Aarhus University Seal

Overexpression of human alpha-Synuclein leads to dysregulated microbiome/metabolites with ageing in a rat model of Parkinson disease

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Yogesh Singh, University of Tübingen
  • ,
  • Christoph Trautwein, University of Tübingen
  • ,
  • Joan Romani, Swiss Federal Institute of Technology Lausanne
  • ,
  • Madhuri S. Salker, University of Tübingen
  • ,
  • Peter H. Neckel, University of Tübingen
  • ,
  • Isabel Fraccaroli, University of Tübingen
  • ,
  • Mahkameh Abeditashi, University of Tübingen
  • ,
  • Nils Woerner, University of Tübingen
  • ,
  • Jakob Admard, University of Tübingen
  • ,
  • Achal Dhariwal, University of Oslo
  • ,
  • Morten K.D. Dueholm, Aalborg University
  • ,
  • Karl Herbert Schäfer, University of Applied Sciences Kaiserslautern
  • ,
  • Florian Lang, University of Tübingen
  • ,
  • Daniel E. Otzen
  • Hilal A. Lashuel, Swiss Federal Institute of Technology Lausanne
  • ,
  • Olaf Riess, University of Tübingen
  • ,
  • Nicolas Casadei, University of Tübingen

Background: Braak’s hypothesis states that sporadic Parkinson’s disease (PD) follows a specific progression of pathology from the peripheral to the central nervous system, and this progression can be monitored by detecting the accumulation of alpha-Synuclein (α-Syn) protein. Consequently, there is growing interest in understanding how the gut (commensal) microbiome can regulate α-Syn accumulation, as this could potentially lead to PD. Methods: We used 16S rRNA and shotgun sequencing to characterise microbial diversity. 1H-NMR was employed to understand the metabolite production and intestinal inflammation estimated using ELISA and RNA-sequencing from feces and the intestinal epithelial layer respectively. The Na+ channel current and gut permeability were measured using an Ussing chamber. Immunohistochemistry and immunofluorescence imaging were applied to detect the α-Syn protein. LC-MS/MS was used for characterization of proteins from metabolite treated neuronal cells. Finally, Metascape and Ingenuity Pathway Analysis (IPA) bioinformatics tools were used for identification of dysregulated pathways. Results: We studied a transgenic (TG) rat model overexpressing the human SNCA gene and found that a progressive gut microbial composition alteration characterized by the reduction of Firmicutes to Bacteroidetes ratio could be detected in the young TG rats. Interestingly, this ratio then increased with ageing. The dynamics of Lactobacillus and Alistipes were monitored and reduced Lactobacillus and increased Alistipes abundance was discerned in ageing TG rats. Additionally, the SNCA gene overexpression resulted in gut α-Syn protein expression and increased with advanced age. Further, older TG animals had increased intestinal inflammation, decreased Na+ current and a robust alteration in metabolite production characterized by the increase of succinate levels in feces and serum. Manipulation of the gut bacteria by short-term antibiotic cocktail treatment revealed a complete loss of short-chain fatty acids and a reduction in succinate levels. Although antibiotic cocktail treatment did not change α-Syn expression in the enteric nervous system of the colon, however, reduced α-Syn expression was detected in the olfactory bulbs (forebrain) of the TG rats. Conclusion: Our data emphasize that the gut microbiome dysbiosis synchronous with ageing leads to a specific alteration of gut metabolites and can be modulated by antibiotics which may affect PD pathology.

Original languageEnglish
Article number44
JournalMolecular Neurodegeneration
Publication statusPublished - Jul 2023

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).

    Research areas

  • Antibiotics, Gut microbiome, Intestinal inflammation, PD, α-Synuclein

See relations at Aarhus University Citationformats

ID: 333981321