SB. Intestinal goblet cells and mucins in health and disease: recent insights and progress. Curr Gastroenterol Rep 2010;12:319-30.
DOI: https://doi.org/10.1007/s11894-010-0131-2
Pedemonte N, Galietta LJ. Structure and function of TMEM16 proteins (anoctamins). Physiol Rev 2014;94:419-59.
DOI: https://doi.org/10.1152/physrev.00039.2011
Keely S, Kelly CJ, Weissmueller T, Burgess A, Wagner BD, Robertson CE, et al. Activated fluid transport regulates bacterial-epithelial interactions and significantly shifts the murine colonic microbiome. Gut Microbes 2012;3:250-60.
DOI: https://doi.org/10.4161/gmic.20529
Kong S, Zhang YH, Zhang W. Regulation of intestinal epithelial cells properties and functions by amino acids. BioMed Res Int 2018;2018:2819154.
DOI: https://doi.org/10.1155/2018/2819154
Miron N, Cristea V. Enterocytes: active cells in tolerance to food and microbial antigens in the gut. Clin Exp Immunol 2012;167:405-12.
DOI: https://doi.org/10.1111/j.1365-2249.2011.04523.x
Clevers HC, Bevins CL. Paneth cells: maestros of the small intestinal crypts. Ann Rev Physiol 2013;75:289-311.
DOI: https://doi.org/10.1146/annurev-physiol-030212-183744
Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol 2009;9:799-809.
DOI: https://doi.org/10.1038/nri2653
Lu Z, Ding L, Lu Q, Chen YH. Claudins in intestines: Distribution and functional significance in health and diseases. Tissue Barriers 2013;1:e24978.
DOI: https://doi.org/10.4161/tisb.24978
Anderson JM, Van Itallie CM. Physiology and function of the tight junction. Cold Spring Harb Perspect Biol 2009;1:a002584.
DOI: https://doi.org/10.1101/cshperspect.a002584
Hartsock A, Nelson WJ. Adherens and tight junctions: structure, function and connections to the actin cytoskeleton. Biochim Biophys Acta 2008;1778:660-9.
DOI: https://doi.org/10.1016/j.bbamem.2007.07.012
Pinchuk IV, Mifflin RC, Saada JI, Powell DW. Intestinal mesenchymal cells. Curr Gastroenterol Rep 2010;12:310-8.
DOI: https://doi.org/10.1007/s11894-010-0135-y
Powell DW, Mifflin RC, Valentich JD, Crowe SE, Saada JI, West AB. Myofibroblasts. II. Intestinal subepithelial myofibroblasts. Am J Physiol 1999;277:C183-201.
DOI: https://doi.org/10.1152/ajpcell.1999.277.2.C183
Kurahashi M, Nakano Y, Peri LE, Townsend JB, Ward SM, Sanders KM. A novel population of subepithelial platelet-derived growth factor receptor alpha-positive cells in the mouse and human colon. Am J Physiol Gastrointest Liver Physiol 2013;304:G823-34.
DOI: https://doi.org/10.1152/ajpgi.00001.2013
Higuchi Y, Kojima M, Ishii G, Aoyagi K, Sasaki H, Ochiai A. Gastrointestinal fibroblasts have specialized, diverse transcriptional phenotypes: A comprehensive gene expression analysis of human fibroblasts. PloS One 2015;10:e0129241.
DOI: https://doi.org/10.1371/journal.pone.0129241
Mifflin RC, Pinchuk IV, Saada JI, Powell DW. Intestinal myofibroblasts: targets for stem cell therapy. Am J Physiol Gastrointest Liver Physiol 2011;300:G684-96.
DOI: https://doi.org/10.1152/ajpgi.00474.2010
Furness JB, Callaghan BP, Rivera LR, Cho HJ. The enteric nervous system and gastrointestinal innervation: integrated local and central control. Adv Exp Med Biol 2014;817:39-71.
DOI: https://doi.org/10.1007/978-1-4939-0897-4_3
Puzan M, Hosic S, Ghio C, Koppes A. Enteric nervous system regulation of intestinal stem cell differentiation and epithelial monolayer function. Sci Rep 2018;8:6313.
DOI: https://doi.org/10.1038/s41598-018-24768-3
Fornai M, van den Wijngaard RM, Antonioli L, Pellegrini C, Blandizzi C, de Jonge WJ. Neuronal regulation of intestinal immune functions in health and disease. Neurogastroenterol Motil 2018;30:e13406.
DOI: https://doi.org/10.1111/nmo.13406
Longo WE, Vernava AM, 3rd. Prokinetic agents for lower gastrointestinal motility disorders. Dis Colon Rectum 1993;36:696-708.
DOI: https://doi.org/10.1007/BF02238599
Feng XY, Zhang DN, Wang YA, Fan RF, Hong F, Zhang Y, et al. Dopamine enhances duodenal epithelial permeability via the dopamine D5 receptor in rodent. Acta Physiol (Oxf) 2017;220:113-23.
DOI: https://doi.org/10.1111/apha.12806
Li Y, Zhang Y, Zhang XL, Feng XY, Liu CZ, Zhang XN, et al. Dopamine promotes colonic mucus secretion through dopamine D5 receptor in rats. Am J Physiol Cell Physiol 2019;316:C393-403.
DOI: https://doi.org/10.1152/ajpcell.00261.2017
Lundgren O, Jodal M, Jansson M, Ryberg AT, Svensson L. Intestinal epithelial stem/progenitor cells are controlled by mucosal afferent nerves. PloS One 2011;6:e16295.
DOI: https://doi.org/10.1371/journal.pone.0016295
Gross ER, Gershon MD, Margolis KG, Gertsberg ZV, Li Z, Cowles RA. Neuronal serotonin regulates growth of the intestinal mucosa in mice. Gastroenterology 2012;143:408-17.
DOI: https://doi.org/10.1053/j.gastro.2012.05.007
Neunlist M, Rolli-Derkinderen M, Latorre R, Van Landeghem L, Coron E, Derkinderen P, De Giorgio R, et al. Enteric glial cells: recent developments and future directions. Gastroenterology 2014;147:1230-7.
DOI: https://doi.org/10.1053/j.gastro.2014.09.040
Yu YB, Li YQ. Enteric glial cells and their role in the intestinal epithelial barrier. World J Gastroenterol 2014;20:11273-80.
DOI: https://doi.org/10.3748/wjg.v20.i32.11273
Vergnolle N, Cirillo C. Neurons and glia in the enteric nervous system and epithelial barrier function. Physiology 2018;33:269-80.
DOI: https://doi.org/10.1152/physiol.00009.2018
Delvalle NM, Fried DE, Rivera-Lopez G, Gaudette L, Gulbransen BD. Cholinergic activation of enteric glia is a physiological mechanism that contributes to the regulation of gastrointestinal motility. Am J Physiol Gastrointest Liver Physiol 2018;315:G473-83.
DOI: https://doi.org/10.1152/ajpgi.00155.2018
Gomez-Pinilla PJ, Gibbons SJ, Bardsley MR, Lorincz A, Pozo MJ, Pasricha PJ, et al. Ano1 is a selective marker of interstitial cells of Cajal in the human and mouse gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol 2009;296:G1370-81.
DOI: https://doi.org/10.1152/ajpgi.00074.2009
Clairembault T, Leclair-Visonneau L, Coron E, Bourreille A, Le Dily S, Vavasseur F, et al. Structural alterations of the intestinal epithelial barrier in Parkinson's disease. Acta Neuropathol Commun 2015;3:12.
DOI: https://doi.org/10.1186/s40478-015-0196-0
Bischoff SC, Barbara G, Buurman W, Ockhuizen T, Schulzk JD, Serino M, et al. Intestinal permeability--a new target for disease prevention and therapy. BMC Gastroenterol 2014;14:189.
DOI: https://doi.org/10.1186/s12876-014-0189-7
Kelly LP, Carvey PM, Keshavarzian A, Shannon KM, Shaikh M, Bakayet RAE, al. Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson's disease. Mov Dis 2014;29:999-1009.
DOI: https://doi.org/10.1002/mds.25736
Pellegrini C, Ippolito C, Segnani C, Dolfi A, Errede M, Virgintino D, et al. Pathological remodelling of colonic wall following dopaminergic nigrostriatal neurodegeneration. Neurobiol Dis 2020;139:104821.
DOI: https://doi.org/10.1016/j.nbd.2020.104821
Zhang X, Li Y, Liu C, Fan R, Wang P, Zheng L, et al. Alteration of enteric monoamines with monoamine receptors and colonic dysmotility in 6-hydroxydopamine-induced Parkinson's disease rats. Transl Res 2015;166:152-62.
DOI: https://doi.org/10.1016/j.trsl.2015.02.003
Fornai M, Pellegrini C, Antonioli L, Segnani C, Ippolito C, Barocelli E, et al. Enteric dysfunctions in experimental Parkinson's disease: Alterations of excitatory cholinergic neurotransmission regulating colonic motility in rats. J Pharmacol Exp Ther 2016;356:434-44.
DOI: https://doi.org/10.1124/jpet.115.228510
Singaram C, Ashraf W, Gaumnitz EA, Torbey C, Sengupta A, Pfeiffer R, et al. Dopaminergic defect of enteric nervous system in Parkinson's disease patients with chronic constipation. Lancet 1995;346:861-4.
DOI: https://doi.org/10.1016/S0140-6736(95)92707-7
Annerino DM, Arshad S, Taylor GM, Adler CH, Beach TG, Greene JG. Parkinson's disease is not associated with gastrointestinal myenteric ganglion neuron loss. Acta Neuropathol 2012;124:665-80.
DOI: https://doi.org/10.1007/s00401-012-1040-2
Corbille AG, Coron E, Neunlist M, Derkinderen P, Lebouvier T. Appraisal of the dopaminergic and noradrenergic innervation of the submucosal plexus in PD. J Parkinsons Dis 2014;4:571-6.
DOI: https://doi.org/10.3233/JPD-140422
Devos D, Lebouvier T, Lardeux B, Biraud M, Rouaud T, Pouclet H, et al. Colonic inflammation in Parkinson's disease. Neurobiol Dis 2013;50:42-8.
DOI: https://doi.org/10.1016/j.nbd.2012.09.007
Wakabayashi K. Where and how alpha-synuclein pathology spreads in Parkinson's disease. Neuropathology 2020;40:415-25.
DOI: https://doi.org/10.1111/neup.12691
Hilton D, Stephens M, Kirk L, Edwards P, Potter R, Zajicek J, et al. Accumulation of alpha-synuclein in the bowel of patients in the pre-clinical phase of Parkinson's disease. Acta Neuropathol 2014;127:235-41.
DOI: https://doi.org/10.1007/s00401-013-1214-6
Cersosimo MG. Gastrointestinal biopsies for the diagnosis of alpha-synuclein pathology in Parkinson's disease. Gastroenterol Res Pract 2015;2015:476041.
DOI: https://doi.org/10.1155/2015/476041
Corbille AG, Clairembault T, Coron E, Leclair-Visonneau L, Preterre C, Neunlist M, et al. What a gastrointestinal biopsy can tell us about Parkinson's disease? Neurogastroenterol Motil 2016;28:966-74.
DOI: https://doi.org/10.1111/nmo.12797
Anderson G, Noorian AR, Taylor G, Anitha M, Bernhard D, Srinivasan S, et al. Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease. Exp Neurol 2007;207:4-12.
DOI: https://doi.org/10.1016/j.expneurol.2007.05.010
Natale G, Kastsiushenka O, Fulceri F, Ruggieri S, Paparelli A, Fornai F. MPTP-induced parkinsonism extends to a subclass of TH-positive neurons in the gut. Brain Res 2010;1355:195-206.
DOI: https://doi.org/10.1016/j.brainres.2010.07.076
Colucci M, Cervio M, Faniglione M, De Angelis S, Pajoro M, Levandis G, et al. Intestinal dysmotility and enteric neurochemical changes in a Parkinson's disease rat model. Auton Neurosci 2012;169:77-86.
DOI: https://doi.org/10.1016/j.autneu.2012.04.005
Tasselli M, Chaumette T, Paillusson S, Monnet Y, Lafoux A, Huchet-Cadiou C, et al. Effects of oral administration of rotenone on gastrointestinal functions in mice. Neurogastroenterol Motil 2013;25:e183-93.
DOI: https://doi.org/10.1111/nmo.12070
Pellegrini C, Fornai M, Colucci R, Tirotta E, Blandini F, Levandis G, et al. Alteration of colonic excitatory tachykininergic motility and enteric inflammation following dopaminergic nigrostriatal neurodegeneration. J Neuroinflamm 2016;13:146.
DOI: https://doi.org/10.1186/s12974-016-0608-5
Benvenuti L, D'Antongiovanni V, Pellegrini C, Antonioli L, Bernardini N, Blandizzi C, et al. Enteric glia at the crossroads between intestinal immune system and epithelial barrier: Implications for Parkinson disease. Int J Mol Sci 2020;21:9199.
DOI: https://doi.org/10.3390/ijms21239199
How to Cite
Pellegrini, C., D’Antongiovanni, V., Ippolito, C., Segnani, C., Antonioli, L., Fornai, M., & Bernardini, N. (2021). From the intestinal mucosal barrier to the enteric neuromuscular compartment: an integrated overview on the morphological changes in Parkinson’s disease. European Journal of Histochemistry, 65(s1). https://doi.org/10.4081/ejh.2021.3278
Copyright (c) 2021 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
Similar Articles
- Arianna Casini, Romina Mancinelli, Caterina Loredana Mammola, Luigi Pannarale, Piero Chirletti, Paolo Onori, Rosa Vaccaro, Distribution of alpha-synuclein in normal human jejunum and its relations with the chemosensory and neuroendocrine system , European Journal of Histochemistry: Vol. 65 No. 4 (2021)
- Francesca Bianco, Giulia Lattanzio, Luca Lorenzini, Chiara Diquigiovanni, Maurizio Mazzoni, Paolo Clavenzani, Laura Calzà, Luciana Giardino, Catia Sternini, Elena Bonora, Roberto De Giorgio, Novel understanding on genetic mechanisms of enteric neuropathies leading to severe gut dysmotility , European Journal of Histochemistry: Vol. 65 No. s1 (2021): Special Collection on Advances in Neuromorphology in Health and Disease
- Federico Angelo Cazzaniga, Edoardo Bistaffa, Chiara Maria Giulia De Luca, Giuseppe Bufano, Antonio Indaco, Giorgio Giaccone, Fabio Moda, Sporadic Creutzfeldt-Jakob disease: Real-Time Quaking Induced Conversion (RT-QuIC) assay represents a major diagnostic advance , European Journal of Histochemistry: Vol. 65 No. s1 (2021): Special Collection on Advances in Neuromorphology in Health and Disease
- G. Tsirakis, C. A. Pappa, M. Kaparou, V. Katsomitrou, A. Hatzivasili, T. Alegakis, A. Xekalou, E. N. Stathopoulos, M. Alexandrakis, Assessment of proliferating cell nuclear antigen and its relationship with proinflammatory cytokines and parameters of disease activity in multiple myeloma patients , European Journal of Histochemistry: Vol. 55 No. 3 (2011)
- C. Severi, R. Sferra, A. Scirocco, A. Vetuschi, N. Pallotta, A. Pronio, R. Caronna, G. Di Rocco, E. Gaudio, E. Corazziari, P. Onori, Contribution of intestinal smooth muscle to Crohn's disease fibrogenesis , European Journal of Histochemistry: Vol. 58 No. 4 (2014)
- Yan Wang, Jie Sun, Ninghua Yao, Correlation of the AKT/mTOR signaling pathway with the clinicopathological features and prognosis of nasopharyngeal carcinoma , European Journal of Histochemistry: Vol. 65 No. 4 (2021)
- Ilen Röhe, Friedrich Joseph Hüttner, Johanna Plendl, Barbara Drewes, Jürgen Zentek, Comparison of different histological protocols for the preservation and quantification of the intestinal mucus layer in pigs , European Journal of Histochemistry: Vol. 62 No. 1 (2018)
- E. Akat, H. Arıkan, B. Göçmen, Histochemical and biometric study of the gastrointestinal system of Hyla orientalis (Bedriaga, 1890) (Anura, Hylidae) , European Journal of Histochemistry: Vol. 58 No. 4 (2014)
- Filippo Vernia, Tiziana Tatti, Stefano Necozione, Annalisa Capannolo, Nicola Cesaro, Marco Magistroni, Marco Valvano, Simona Pompili, Roberta Sferra, Antonella Vetuschi, Giovanni Latella, Is mastocytic colitis a specific clinical-pathological entity? , European Journal of Histochemistry: Vol. 66 No. 4 (2022)
- Y. Dong, C. Yang, Z. Wang, Z. Qin, J. Cao, Y. Chen, The injury of serotonin on intestinal epithelium cell renewal of weaned diarrhoea mice , European Journal of Histochemistry: Vol. 60 No. 4 (2016)
You may also start an advanced similarity search for this article.
Publication Facts
Metric
This article
Other articles
Peer reviewers
1
2.4
Reviewer profiles N/A
Author statements
Author statements
This article
Other articles
Data availability
N/A
16%
External funding
N/A
32%
Competing interests
N/A
11%
Metric
This journal
Other journals
Articles accepted
57%
33%
Days to publication
184
145
- Editor & editorial board
- profiles
- Academic society
- N/A
- Publisher
- PAGEPress Publications, Pavia, Italy
To learn about these publication facts, click 
PF is maintained by the Public Knowledge Project
