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Cited by 974Parkinson's Disease Mechanisms and TreatmentsGastrointestinal motility and disordersGut microbiota and health

Increased Intestinal Permeability Correlates with Sigmoid Mucosa alpha-Synuclein Staining and Endotoxin Exposure Markers in Early Parkinson's Disease

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Forsyth, Christopher B., Shannon, Kathleen M., Kordower, Jeffrey H., Voigt, Robin M., Shaikh, Maliha, Jaglin, Jean A., Estes, Jacob D., Dodiya, Hemraj B. +1 more·2011·PLoS ONE
DOI 10.1371/journal.pone.0028032PMC PMC3228722
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Abstract

UNLABELLED: Parkinson's disease (PD) is the second most common neurodegenerative disorder of aging. The pathological hallmark of PD is neuronal inclusions termed Lewy bodies whose main component is alpha-synuclein protein. The finding of these Lewy bodies in the intestinal enteric nerves led to the hypothesis that the intestine might be an early site of PD disease in response to an environmental toxin or pathogen. One potential mechanism for environmental toxin(s) and proinflammatory luminal products to gain access to mucosal neuronal tissue and promote oxidative stress is compromised intestinal barrier integrity. However, the role of intestinal permeability in PD has never been tested. We hypothesized that PD subjects might exhibit increased intestinal permeability to proinflammatory bacterial products in the intestine. To test our hypothesis we evaluated intestinal permeability in subjects newly diagnosed with PD and compared their values to healthy subjects. In addition, we obtained intestinal biopsies from both groups and used immunohistochemistry to assess bacterial translocation, nitrotyrosine (oxidative stress), and alpha-synuclein. We also evaluated serum markers of endotoxin exposure including LPS binding protein (LBP). Our data show that our PD subjects exhibit significantly greater intestinal permeability (gut leakiness) than controls. In addition, this intestinal hyperpermeability significantly correlated with increased intestinal mucosa staining for E. coli bacteria, nitrotyrosine, and alpha-synuclein as well as serum LBP levels in PD subjects. These data represent not only the first demonstration of abnormal intestinal permeability in PD subjects but also the first correlation of increased intestinal permeability in PD with intestinal alpha-synuclein (the hallmark of PD), as well as staining for gram negative bacteria and tissue oxidative stress. Our study may thus shed new light on PD pathogenesis as well as provide a new method for earlier diagnosis of PD and suggests potential therapeutic targets in PD subjects. TRIAL REGISTRATION: Clinicaltrials.gov NCT01155492.

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  • A leaky gut barrier has been linked to PD pathogenesis involving local flux of bacterial toxins, microbes, and potentially molecules like α-synuclein across the gastrointestinal epithelium.

    “A leaky gut barrier has been linked to PD pathogenesis involving local flux of bacterial toxins, microbes, and potentially molecules like α-synuclein across the gastrointestinal epithelium [29–31]”

    From The gut–brain axis in early Parkinson’s disease: from prodrome to prevention (2025) · cites this paper as [31]

    The Introduction and Discussion link increased intestinal permeability in PD to the passage of bacteria and endotoxins across the gut barrier, and report a correlation with intestinal α-synuclein staining. They do not suggest that α-synuclein itself crosses the gastrointestinal epithelium; instead, they propose that local inflammatory and oxidative injury may contribute to its accumulation in enteric neurons. The Discussion also cautions that this observational study cannot establish a causal role in PD pathogenesis. (LLM, conf=0.88)

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  • Increased intestinal permeability is associated with increased bacteria and exposure to the bacterial endotoxin in Parkinson's disease, while increased intestinal alpha-synuclein and 3-nitrotyrosine staining (associated with oxidative stress) leads to high intestinal permeability.

    “Increased intestinal permeability is associated with increased bacteria and exposure to the bacterial endotoxin in Parkinson's disease, while increased intestinal a-synuclein and 3nitrotyrosine staining (associated with oxidative stress) leads to high intestinal permeability.127”

    From The role of gut dysbiosis in Parkinson’s disease: mechanistic insights and therapeutic options (2021) · cites this paper as [127]

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  • Intestinal permeability increases early in Parkinson's disease.

    “Intestinal permeability increases early in Parkinson’s disease”

    From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [92]

  • Parkinson's disease patients have increased gastrointestinal permeability and LPS binding protein (LBP), and a proportion have elevated blood endotoxin.

    “PD patients have increased gastrointestinal permeability [92] and LPS binding protein (LBP) [92], and a proportion of PD patients have elevated blood endotoxin [93].”

    From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [92]

  • Serum from Parkinson's disease patients contains low levels of LPS binding protein, indicative of a chronic systemic exposure to LPS and gram-negative endobacteria.

    “serum from PD patients contains low levels of LPS binding protein [145,146], which are indicative of a chronic systemic exposure to LPS and gram negative endobacteria [147,148,149]”

    From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [146]

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Research works printed but not linked: 3

  1. [21]Kupsky WJ Grimes MM Sweeting J Bertsch R Cote LJ 1987 Parkinson's disease and megacolon: concentric hyaline inclusions (Lewy bodies) in enteric ganglion cells. Neurology 37 1253 1255 3037441
  2. [25]Wakabayashi K Takahashi H 1997 Neuropathology of autonomic nervous system in Parkinson's disease. Eur Neurol 38 Suppl 2 2 7 9387796
  3. [29]Shannon KM Keshavarzian A Mutlu E Dodiya HB Daian D 2011 Alpha-synuclein in colonic submucosa in early untreated Parkinson's disease. Mov Disord 21766334

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Authors
Forsyth, C. B., Shannon, K. M., Kordower, J. H., Voigt, R. M., Shaikh, M., Jaglin, J. A., Estes, J. D., Dodiya, H. B., & Keshavarzian, A.
Affiliations
  • Rush University Medical Center (US)
  • National Cancer Institute (US)
Corresponding author
Forsyth, Christopher B.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2011-12-01
Volume
6
Issue
12
Pages
e28032
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0028032
PMC
PMC3228722
OpenAlex
W1992780204
Cited by
974
References
48
Citations by year
2026: 72 · 2025: 73 · 2024: 86 · 2023: 108 · 2022: 108 · 2021: 132 · 2020: 96 · 2019: 72 · 2018: 66 · 2017: 44 · 2016: 33 · 2015: 36 · 2014: 20 · 2013: 13 · 2012: 14
FWCI
9.55
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
Parkinson's Disease Foundation
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Keywords
Parkinson's disease, intestinal permeability, alpha-synuclein, Lewy bodies, endotoxin exposure, bacterial translocation, nitrotyrosine, oxidative stress, LPS-binding protein, Escherichia coli, intestinal barrier integrity, early diagnosis, gut-brain axis
MeSH terms
Lipopolysaccharide-Binding Protein, Acute-Phase Proteins, Aged, Carrier Proteins, Endotoxins, Escherichia coli, Escherichia coli Infections, Female, Humans, Immunoenzyme Techniques, Intestinal Mucosa, Intestines, Male, Membrane Glycoproteins, Middle Aged, Neurons, Parkinson Disease, Permeability, Sucrose, Tyrosine, Biomarkers, Oxidative Stress, alpha-Synuclein

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