The Endotoxin Hypothesis of Parkinson's Disease.
Parkinson's disease
endotoxin
gut
inflammation
lipopolysaccharide
microglia
neurodegeneration
neuroinflammation
Journal
Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688
Informations de publication
Date de publication:
07 2023
07 2023
Historique:
revised:
14
04
2023
received:
09
03
2023
accepted:
19
04
2023
medline:
31
7
2023
pubmed:
9
5
2023
entrez:
9
5
2023
Statut:
ppublish
Résumé
The endotoxin hypothesis of Parkinson's disease (PD) is the idea that lipopolysaccharide (LPS) endotoxins contribute to the pathogenesis of this disorder. LPS endotoxins are found in, and released from, the outer membrane of Gram-negative bacteria, for example in the gut. It is proposed that gut dysfunction in early PD leads to elevated LPS levels in the gut wall and blood, which promotes both α-synuclein aggregation in the enteric neurons and a peripheral inflammatory response. Communication to the brain via circulating LPS and cytokines in the blood and/or the gut-brain axis leads to neuroinflammation and spreading of α-synuclein pathology, exacerbating neurodegeneration in brainstem nuclei and loss of dopaminergic neurons in the substantia nigra, and manifesting in the clinical symptoms of PD. The evidence supporting this hypothesis includes: (1) gut dysfunction, permeability, and bacterial changes occur early in PD, (2) serum levels of LPS are increased in a proportion of PD patients, (3) LPS induces α-synuclein expression, aggregation, and neurotoxicity, (4) LPS causes activation of peripheral monocytes leading to inflammatory cytokine production, and (5) blood LPS causes brain inflammation and specific loss of midbrain dopaminergic neurons, mediated by microglia. If the hypothesis is correct, then treatment options might include: (1) changing the gut microbiome, (2) reducing gut permeability, (3) reducing circulating LPS levels, or (4) blocking the response of immune cells and microglia to LPS. However, the hypothesis has a number of limitations and requires further testing, in particular whether reducing LPS levels can reduce PD incidence, progression, or severity. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Substances chimiques
alpha-Synuclein
0
Endotoxins
0
Lipopolysaccharides
0
Types de publication
Journal Article
Review
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1143-1155Subventions
Organisme : Medical Research Council
ID : MR/R007446/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L010593
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L010593/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/W029235/1
Pays : United Kingdom
Organisme : Department of Health
ID : NIHR203312
Pays : United Kingdom
Informations de copyright
© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Références
Mov Disord. 2021 Jan;36(1):25-36
pubmed: 33314312
Front Immunol. 2015 Jan 06;5:680
pubmed: 25610440
Mov Disord. 2012 May;27(6):709-15
pubmed: 21766334
Obes Rev. 2016 Apr;17(4):297-312
pubmed: 26712364
Neurobiol Aging. 2007 Jun;28(6):894-906
pubmed: 21887889
Brain Behav Immun. 2020 Jul;87:473-488
pubmed: 32006615
PLoS One. 2013 Nov 25;8(11):e80192
pubmed: 24282521
Gastroenterology. 1991 Jul;101(1):84-9
pubmed: 1904381
J Neuroinflammation. 2022 Jun 6;19(1):135
pubmed: 35668422
Sci Rep. 2016 Aug 04;6:30891
pubmed: 27488222
Stem Cells. 2014 Sep;32(9):2338-49
pubmed: 24801745
J Neuroinflammation. 2021 Oct 11;18(1):225
pubmed: 34635136
PLoS One. 2016 Mar 16;11(3):e0151569
pubmed: 26982707
Scand J Immunol. 2021 May;93(5):e13022
pubmed: 33471378
Front Public Health. 2021 Dec 07;9:776847
pubmed: 34950630
Glia. 2013 Jan;61(1):71-90
pubmed: 22674585
World J Gastrointest Pathophysiol. 2014 Nov 15;5(4):400-4
pubmed: 25400983
Cell. 2016 Jun 2;165(6):1551
pubmed: 27259157
J Infect Dis. 2005 Dec 15;192(12):2074-80
pubmed: 16288370
Glia. 2007 Apr 1;55(5):453-62
pubmed: 17203472
J Parkinsons Dis. 2021;11(3):1129-1139
pubmed: 33720853
J Neuroinflammation. 2019 Sep 13;16(1):180
pubmed: 31519175
Nature. 2014 Oct 9;514(7521):187-92
pubmed: 25119034
Oxid Med Cell Longev. 2020 Jan 31;2020:8630275
pubmed: 32089785
Occup Environ Med. 2003 May;60(5):378
pubmed: 12709528
Front Aging Neurosci. 2019 Aug 27;11:210
pubmed: 31507404
J Neurosci. 2012 Feb 22;32(8):2657-66
pubmed: 22357850
Sci Rep. 2021 Feb 18;11(1):4192
pubmed: 33603020
Immunopharmacol Immunotoxicol. 2022 Jun;44(3):326-337
pubmed: 35260024
Neurotoxicology. 2008 Sep;29(5):864-70
pubmed: 18471886
J Neurosci Res. 2005 Jan 1-15;79(1-2):208-15
pubmed: 15558752
J Immunol. 2016 Sep 15;197(6):2390-9
pubmed: 27534554
Parkinsonism Relat Disord. 2019 Feb;59:26-31
pubmed: 30448099
Neurosci Lett. 2006 Mar 20;396(1):67-72
pubmed: 16330147
Crit Rev Clin Lab Sci. 2016;53(3):197-215
pubmed: 26732012
J Neurosci. 2001 Sep 1;21(17):6480-91
pubmed: 11517237
BMB Rep. 2017 Feb;50(2):55-57
pubmed: 28115037
Mov Disord. 2020 Jun;35(6):921-933
pubmed: 32092186
Toxicol Sci. 2018 Nov 1;166(1):3-15
pubmed: 30203060
Acta Neuropathol Commun. 2020 Dec 3;8(1):211
pubmed: 33272323
Glia. 2014 Sep;62(9):1463-75
pubmed: 24838858
J Neurochem. 1998 Apr;70(4):1584-92
pubmed: 9580157
Am J Clin Nutr. 2007 Nov;86(5):1286-92
pubmed: 17991637
Sci Rep. 2018 Jan 19;8(1):1275
pubmed: 29352191
Nature. 2018 Apr;556(7701):332-338
pubmed: 29643512
Glia. 2013 Jun;61(6):855-68
pubmed: 23536230
J Exp Med. 1989 Jan 1;169(1):175-83
pubmed: 2462607
Vaccine. 2014 Oct 21;32(46):6107-14
pubmed: 25242628
Cytokine. 2008 May;42(2):145-151
pubmed: 18304834
Alzheimers Res Ther. 2022 Nov 11;14(1):169
pubmed: 36369100
Lancet. 2021 Jun 12;397(10291):2284-2303
pubmed: 33848468
Eur Neurol. 2023;86(1):34-44
pubmed: 36470230
J Neurol Neurosurg Psychiatry. 2016 Jul;87(7):710-6
pubmed: 26345189
Front Neurol. 2022 Mar 29;13:831090
pubmed: 35422756
Mov Disord. 2019 Nov;34(11):1711-1721
pubmed: 31449711
Neural Regen Res. 2021 Oct;16(10):1928-1934
pubmed: 33642362
Eur J Microbiol Immunol (Bp). 2018 Aug 21;8(3):63-69
pubmed: 30345085
Nat Rev Immunol. 2022 Nov;22(11):657-673
pubmed: 35246670
Nat Commun. 2019 Jan 18;10(1):310
pubmed: 30659181
Clin Chem. 1994 Aug;40(8):1575-9
pubmed: 8045000
Front Neurosci. 2015 Sep 01;9:306
pubmed: 26388718
Eur J Clin Microbiol Infect Dis. 2020 Nov;39(11):2013-2018
pubmed: 32564247
PeerJ. 2017 Aug 10;5:e3647
pubmed: 28828251
J Neurosci. 2008 Oct 22;28(43):10825-34
pubmed: 18945890
Parkinsonism Relat Disord. 2014 Dec;20(12):1371-5
pubmed: 25293395
Environ Health Perspect. 2011 Jun;119(6):807-14
pubmed: 21245015
Cell. 2016 Dec 1;167(6):1469-1480.e12
pubmed: 27912057
Acta Neuropathol. 2014 Nov;128(5):651-63
pubmed: 25284487
Pediatr Dent. 2015 Sep-Oct;37(5):35-40
pubmed: 26531074
Crit Care Med. 2010 Aug;38(8):1685-94
pubmed: 20562702
Atherosclerosis. 2009 Jan;202(1):76-83
pubmed: 18495130
J Chemother. 2001 Nov;13 Spec No 1(1):159-72
pubmed: 11936361
Gut. 2019 May;68(5):829-843
pubmed: 30554160
Hum Mol Genet. 2019 Nov 21;28(R2):R215-R218
pubmed: 31518392
Peptides. 2014 Dec;62:197-202
pubmed: 25278492
Cell Death Dis. 2021 Jul 17;12(8):715
pubmed: 34274951
PLoS One. 2015 Nov 05;10(11):e0142164
pubmed: 26539989
J Neurosci. 2005 Feb 16;25(7):1788-96
pubmed: 15716415
J Neuroimaging. 2018 Sep;28(5):496-505
pubmed: 29727504
Acta Neuropathol. 2003 Dec;106(6):518-26
pubmed: 14513261
Nat Rev Microbiol. 2010 Jan;8(1):8-14
pubmed: 19946286
Front Endocrinol (Lausanne). 2021 Dec 16;12:796212
pubmed: 34975767
Annu Rev Biochem. 2002;71:635-700
pubmed: 12045108
Neurology. 1988 Aug;38(8):1285-91
pubmed: 3399080
J Immunol. 2015 Nov 15;195(10):4999-5010
pubmed: 26466961
J Endotoxin Res. 2007;13(5):251-79
pubmed: 17986486
Microb Pathog. 2021 Nov;160:105187
pubmed: 34530073
Parkinsonism Relat Disord. 2016 Jul;28:18-22
pubmed: 27234704
Inflamm Bowel Dis. 2012 Oct;18(10):1932-9
pubmed: 22344959
Brain Behav Immun. 2019 Oct;81:41-51
pubmed: 31271873
Gut. 1998 Oct;43(4):506-11
pubmed: 9824578
J Immunol. 2011 Apr 15;186(8):4973-83
pubmed: 21402900
Sci Rep. 2017 Oct 13;7(1):13113
pubmed: 29030613
J Neuroinflammation. 2005 Sep 12;2:20
pubmed: 16156895
Int J Environ Res Public Health. 2018 Jul 26;15(8):
pubmed: 30049978
Infect Immun. 1994 Oct;62(10):4549-55
pubmed: 7927720
NPJ Parkinsons Dis. 2021 May 26;7(1):45
pubmed: 34039994
Infect Immun. 2001 Nov;69(11):6942-50
pubmed: 11598069
Cochrane Database Syst Rev. 2011 Nov 09;(11):CD008453
pubmed: 22071847
Immunol Rev. 2015 May;265(1):6-21
pubmed: 25879280
PLoS Biol. 2016 Aug 19;14(8):e1002533
pubmed: 27541692
Sci Rep. 2018 Nov 14;8(1):16798
pubmed: 30429533
Brain Behav Immun Health. 2020 Mar 18;4:100060
pubmed: 34589845
World J Gastroenterol. 2017 Jan 28;23(4):712-722
pubmed: 28216979
Clin Microbiol Rev. 1995 Apr;8(2):268-92
pubmed: 7621402
Mov Disord. 2015 Mar;30(3):350-8
pubmed: 25476529
J Neurochem. 2008 Apr;105(2):445-59
pubmed: 18047562
Mov Disord. 2002 Jan;17(1):116-24
pubmed: 11835448
Chem Phys Lipids. 2021 Mar;235:105029
pubmed: 33338469
Microbiome. 2021 Nov 17;9(1):226
pubmed: 34784980
J Endotoxin Res. 2002;8(2):115-26
pubmed: 12028751
Front Neurosci. 2019 Aug 07;13:839
pubmed: 31440136
PLoS One. 2013 Jul 01;8(7):e69123
pubmed: 23840908
Proc Natl Acad Sci U S A. 2015 Oct 6;112(40):12468-73
pubmed: 26385967
Proc Natl Acad Sci U S A. 2021 Mar 9;118(10):
pubmed: 33658371
Acta Neuropathol. 2021 Apr;141(4):527-545
pubmed: 33555429
J Gerontol A Biol Sci Med Sci. 2020 Jun 18;75(7):e9-e21
pubmed: 32129462
Neurogastroenterol Motil. 2018 Jun;30(6):e13366
pubmed: 29878576
Int J Syst Evol Microbiol. 2004 Sep;54(Pt 5):1469-1476
pubmed: 15388697
J Neurochem. 2018 Jan;144(2):172-185
pubmed: 29023711
J Neurosci. 2014 Jun 18;34(25):8546-56
pubmed: 24948809
Sci Rep. 2020 Sep 14;10(1):15054
pubmed: 32929122
Nature. 2012 Oct 11;490(7419):288-91
pubmed: 22895188
Am J Gastroenterol. 2002 Aug;97(8):2000-4
pubmed: 12190167
Eur J Neurol. 2020 Jan;27(1):27-42
pubmed: 31631455
Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):9587-92
pubmed: 27482083
Immunol Rev. 2015 May;265(1):75-84
pubmed: 25879285
Mov Disord. 2014 Jul;29(8):999-1009
pubmed: 24898698
PLoS One. 2011;6(12):e28032
pubmed: 22145021
Transl Neurodegener. 2015 Jan 08;4(1):1
pubmed: 25671103
Immunobiology. 1993 Apr;187(3-5):227-32
pubmed: 7687234
NPJ Parkinsons Dis. 2022 Mar 15;8(1):24
pubmed: 35292674
NPJ Parkinsons Dis. 2017 Jan 11;3:3
pubmed: 28649603
J Infect Dis. 2001 Apr 1;183(7):1079-86
pubmed: 11237833
Mov Disord. 2016 Jul;31(7):995-1003
pubmed: 26999434
Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):18054-9
pubmed: 23071332
JAMA Neurol. 2016 Nov 01;73(11):1316-1324
pubmed: 27668667
Clin Neurol Neurosurg. 2017 Sep;160:101-104
pubmed: 28704778
Brain Behav Immun. 2017 Feb;60:1-12
pubmed: 26995317