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Cited by 22Parkinson's Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration MechanismsGut microbiota and health

α-Synuclein expression in response to bacterial ligands and metabolites in gut enteroendocrine cells: an in vitro proof of concept study

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Hurley, Michael J, Menozzi, Elisa, Koletsi, Sofia, Bates, Rachel, Gegg, Matthew E, Chau, Kai-Yin, Blottière, Hervé M, Macnaughtan, Jane +1 more·2023·Brain Communications
DOI 10.1093/braincomms/fcad285PMC PMC10636561

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Abstract

Caudo-rostral migration of pathological forms of α-synuclein from the gut to the brain is proposed as an early feature in Parkinson's disease pathogenesis, but the underlying mechanisms remain unknown. Intestinal epithelial enteroendocrine cells sense and respond to numerous luminal signals, including bacterial factors, and transmit this information to the brain via the enteric nervous system and vagus nerve. There is evidence that gut bacteria composition and their metabolites change in Parkinson's disease patients, and these alterations can trigger α-synuclein pathology in animal models of the disorder. Here, we investigated the effect of toll-like receptor and free fatty acid receptor agonists on the intracellular level of α-synuclein and its release using mouse secretin tumour cell line 1 enteroendocrine cells. Secretin tumour cell line 1 enteroendocrine cells were treated for 24 or 48 h with toll-like receptor agonists (toll-like receptor 4 selective lipopolysaccharide; toll-like receptor 2 selective Pam3CysSerLys4) and the free fatty acid receptor 2/3 agonists butyrate, propionate and acetate. The effect of selective receptor antagonists on the agonists' effects after 24 hours was also investigated. The level of α-synuclein protein was measured in cell lysates and cell culture media by western blot and enzyme-linked immunosorbent assay. The level of α-synuclein and tumour necrosis factor messenger RNA was measured by quantitative reverse transcription real-time polymerase chain reaction. Stimulation of secretin tumour cell line 1 enteroendocrine cells for 24 and 48 hours with toll-like receptor and free fatty acid receptor agonists significantly increased the amount of intracellular α-synuclein and the release of α-synuclein from the cells into the culture medium. Both effects were significantly reduced by antagonists selective for each receptor. Toll-like receptor and free fatty acid receptor agonists also significantly increased tumour necrosis factor transcription, and this was effectively inhibited by corresponding antagonists. Elevated intracellular α-synuclein increases the likelihood of aggregation and conversion to toxic forms. Factors derived from bacteria induce α-synuclein accumulation in secretin tumour cell line 1 enteroendocrine cells. Here, we provide support for a mechanism by which exposure of enteroendocrine cells to specific bacterial factors found in Parkinson's disease gut dysbiosis might facilitate accumulation of α-synuclein pathology in the gut.

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  • Following exposure to bacterial metabolites such as lipopolysaccharide (LPS), intracellular levels of α-synuclein in enteroendocrine cells have been shown to increase.

    “Following exposure to bacterial metabolites such as lipopolysaccharide (LPS), intracellular levels of α-synuclein in enteroendocrine cells have been shown to increase, suggesting that under specific microbial conditions enteroendocrine cells could be the initial source of PD pathogenesis [138].”

    From The gut–brain axis in early Parkinson’s disease: from prodrome to prevention (2025) · cites this paper as [138]

    The Results (α-Synuclein expression) report that LPS exposure significantly increased intracellular α-synuclein in STC-1 enteroendocrine cells after 24 and 48 hours. The Discussion distinguishes LPS, a structural bacterial component, from bacterial metabolites such as short-chain fatty acids; calling LPS a metabolite is inaccurate. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Under specific microbial conditions, enteroendocrine cells could be the initial source of PD pathogenesis.

    “Following exposure to bacterial metabolites such as lipopolysaccharide (LPS), intracellular levels of α-synuclein in enteroendocrine cells have been shown to increase, suggesting that under specific microbial conditions enteroendocrine cells could be the initial source of PD pathogenesis [138].”

    From The gut–brain axis in early Parkinson’s disease: from prodrome to prevention (2025) · cites this paper as [138]

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Authors
Hurley, M. J., Menozzi, E., Koletsi, S., Bates, R., Gegg, M. E., Chau, K.-Y., Blottière, H. M., Macnaughtan, J., & Schapira, A. H. V.
Affiliations
  • Aligning Science Across Parkinson's (US)
  • Université Paris-Saclay (FR)
Corresponding author
Schapira, Anthony H V
ORCID
Venue
Brain Communications
Publisher
Oxford University Press (OUP)
Published
2023
Volume
5
Issue
6
Pages
fcad285-fcad285
ISSN
2632-1297 (ISSN-L)
DOI
10.1093/braincomms/fcad285
PMC
PMC10636561
OpenAlex
W4387928799
Cited by
22
References
5
Citations by year
2026: 8 · 2025: 8 · 2024: 6
FWCI
3.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion, cc-by)
Funders
  • Aligning Science Across Parkinson’s (000420)
  • Michael J. Fox Foundation
  • for Parkinson’s Research
  • a Royal Free Charity Fellowship
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Keywords
alpha-synuclein, Parkinson's disease, enteroendocrine cells, gut-brain axis, TLR agonists, lipopolysaccharide, butyrate, propionate, acetate, TNF-α, bacterial metabolites, gut dysbiosis

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