Kayvon Moin http://orcid.org/0000-0002-6341-9920 Carly Funk Meagan Josephs Kyle Coombes Madeleine Yeakle Dhir Gala Mohammad Ahmed-Khan


Gastrointestinal (GI) involvement in the pathogenesis of Parkinsons Disease (PD) has been widely recognized and supported in recent literature. Prospective and retrospective studies found non-motor symptoms within the GI, specifically constipation, precede cardinal signs and cognitive decline by almost 20 years. In 2002, Braak et al. were the first to propose that PD is a six-stage propagating neuropathological process originating from the GI tract (GIT). Aggregated α-synuclein (α-syn) protein from the GIT is pathognomonic for the development of PD. This article reviews the current literature from the past 10 years as well as original research found in PubMed on the combined effects of enteric glial cells and lectins on the development of Parkinsons Disease. Studies have found that these aggregated and phosphorylated proteins gain access to the brain via retrograde transport through fast and slow fibers of intestinal neurons. Plant lectins, commonly found within plant-based diets, have been found to induce Leaky Gut Syndrome and can activate enteric glial cells, causing the release of pro-inflammatory cytokines. Oxidative stress on the enteric neurons, caused by a chronic neuro-inflammatory state, can cause a-syn aggregation and lead to Lewy Body formation, a hallmark finding in PD. Although the current literature provides a connection between the consumption of plant lectins and the pathophysiology of PD, further research is required to evaluate confounding variables such as food antigen mimicry and other harmful substances found in our diets.



Parkinsons Disease, Enteric Nervous System, Lewy Bodies, Gastrointestinal Tract, Plant Lectin

1. Elbaz A, Carcaillon L, Kab S, Moisan F. Epidemiology of Parkinson's disease. Rev Neurol (Paris). 2016;172(1):14-26. doi: 10.1016/j.neurol.2015.09.012. PubMed PMID: 26718594.
2. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol. 1999;56(1):33-9. doi: 10.1001/archneur.56.1.33. PubMed PMID: 9923759.
3. Travagli RA, Browning KN, Camilleri M. Parkinson disease and the gut: new insights into pathogenesis and clinical relevance. Nat Rev Gastroenterol Hepatol. 2020;17(11):673-85. doi: 10.1038/s41575-020-0339-z. PubMed PMID: 32737460.
4. Katzenschlager R, Lees AJ. Treatment of Parkinson's disease: levodopa as the first choice. J Neurol. 2002;249 Suppl 2:II19-24. doi: 10.1007/s00415-002-1204-4. PubMed PMID: 12375059.
5. Warnecke T, Schafer KH, Claus I, Del Tredici K, Jost WH. Gastrointestinal involvement in Parkinson's disease: pathophysiology, diagnosis, and management. NPJ Parkinsons Dis. 2022;8(1):31. doi: 10.1038/s41531-022-00295-x. PubMed PMID: 35332158; PubMed Central PMCID: PMCPMC8948218.
6. Malek N, Swallow D, Grosset KA, Anichtchik O, Spillantini M, Grosset DG. Alpha-synuclein in peripheral tissues and body fluids as a biomarker for Parkinson's disease - a systematic review. Acta Neurol Scand. 2014;130(2):59-72. doi: 10.1111/ane.12247. PubMed PMID: 24702516.
7. Uversky VN, Li J, Souillac P, Millett IS, Doniach S, Jakes R, et al. Biophysical properties of the synucleins and their propensities to fibrillate: inhibition of alpha-synuclein assembly by beta- and gamma-synucleins. J Biol Chem. 2002;277(14):11970-8. doi: 10.1074/jbc.M109541200. PubMed PMID: 11812782.
8. Yoo BB, Mazmanian SK. The Enteric Network: Interactions between the Immune and Nervous Systems of the Gut. Immunity. 2017;46(6):910-26. doi: 10.1016/j.immuni.2017.05.011. PubMed PMID: 28636959; PubMed Central PMCID: PMCPMC5551410.
9. Suzuki T. Regulation of intestinal epithelial permeability by tight junctions. Cell Mol Life Sci. 2013;70(4):631-59. doi: 10.1007/s00018-012-1070-x. PubMed PMID: 22782113.
10. Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol. 2009;9(11):799-809. doi: 10.1038/nri2653. PubMed PMID: 19855405.
11. Furness JB. The enteric nervous system and neurogastroenterology. Nat Rev Gastroenterol Hepatol. 2012;9(5):286-94. doi: 10.1038/nrgastro.2012.32. PubMed PMID: 22392290.
12. Yu YB, Li YQ. Enteric glial cells and their role in the intestinal epithelial barrier. World J Gastroenterol. 2014;20(32):11273-80. doi: 10.3748/wjg.v20.i32.11273. PubMed PMID: 25170211; PubMed Central PMCID: PMCPMC4145765.
13. Cirillo C, Sarnelli G, Esposito G, Turco F, Steardo L, Cuomo R. S100B protein in the gut: the evidence for enteroglial-sustained intestinal inflammation. World J Gastroenterol. 2011;17(10):1261-6. doi: 10.3748/wjg.v17.i10.1261. PubMed PMID: 21455324; PubMed Central PMCID: PMCPMC3068260.
14. Furness JB, Kunze WA, Bertrand PP, Clerc N, Bornstein JC. Intrinsic primary afferent neurons of the intestine. Prog Neurobiol. 1998;54(1):1-18. doi: 10.1016/s0301-0082(97)00051-8. PubMed PMID: 9460790.
15. Lebouvier T, Chaumette T, Paillusson S, Duyckaerts C, Bruley des Varannes S, Neunlist M, et al. The second brain and Parkinson's disease. Eur J Neurosci. 2009;30(5):735-41. doi: 10.1111/j.1460-9568.2009.06873.x. PubMed PMID: 19712093.
16. Miyano Y, Sakata I, Kuroda K, Aizawa S, Tanaka T, Jogahara T, et al. The role of the vagus nerve in the migrating motor complex and ghrelin- and motilin-induced gastric contraction in suncus. PLoS One. 2013;8(5):e64777. doi: 10.1371/journal.pone.0064777. PubMed PMID: 23724093; PubMed Central PMCID: PMCPMC3665597.
17. Keast JR, Furness JB, Costa M. Different substance P receptors are found on mucosal epithelial cells and submucous neurons of the guinea-pig small intestine. Naunyn Schmiedebergs Arch Pharmacol. 1985;329(4):382-7. doi: 10.1007/BF00496372. PubMed PMID: 2412139.
18. Neunlist M, Toumi F, Oreschkova T, Denis M, Leborgne J, Laboisse CL, et al. Human ENS regulates the intestinal epithelial barrier permeability and a tight junction-associated protein ZO-1 via VIPergic pathways. Am J Physiol Gastrointest Liver Physiol. 2003;285(5):G1028-36. doi: 10.1152/ajpgi.00066.2003. PubMed PMID: 12881224.
19. Chandrasekharan B, Jeppsson S, Pienkowski S, Belsham DD, Sitaraman SV, Merlin D, et al. Tumor necrosis factor-neuropeptide Y cross talk regulates inflammation, epithelial barrier functions, and colonic motility. Inflamm Bowel Dis. 2013;19(12):2535-46. doi: 10.1097/01.MIB.0000437042.59208.9f. PubMed PMID: 24108115; PubMed Central PMCID: PMCPMC4180268.
20. Cersosimo MG, Benarroch EE. Neural control of the gastrointestinal tract: implications for Parkinson disease. Mov Disord. 2008;23(8):1065-75. doi: 10.1002/mds.22051. PubMed PMID: 18442139.
21. Kiela PR, Ghishan FK. Ion transport in the intestine. Curr Opin Gastroenterol. 2009;25(2):87-91. doi: 10.1097/MOG.0b013e3283260900. PubMed PMID: 19528875; PubMed Central PMCID: PMCPMC4427515.
22. Ahluwalia B, Magnusson MK, Ohman L. Mucosal immune system of the gastrointestinal tract: maintaining balance between the good and the bad. Scand J Gastroenterol. 2017;52(11):1185-93. doi: 10.1080/00365521.2017.1349173. PubMed PMID: 28697651.
23. Seguella L, Sarnelli G, Esposito G. Leaky gut, dysbiosis, and enteric glia activation: the trilogy behind the intestinal origin of Parkinson's disease. Neural Regen Res. 2020;15(6):1037-8. doi: 10.4103/1673-5374.270308. PubMed PMID: 31823880; PMCPMC7034261.
24. Braak H, Rub U, Gai WP, 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 (Vienna). 2003;110(5):517-36. doi: 10.1007/s00702-002-0808-2. PubMed PMID: 12721813.
25. Prusiner SB. Prions. Proc Natl Acad Sci U S A. 1998;95(23):13363-83. doi: 10.1073/pnas.95.23.13363. PubMed PMID: 9811807; PubMed Central PMCID: PMCPMC33918.
26. Wadsworth JD, Jackson GS, Hill AF, Collinge J. Molecular biology of prion propagation. Curr Opin Genet Dev. 1999;9(3):338-45. doi: 10.1016/s0959-437x(99)80051-3. PubMed PMID: 10377292.
27. Brown P. The pathogenesis of transmissible spongiform encephalopathy: routes to the brain and the erection of therapeutic barricades. Cell Mol Life Sci. 2001;58(2):259-65. doi: 10.1007/PL00000853. PubMed PMID: 11289307.
28. Nicotera P. A route for prion neuroinvasion. Neuron. 2001;31(3):345-8. doi: 10.1016/s0896-6273(01)00385-3. PubMed PMID: 11516392.
29. Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Bjorklund T, et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 2014;128(6):805-20. doi: 10.1007/s00401-014-1343-6. PubMed PMID: 25296989.
30. Hawkes CH, Del Tredici K, Braak H. Parkinson's disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol. 2007;33(6):599-614. doi: 10.1111/j.1365-2990.2007.00874.x. PubMed PMID: 17961138; PubMed Central PMCID: PMCPMC7194308.
31. Del Tredici K, Rub U, De Vos RA, Bohl JR, Braak H. Where does parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol. 2002;61(5):413-26. doi: 10.1093/jnen/61.5.413. PubMed PMID: 12030260.
32. Bloch A, Probst A, Bissig H, Adams H, Tolnay M. Alpha-synuclein pathology of the spinal and peripheral autonomic nervous system in neurologically unimpaired elderly subjects. Neuropathol Appl Neurobiol. 2006;32(3):284-95. doi: 10.1111/j.1365-2990.2006.00727.x. PubMed PMID: 16640647.
33. Halliday G, Hely M, Reid W, Morris J. The progression of pathology in longitudinally followed patients with Parkinson's disease. Acta Neuropathol. 2008;115(4):409-15. doi: 10.1007/s00401-008-0344-8. PubMed PMID: 18231798.
34. Liautard JP. Are prions misfolded molecular chaperones? FEBS Lett. 1991;294(3):155-7. doi: 10.1016/0014-5793(91)80657-o. PubMed PMID: 1756852.
35. Svensson E, Horvath-Puho E, Thomsen RW, Djurhuus JC, Pedersen L, Borghammer P, et al. Vagotomy and subsequent risk of Parkinson's disease. Ann Neurol. 2015;78(4):522-9. doi: 10.1002/ana.24448. PubMed PMID: 26031848.
36. Pan-Montojo F, Schwarz M, Winkler C, Arnhold M, O'Sullivan GA, Pal A, et al. Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci Rep. 2012;2:898. doi: 10.1038/srep00898. PubMed PMID: 23205266; PubMed Central PMCID: PMCPMC3510466.
37. Anselmi L, Toti L, Bove C, Hampton J, Travagli RA. A Nigro-Vagal Pathway Controls Gastric Motility and Is Affected in a Rat Model of Parkinsonism. Gastroenterology. 2017;153(6):1581-93. doi: 10.1053/j.gastro.2017.08.069. PubMed PMID: 28912019; PubMed Central PMCID: PMCPMC5705565.
38. Naudet N, Antier E, Gaillard D, Morignat E, Lakhdar L, Baron T, et al. Oral Exposure to Paraquat Triggers Earlier Expression of Phosphorylated alpha-Synuclein in the Enteric Nervous System of A53T Mutant Human alpha-Synuclein Transgenic Mice. J Neuropathol Exp Neurol. 2017;76(12):1046-57. doi: 10.1093/jnen/nlx092. PubMed PMID: 29040593; PubMed Central PMCID: PMCPMC5939863.
39. Goedert M, Spillantini MG, Del Tredici K, Braak H. 100 years of Lewy pathology. Nat Rev Neurol. 2013;9(1):13-24. doi: 10.1038/nrneurol.2012.242. PubMed PMID: 23183883.
40. Vasconcelos IM, Oliveira JT. Antinutritional properties of plant lectins. Toxicon. 2004;44(4):385-403. doi: 10.1016/j.toxicon.2004.05.005. PubMed PMID: 15302522.
41. Polito L, Bortolotti M, Battelli MG, Calafato G, Bolognesi A. Ricin: An Ancient Story for a Timeless Plant Toxin. Toxins (Basel). 2019;11(6). doi: 10.3390/toxins11060324. PubMed PMID: 31174319; PubMed Central PMCID: PMCPMC6628454.
42. Balint GA. Ricin: the toxic protein of castor oil seeds. Toxicology. 1974;2(1):77-102. doi: 10.1016/0300-483x(74)90044-4. PubMed PMID: 4823740.
43. Watkins WM, Morgan WT. Neutralization of the anti-H agglutinin in eel serum by simple sugars. Nature. 1952;169(4307):825-6. doi: 10.1038/169825a0. PubMed PMID: 14941057.
44. Boyd WC, Shapleigh E. Specific Precipitating Activity of Plant Agglutinins (Lectins). Science. 1954;119(3091):419. doi: 10.1126/science.119.3091.419. PubMed PMID: 17842730.
45. Tsaneva M, Van Damme EJM. 130 years of Plant Lectin Research. Glycoconj J. 2020;37(5):533-51. doi: 10.1007/s10719-020-09942-y. PubMed PMID: 32860551; PubMed Central PMCID: PMCPMC7455784.
46. Chrispeels MJ, Raikhel NV. Lectins, lectin genes, and their role in plant defense. Plant Cell. 1991;3(1):1-9. doi: 10.1105/tpc.3.1.1. PubMed PMID: 1824332; PubMed Central PMCID: PMCPMC159974.
47. Lerouge P, Roche P, Faucher C, Maillet F, Truchet G, Prome JC, et al. Symbiotic host-specificity of Rhizobium meliloti is determined by a sulphated and acylated glucosamine oligosaccharide signal. Nature. 1990;344(6268):781-4. doi: 10.1038/344781a0. PubMed PMID: 2330031.
48. Rudiger H. Plant lectins - more than just tools for glycoscientists: occurrence, structure, and possible functions of plant lectins. Acta Anat (Basel). 1998;161(1-4):130-52. doi: 10.1159/000046454. PubMed PMID: 9780355.
49. Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. 2019;68(8):1516-26. doi: 10.1136/gutjnl-2019-318427. PubMed PMID: 31076401; PubMed Central PMCID: PMCPMC6790068.
50. Kinashi Y, Hase K. Partners in Leaky Gut Syndrome: Intestinal Dysbiosis and Autoimmunity. Front Immunol. 2021;12:673708. doi: 10.3389/fimmu.2021.673708. PubMed PMID: 33968085; PubMed Central PMCID: PMCPMC8100306.
51. Ovelgonne JH, Koninkx JF, Pusztai A, Bardocz S, Kok W, Ewen SW, et al. Decreased levels of heat shock proteins in gut epithelial cells after exposure to plant lectins. Gut. 2000;46(5):679-87. doi: 10.1136/gut.46.5.680. PubMed PMID: 10764712; PubMed Central PMCID: PMCPMC1727920.
52. Otte JM, Chen C, Brunke G, Kiehne K, Schmitz F, Folsch UR, et al. Mechanisms of lectin (phytohemagglutinin)-induced growth in small intestinal epithelial cells. Digestion. 2001;64(3):169-78. doi: 10.1159/000048858. PubMed PMID: 11786665.
53. Baintner K, Jakab G, Gyori Z, Kiss P. Binding of FITC-labelled lectins to the gastrointestinal epithelium of the rat. Pathol Oncol Res. 2000;6(3):179-83. doi: 10.1007/BF03032370. PubMed PMID: 11033457.
54. Sun MF, Shen YQ. Dysbiosis of gut microbiota and microbial metabolites in Parkinson's Disease. Ageing Res Rev. 2018;45:53-61. doi: 10.1016/j.arr.2018.04.004. PubMed PMID: 29705121.
55. Wallen ZD, Appah M, Dean MN, Sesler CL, Factor SA, Molho E, et al. Characterizing dysbiosis of gut microbiome in PD: evidence for overabundance of opportunistic pathogens. NPJ Parkinsons Dis. 2020;6:11. doi: 10.1038/s41531-020-0112-6. PubMed PMID: 32566740; PubMed Central PMCID: PMCPMC7293233.
56. Suzuki T. Regulation of the intestinal barrier by nutrients: The role of tight junctions. Anim Sci J. 2020;91(1):e13357. doi: 10.1111/asj.13357. PubMed PMID: 32219956; PubMed Central PMCID: PMCPMC7187240.
57. Nachbar MS, Oppenheim JD, Thomas JO. Lectins in the U.S. Diet. Isolation and characterization of a lectin from the tomato (Lycopersicon esculentum). J Biol Chem. 1980;255(5):2056-61. PubMed PMID: 7354077.
58. Ortega-Barria E, Ward HD, Keusch GT, Pereira ME. Growth inhibition of the intestinal parasite Giardia lamblia by a dietary lectin is associated with arrest of the cell cycle. J Clin Invest. 1994;94(6):2283-8. doi: 10.1172/JCI117591. PubMed PMID: 7989583; PubMed Central PMCID: PMCPMC330055.
59. Karlsson A. Wheat germ agglutinin induces NADPH-oxidase activity in human neutrophils by interaction with mobilizable receptors. Infect Immun. 1999;67(7):3461-8. doi: 10.1128/IAI.67.7.3461-3468.1999. PubMed PMID: 10377127; PubMed Central PMCID: PMCPMC116532.
60. Haas H, Falcone FH, Schramm G, Haisch K, Gibbs BF, Klaucke J, et al. Dietary lectins can induce in vitro release of IL-4 and IL-13 from human basophils. Eur J Immunol. 1999;29(3):918-27. doi: 10.1002/(SICI)1521-4141(199903)29:03<918::AID-IMMU918>3.0.CO;2-T. PubMed PMID: 10092096.
61. Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol. 2009;27:229-65. doi: 10.1146/annurev.immunol.021908.132715. PubMed PMID: 19302040.
62. Gong T, Wang X, Yang Y, Yan Y, Yu C, Zhou R, et al. Plant Lectins Activate the NLRP3 Inflammasome To Promote Inflammatory Disorders. J Immunol. 2017;198(5):2082-92. doi: 10.4049/jimmunol.1600145. PubMed PMID: 28087670.
63. Lee KH, Kang TB. The Molecular Links between Cell Death and Inflammasome. Cells. 2019;8(9). doi: 10.3390/cells8091057. PubMed PMID: 31509938; PubMed Central PMCID: PMCPMC6769855.
64. Hashimoto M, Hsu LJ, Xia Y, Takeda A, Sisk A, Sundsmo M, et al. Oxidative stress induces amyloid-like aggregate formation of NACP/alpha-synuclein in vitro. Neuroreport. 1999;10(4):717-21. doi: 10.1097/00001756-199903170-00011. PubMed PMID: 10208537.
65. Scudamore O, Ciossek T. Increased Oxidative Stress Exacerbates alpha-Synuclein Aggregation In Vivo. J Neuropathol Exp Neurol. 2018;77(6):443-53. doi: 10.1093/jnen/nly024. PubMed PMID: 29718367.
66. Bottner M, Fricke T, Muller M, Barrenschee M, Deuschl G, Schneider SA, et al. Alpha-synuclein is associated with the synaptic vesicle apparatus in the human and rat enteric nervous system. Brain Res. 2015;1614:51-9. doi: 10.1016/j.brainres.2015.04.015. PubMed PMID: 25896939.
67. Wong YC, Krainc D. alpha-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat Med. 2017;23(2):1-13. doi: 10.1038/nm.4269. PubMed PMID: 28170377; PubMed Central PMCID: PMCPMC8480197.
68. Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD, et al. Frequency of bowel movements and the future risk of Parkinson's disease. Neurology. 2001;57(3):456-62. doi: 10.1212/wnl.57.3.456. PubMed PMID: 11502913.
69. Gao X, Chen H, Schwarzschild MA, Ascherio A. A prospective study of bowel movement frequency and risk of Parkinson's disease. Am J Epidemiol. 2011;174(5):546-51. doi: 10.1093/aje/kwr119. PubMed PMID: 21719744; PubMed Central PMCID: PMCPMC3202149.
70. Ross GW, Abbott RD, Petrovitch H, Tanner CM, White LR. Pre-motor features of Parkinson's disease: the Honolulu-Asia Aging Study experience. Parkinsonism Relat Disord. 2012;18 Suppl 1:S199-202. doi: 10.1016/S1353-8020(11)70062-1. PubMed PMID: 22166434.
71. Aube AC, Cabarrocas J, Bauer J, Philippe D, Aubert P, Doulay F, et al. Changes in enteric neurone phenotype and intestinal functions in a transgenic mouse model of enteric glia disruption. Gut. 2006;55(5):630-7. doi: 10.1136/gut.2005.067595. PubMed PMID: 16236773; PubMed Central PMCID: PMCPMC1856141.
72. Vojdani A, Lerner A, Vojdani E. Cross-Reactivity and Sequence Homology Between Alpha-Synuclein and Food Products: A Step Further for Parkinson's Disease Synucleinopathy. Cells. 2021;10(5). doi: 10.3390/cells10051111. PubMed PMID: 34063062; PubMed Central PMCID: PMCPMC8147930.
73. Agarwal P, Wang Y, Buchman AS, Holland TM, Bennett DA, Morris MC. MIND Diet Associated with Reduced Incidence and Delayed Progression of ParkinsonismA in Old Age. J Nutr Health Aging. 2018;22(10):1211-5. doi: 10.1007/s12603-018-1094-5. PubMed PMID: 30498828; PubMed Central PMCID: PMCPMC6436549.
74. Asemi Z, Samimi M, Tabassi Z, Shakeri H, Sabihi SS, Esmaillzadeh A. Effects of DASH diet on lipid profiles and biomarkers of oxidative stress in overweight and obese women with polycystic ovary syndrome: a randomized clinical trial. Nutrition. 2014;30(11-12):1287-93. doi: 10.1016/j.nut.2014.03.008. PubMed PMID: 25194966.
75. Tiwari, P.C. and Pal.R, The potential role of neuroinflammation and transcription factors in Parkinson disease. Dialogues Clin Neurosci, 2017. 19(1): p. 71-80.
How to Cite
Moin, K., Funk, C., Josephs, M., Coombes, K., Yeakle, M., Gala, D., & Ahmed-Khan, M. (2022). Gut-brain axis: Review on the association between Parkinsons disease and plant lectins. Archive of Clinical Cases, 9(4), Arch Clin Cases 2022; 9(4):177-183. https://doi.org/10.22551/2022.37.0904.10228

How to Cite

Moin, K., Funk, C., Josephs, M., Coombes, K., Yeakle, M., Gala, D., & Ahmed-Khan, M. (2022). Gut-brain axis: Review on the association between Parkinsons disease and plant lectins. Archive of Clinical Cases, 9(4), Arch Clin Cases 2022; 9(4):177-183. https://doi.org/10.22551/2022.37.0904.10228