Top

Published in:

24-11-2021 | Parkinson's Disease | Neurology and Preclinical Neurological Studies - Review Article

Gastrointestinal mucosal biopsies in Parkinson’s disease: beyond alpha-synuclein detection

Authors: Pascal Derkinderen, François Cossais, Adrien de Guilhem de Lataillade, Laurène Leclair-Visonneau, Michel Neunlist, Sébastien Paillusson, Roberto De Giorgio

Published in: Journal of Neural Transmission | Issue 9/2022

Abstract

Alpha-synuclein deposits, the pathological hallmarks of Parkinson’s disease, are consistently found in the gastrointestinal tract of parkinsonian subjects. These observations have raised the potential that endoscopically obtainable mucosal biopsies can aid to a molecular diagnosis of the disease. The possible usefulness of mucosal biopsies is, however, not limited to the detection of alpha-synuclein, but also extends to other essential aspects underlying pathophysiological mechanisms of gastrointestinal manifestations in Parkinson’s disease. The aim of the current review is to provide an appraisal of the existing studies showing that gastrointestinal biopsies can be used for the analysis of enteric neuronal and glial cell morphology, intestinal epithelial barrier function, and gastrointestinal inflammation in Parkinson’s disease. A perspective on the generation of organoids with GI biopsies and the potential use of single-cell and spatial transcriptomic technologies will be also addressed.

Ahn EH, Kang SS, Liu X et al (2021) BDNF and netrin-1 repression by C/EBPβ in the gut triggers Parkinson’s disease pathologies, associated with constipation and motor dysfunctions. Prog Neurobiol 198:101905. https://doi.org/10.1016/j.pneurobio.2020.101905CrossRefPubMed

Anlauf M, Schäfer MK-H, Eiden L, Weihe E (2003) Chemical coding of the human gastrointestinal nervous system: cholinergic, VIPergic, and catecholaminergic phenotypes. J Comp Neurol 459:90–111. https://doi.org/10.1002/cne.10599CrossRefPubMed

Annerino DM, Arshad S, Taylor GM et al (2012) Parkinson’s disease is not associated with gastrointestinal myenteric ganglion neuron loss. Acta Neuropathol 124:665–680. https://doi.org/10.1007/s00401-012-1040-2CrossRefPubMedPubMedCentral

Barrenschee M, Zorenkov D, Böttner M et al (2017) Distinct pattern of enteric phospho-alpha-synuclein aggregates and gene expression profiles in patients with Parkinson’s disease. Acta Neuropathol Commun 5:1. https://doi.org/10.1186/s40478-016-0408-2CrossRefPubMedPubMedCentral

Bassotti G, Villanacci V, Maurer CA et al (2006) The role of glial cells and apoptosis of enteric neurones in the neuropathology of intractable slow transit constipation. Gut 55:41–46. https://doi.org/10.1136/gut.2005.073197CrossRefPubMedPubMedCentral

Baumuratov AS, Antony PMA, Ostaszewski M et al (2016) Enteric neurons from Parkinson’s disease patients display ex vivo aberrations in mitochondrial structure. Sci Rep 6:33117. https://doi.org/10.1038/srep33117CrossRefPubMedPubMedCentral

Beach TG, Adler CH, Sue LI et al (2010) Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 119:689–702. https://doi.org/10.1007/s00401-010-0664-3CrossRefPubMedPubMedCentral

Berg D, Borghammer P, Fereshtehnejad S-M et al (2021) Prodromal Parkinson disease subtypes—key to understanding heterogeneity. Nat Rev Neurol 17:349–361. https://doi.org/10.1038/s41582-021-00486-9CrossRefPubMed

Borghammer P, Van Den Berge N (2019) Brain-first versus gut-first Parkinson’s disease: a hypothesis. J Parkinsons Dis 9:S281–S295. https://doi.org/10.3233/JPD-191721CrossRefPubMedPubMedCentral

Boschetti E, Malagelada C, Accarino A et al (2019) Enteric neuron density correlates with clinical features of severe gut dysmotility. Am J Physiol Gastrointest Liver Physiol 317:G793–G801. https://doi.org/10.1152/ajpgi.00199.2019CrossRefPubMedPubMedCentral

Braak H, Del Tredici K, Rüb U et al (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211CrossRef

Braak H, de Vos RA, Bohl J, Del Tredici K (2006) 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. https://doi.org/10.1016/j.neulet.2005.11.012CrossRefPubMed

Chapelet G, Leclair-Visonneau L, Clairembault T et al (2019) Can the gut be the missing piece in uncovering PD pathogenesis? Parkinsonism Relat Disord 59:26–31. https://doi.org/10.1016/j.parkreldis.2018.11.014CrossRefPubMed

Chen F, Yu Y, Wang P et al (2014) Brain-derived neurotrophic factor accelerates gut motility in slow-transit constipation. Acta Physiol (oxf) 212:226–238. https://doi.org/10.1111/apha.12374CrossRef

Chen Y, Yu M, Liu X et al (2015) Clinical characteristics and peripheral T cell subsets in Parkinson’s disease patients with constipation. Int J Clin Exp Pathol 8:2495–2504PubMedPubMedCentral

Clairembault T, Kamphuis W, Leclair-Visonneau L et al (2014) Enteric GFAP expression and phosphorylation in Parkinson’s disease. J Neurochem 130:805–815. https://doi.org/10.1111/jnc.12742CrossRefPubMed

Clairembault T, Leclair-Visonneau L, Coron E et al (2015) Structural alterations of the intestinal epithelial barrier in Parkinson’s disease. Acta Neuropathol Commun 3:12. https://doi.org/10.1186/s40478-015-0196-0CrossRefPubMedPubMedCentral

Co JY, Margalef-Català M, Li X et al (2019) Controlling epithelial polarity: a human enteroid model for host-pathogen interactions. Cell Rep 26:2509-2520.e4. https://doi.org/10.1016/j.celrep.2019.01.108CrossRefPubMedPubMedCentral

Corbillé A-G, Coron E, Neunlist M et al (2014) Appraisal of the dopaminergic and noradrenergic innervation of the submucosal plexus in PD. J Parkinsons Dis 4:571–576. https://doi.org/10.3233/JPD-140422CrossRefPubMed

Corbillé A-G, Preterre C, Rolli-Derkinderen M et al (2017) Biochemical analysis of α-synuclein extracted from control and Parkinson’s disease colonic biopsies. Neurosci Lett 641:81–86. https://doi.org/10.1016/j.neulet.2017.01.050CrossRefPubMed

Cossais F, Schaeffer E, Heinzel S et al (2021) Expression profiling of rectal biopsies suggests altered enteric Neuropathological traits in Parkinson’s disease patients. J Parkinsons Dis 11:171–176. https://doi.org/10.3233/JPD-202258CrossRefPubMed

Damier P, Hirsch EC, Zhang P et al (1993) Glutathione peroxidase, glial cells and Parkinson’s disease. Neuroscience 52:1–6. https://doi.org/10.1016/0306-4522(93)90175-fCrossRefPubMed

Davies KN, King D, Billington D, Barrett JA (1996) Intestinal permeability and orocaecal transit time in elderly patients with Parkinson’s disease. Postgrad Med J 72:164–167CrossRef

De Giorgio R, Bianco F, Latorre R et al (2016) Enteric neuropathies: yesterday, today and tomorrow. Adv Exp Med Biol 891:123–133. https://doi.org/10.1007/978-3-319-27592-5_12CrossRefPubMed

de Guilhem de Lataillade A, Verchere J, Oullier T et al (2021) LRRK2 is reduced in Parkinson’s disease gut. Acta Neuropathol 142:601–603. https://doi.org/10.1007/s00401-021-02334-yCrossRefPubMed

Delafoy L, Gelot A, Ardid D et al (2006) Interactive involvement of brain derived neurotrophic factor, nerve growth factor, and calcitonin gene related peptide in colonic hypersensitivity in the rat. Gut 55:940–945. https://doi.org/10.1136/gut.2005.064063CrossRefPubMedPubMedCentral

Desmet A-S, Cirillo C, Tack J et al (2017) Live calcium and mitochondrial imaging in the enteric nervous system of Parkinson patients and controls. Elife 6:e26850. https://doi.org/10.7554/eLife.26850CrossRefPubMedPubMedCentral

Devos D, Lebouvier T, Lardeux B et al (2013) Colonic inflammation in Parkinson’s disease. Neurobiol Dis 50:42–48. https://doi.org/10.1016/j.nbd.2012.09.007CrossRefPubMed

Edwards LL, Pfeiffer RF, Quigley EM et al (1991) Gastrointestinal symptoms in Parkinson’s disease. Mov Disord 6:151–156. https://doi.org/10.1002/mds.870060211CrossRefPubMed

Elmentaite R, Kumasaka N, Roberts K et al (2021) Cells of the human intestinal tract mapped across space and time. Nature 597:250–255. https://doi.org/10.1038/s41586-021-03852-1CrossRefPubMedPubMedCentral

Escartin C, Galea E, Lakatos A et al (2021) Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci 24:312–325. https://doi.org/10.1038/s41593-020-00783-4CrossRefPubMedPubMedCentral

Forsyth CB, Shannon KM, Kordower JH et al (2011) Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS ONE 6:e28032. https://doi.org/10.1371/journal.pone.0028032CrossRefPubMedPubMedCentral

Furness JB, Stebbing MJ (2018) The first brain: species comparisons and evolutionary implications for the enteric and central nervous systems. Neurogastroenterol Motil. https://doi.org/10.1111/nmo.13234CrossRefPubMed

Furness JB, Callaghan BP, Rivera LR, Cho H-J (2014) The enteric nervous system and gastrointestinal innervation: integrated local and central control. Adv Exp Med Biol 817:39–71. https://doi.org/10.1007/978-1-4939-0897-4_3CrossRefPubMed

Gelpi E, Navarro-Otano J, Tolosa E et al (2014) Multiple organ involvement by alpha-synuclein pathology in Lewy body disorders. Mov Disord 29:1010–1018. https://doi.org/10.1002/mds.25776CrossRefPubMed

Giancola F, Torresan F, Repossi R et al (2017) Downregulation of neuronal vasoactive intestinal polypeptide in Parkinson’s disease and chronic constipation. Neurogastroenterol Motil. https://doi.org/10.1111/nmo.12995CrossRefPubMed

Hansen MB (2003) The enteric nervous system I: organisation and classification. Pharmacol Toxicol 92:105–113. https://doi.org/10.1034/j.1600-0773.2003.t01-1-920301.xCrossRefPubMed

Houser MC, Caudle WM, Chang J et al (2021) Experimental colitis promotes sustained, sex-dependent, T-cell-associated neuroinflammation and parkinsonian neuropathology. Acta Neuropathol Commun 9:139. https://doi.org/10.1186/s40478-021-01240-4CrossRefPubMedPubMedCentral

Hui KY, Fernandez-Hernandez H, Hu J et al (2018) Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aai7795CrossRefPubMedPubMedCentral

Islam M, Chen B, Spraggins JM et al (2020) Use of single-cell -omic technologies to study the gastrointestinal tract and diseases, from single cell identities to patient features. Gastroenterology 159:453-466.e1. https://doi.org/10.1053/j.gastro.2020.04.073CrossRefPubMed

Jessen KR, Mirsky R (1980) Glial cells in the enteric nervous system contain glial fibrillary acidic protein. Nature 286:736–737. https://doi.org/10.1038/286736a0CrossRefPubMed

Johnson ME, Stecher B, Labrie V et al (2019) Triggers, facilitators, and aggravators: redefining Parkinson’s disease pathogenesis. Trends Neurosci 42:4–13. https://doi.org/10.1016/j.tins.2018.09.007CrossRefPubMed

Knudsen K, Fedorova TD, Bekker AC et al (2017) Objective colonic dysfunction is far more prevalent than subjective constipation in Parkinson’s disease: a colon transit and volume study. J Parkinsons Dis 7:359–367. https://doi.org/10.3233/JPD-161050CrossRefPubMed

Kulkarni S, Micci M-A, Leser J et al (2017) 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. https://doi.org/10.1073/pnas.1619406114CrossRefPubMedPubMedCentral

Kurian SS, Ferri GL, De Mey J, Polak JM (1983) Immunocytochemistry of serotonin-containing nerves in the human gut. Histochemistry 78:523–529. https://doi.org/10.1007/BF00496204CrossRefPubMed

Langley JN, Magnus R (1905) Some observations of the movements of the intestine before and after degenerative section of the mesenteric nerves. J Physiol 33:34–51. https://doi.org/10.1113/jphysiol.1905.sp001108CrossRefPubMedPubMedCentral

Lastres-Becker I, Ulusoy A, Innamorato NG et al (2012) α-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson’s disease. Hum Mol Genet 21:3173–3192. https://doi.org/10.1093/hmg/dds143CrossRefPubMed

Lebouvier T, Coron E, Chaumette T et al (2010a) Routine colonic biopsies as a new tool to study the enteric nervous system in living patients. Neurogastroenterol Motil 22:e11-14. https://doi.org/10.1111/j.1365-2982.2009.01368.xCrossRefPubMed

Lebouvier T, Neunlist M, Bruley des Varannes S et al (2010b) Colonic biopsies to assess the neuropathology of Parkinson’s disease and its relationship with symptoms. PLoS ONE 5:e12728. https://doi.org/10.1371/journal.pone.0012728CrossRefPubMedPubMedCentral

Leclair-Visonneau L, Neunlist M, Derkinderen P, Lebouvier T (2020) The gut in Parkinson’s disease: bottom-up, top-down, or neither? Neurogastroenterol Motil 32:e13777. https://doi.org/10.1111/nmo.13777CrossRefPubMed

Lionnet A, Wade MA, Corbillé A-G et al (2018) Characterisation of tau in the human and rodent enteric nervous system under physiological conditions and in tauopathy. Acta Neuropathol Commun 6:65. https://doi.org/10.1186/s40478-018-0568-3CrossRefPubMedPubMedCentral

Liu S (2018) Neurotrophic factors in enteric physiology and pathophysiology. Neurogastroenterol Motil 30:e13446. https://doi.org/10.1111/nmo.13446CrossRefPubMedPubMedCentral

Loffet E, Brossard L, Mahe MM (2020) Pluripotent stem cell derived intestinal organoids with an enteric nervous system. Methods Cell Biol 159:175–199. https://doi.org/10.1016/bs.mcb.2020.04.012CrossRefPubMed

Neunlist M, Coquenlorge S, Aubert P et al (2011) Colonic endoscopic full-thickness biopsies: from the neuropathological analysis of the myenteric plexus to the functional study of neuromuscular transmission. Gastrointest Endosc 73:1029–1034. https://doi.org/10.1016/j.gie.2011.01.041CrossRefPubMed

Neunlist M, Rolli-Derkinderen M, Latorre R et al (2014) Enteric glial cells: recent developments and future directions. Gastroenterology 147:1230–1237. https://doi.org/10.1053/j.gastro.2014.09.040CrossRefPubMed

Newcombe J, Woodroofe MN, Cuzner ML (1986) Distribution of glial fibrillary acidic protein in gliosed human white matter. J Neurochem 47:1713–1719. https://doi.org/10.1111/j.1471-4159.1986.tb13079.xCrossRefPubMed

Perez-Pardo P, Dodiya HB, Engen PA et al (2019) Role of TLR4 in the gut-brain axis in Parkinson’s disease: a translational study from men to mice. Gut 68:829–843. https://doi.org/10.1136/gutjnl-2018-316844CrossRefPubMed

Pfeiffer RF (2018) Gastrointestinal dysfunction in Parkinson’s disease. Curr Treat Options Neurol 20:54. https://doi.org/10.1007/s11940-018-0539-9CrossRefPubMed

Pochard C, Leclair-Visonneau L, Coron E et al (2018) Cyclooxygenase 2 is upregulated in the gastrointestinal tract in Parkinson’s disease. Mov Disord 33:493–494. https://doi.org/10.1002/mds.27237CrossRefPubMed

Pouclet H, Lebouvier T, Coron E et al (2012a) A comparison between colonic submucosa and mucosa to detect Lewy pathology in Parkinson’s disease. Neurogastroenterol Motil 24:e202-205. https://doi.org/10.1111/j.1365-2982.2012.01887.xCrossRefPubMed

Pouclet H, Lebouvier T, Coron E et al (2012b) A comparison between rectal and colonic biopsies to detect Lewy pathology in Parkinson’s disease. Neurobiol Dis 45:305–309. https://doi.org/10.1016/j.nbd.2011.08.014CrossRefPubMed

Prigent A, Lionnet A, Durieu E et al (2019) Enteric alpha-synuclein expression is increased in Crohn’s disease. Acta Neuropathol 137:359–361. https://doi.org/10.1007/s00401-018-1943-7CrossRefPubMed

Prospero L, Riezzo G, Linsalata M et al (2021) Psychological and gastrointestinal symptoms of patients with irritable bowel syndrome undergoing a low-FODMAP diet: the role of the intestinal barrier. Nutrients 13:2469. https://doi.org/10.3390/nu13072469CrossRefPubMedPubMedCentral

Raddatz D, Bockemühl M, Ramadori G (2005) Quantitative measurement of cytokine mRNA in inflammatory bowel disease: relation to clinical and endoscopic activity and outcome. Eur J Gastroenterol Hepatol 17:547–557. https://doi.org/10.1097/00042737-200505000-00012CrossRefPubMed

Rolli-Derkinderen M, Leclair-Visonneau L, Bourreille A et al (2020) Is Parkinson’s disease a chronic low-grade inflammatory bowel disease? J Neurol 267:2207–2213. https://doi.org/10.1007/s00415-019-09321-0CrossRefPubMed

Salat-Foix D, Tran K, Ranawaya R et al (2012) Increased intestinal permeability and Parkinson disease patients: chicken or egg? Can J Neurol Sci 39:185–188CrossRef

Santos SF, de Oliveira HL, Yamada ES et al (2019) The gut and Parkinson’s disease—a bidirectional pathway. Front Neurol 10:574. https://doi.org/10.3389/fneur.2019.00574CrossRefPubMedPubMedCentral

Schaeffer E, Kluge A, Böttner M et al (2020) Alpha synuclein connects the gut-brain axis in Parkinson’s disease patients—a view on clinical aspects, cellular pathology and analytical methodology. Front Cell Dev Biol 8:573696. https://doi.org/10.3389/fcell.2020.573696CrossRefPubMedPubMedCentral

Schneider SA, Boettner M, Alexoudi A et al (2016) Can we use peripheral tissue biopsies to diagnose Parkinson’s disease? A review of the literature. Eur J Neurol 23:247–261. https://doi.org/10.1111/ene.12753CrossRefPubMed

Seguella L, Gulbransen BD (2021) Enteric glial biology, intercellular signalling and roles in gastrointestinal disease. Nat Rev Gastroenterol Hepatol 18:571–587. https://doi.org/10.1038/s41575-021-00423-7CrossRefPubMedPubMedCentral

Tong J, Ang L-C, Williams B et al (2015) Low levels of astroglial markers in Parkinson’s disease: relationship to α-synuclein accumulation. Neurobiol Dis 82:243–253. https://doi.org/10.1016/j.nbd.2015.06.010CrossRefPubMedPubMedCentral

Törnblom H, Lindberg G, Nyberg B, Veress B (2002) Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome. Gastroenterology 123:1972–1979. https://doi.org/10.1053/gast.2002.37059CrossRefPubMed

Tsukada Y, Nakamura T, Iimura M et al (2002) Cytokine profile in colonic mucosa of ulcerative colitis correlates with disease activity and response to granulocytapheresis. Am J Gastroenterol 97:2820–2828. https://doi.org/10.1111/j.1572-0241.2002.07029.xCrossRefPubMed

Wallon C, Braaf Y, Wolving M, Olaison G et al (2005) Endoscopic biopsies in Ussing chambers evaluated for studies of macromolecular permeability in the human colon. Scand J Gastroenterol 40:586–595. https://doi.org/10.1080/00365520510012235CrossRefPubMed

Westerhout J, Wortelboer H, Verhoeckx K (2015) Ussing chamber. In: Verhoeckx K, Cotter P, López-Expósito I et al (eds) The impact of food bioactives on health: in vitro and ex vivo models. Springer, Cham (CH)

Zanin M, Santos BFR, Antony PMA et al (2020) Mitochondria interaction networks show altered topological patterns in Parkinson’s disease. NPJ Syst Biol Appl 6:38. https://doi.org/10.1038/s41540-020-00156-4CrossRefPubMedPubMedCentral

Zhou R, Yazdi AS, Menu P, Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469:221–225. https://doi.org/10.1038/nature09663CrossRefPubMed

Zhu F, Li C, Gong J et al (2019) The risk of Parkinson’s disease in inflammatory bowel disease: a systematic review and meta-analysis. Dig Liver Dis 51:38–42. https://doi.org/10.1016/j.dld.2018.09.017CrossRefPubMed

Title: Gastrointestinal mucosal biopsies in Parkinson’s disease: beyond alpha-synuclein detection
Authors: Pascal Derkinderen
François Cossais
Adrien de Guilhem de Lataillade
Laurène Leclair-Visonneau
Michel Neunlist
Sébastien Paillusson
Roberto De Giorgio
Publication date: 24-11-2021
Publisher: Springer Vienna
Keyword: Parkinson's Disease
Published in: Journal of Neural Transmission / Issue 9/2022
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI: https://doi.org/10.1007/s00702-021-02445-6

At a glance: The STEP trials

Springer Medicine

Gastrointestinal mucosal biopsies in Parkinson’s disease: beyond alpha-synuclein detection

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 9/2022

Disease modification in Parkinsonism: obstacles and ways forward

Life style and Parkinson’s disease

Viruses, parkinsonism and Parkinson’s disease: the past, present and future

Glucocerebrosidase mutations and Parkinson disease

Treadmill training and physiotherapy similarly improve dual task gait performance: a randomized-controlled trial in Parkinson’s disease

Implications of dopaminergic medication withdrawal in Parkinson’s disease