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

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 g...

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Autores principales: Singh, Yogesh, Trautwein, Christoph, Romani, Joan, Salker, Madhuri S., Neckel, Peter H., Fraccaroli, Isabel, Abeditashi, Mahkameh, Woerner, Nils, Admard, Jakob, Dhariwal, Achal, Dueholm, Morten K. D., Schäfer, Karl-Herbert, Lang, Florian, Otzen, Daniel E., Lashuel, Hilal A., Riess, Olaf, Casadei, Nicolas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10318726/
https://www.ncbi.nlm.nih.gov/pubmed/37403161
http://dx.doi.org/10.1186/s13024-023-00628-1
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author Singh, Yogesh
Trautwein, Christoph
Romani, Joan
Salker, Madhuri S.
Neckel, Peter H.
Fraccaroli, Isabel
Abeditashi, Mahkameh
Woerner, Nils
Admard, Jakob
Dhariwal, Achal
Dueholm, Morten K. D.
Schäfer, Karl-Herbert
Lang, Florian
Otzen, Daniel E.
Lashuel, Hilal A.
Riess, Olaf
Casadei, Nicolas
author_facet Singh, Yogesh
Trautwein, Christoph
Romani, Joan
Salker, Madhuri S.
Neckel, Peter H.
Fraccaroli, Isabel
Abeditashi, Mahkameh
Woerner, Nils
Admard, Jakob
Dhariwal, Achal
Dueholm, Morten K. D.
Schäfer, Karl-Herbert
Lang, Florian
Otzen, Daniel E.
Lashuel, Hilal A.
Riess, Olaf
Casadei, Nicolas
author_sort Singh, Yogesh
collection PubMed
description 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. (1)H-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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-023-00628-1.
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spelling pubmed-103187262023-07-05 Overexpression of human alpha-Synuclein leads to dysregulated microbiome/metabolites with ageing in a rat model of Parkinson disease Singh, Yogesh Trautwein, Christoph Romani, Joan Salker, Madhuri S. Neckel, Peter H. Fraccaroli, Isabel Abeditashi, Mahkameh Woerner, Nils Admard, Jakob Dhariwal, Achal Dueholm, Morten K. D. Schäfer, Karl-Herbert Lang, Florian Otzen, Daniel E. Lashuel, Hilal A. Riess, Olaf Casadei, Nicolas Mol Neurodegener Research Article 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. (1)H-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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-023-00628-1. BioMed Central 2023-07-04 /pmc/articles/PMC10318726/ /pubmed/37403161 http://dx.doi.org/10.1186/s13024-023-00628-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Singh, Yogesh
Trautwein, Christoph
Romani, Joan
Salker, Madhuri S.
Neckel, Peter H.
Fraccaroli, Isabel
Abeditashi, Mahkameh
Woerner, Nils
Admard, Jakob
Dhariwal, Achal
Dueholm, Morten K. D.
Schäfer, Karl-Herbert
Lang, Florian
Otzen, Daniel E.
Lashuel, Hilal A.
Riess, Olaf
Casadei, Nicolas
Overexpression of human alpha-Synuclein leads to dysregulated microbiome/metabolites with ageing in a rat model of Parkinson disease
title Overexpression of human alpha-Synuclein leads to dysregulated microbiome/metabolites with ageing in a rat model of Parkinson disease
title_full Overexpression of human alpha-Synuclein leads to dysregulated microbiome/metabolites with ageing in a rat model of Parkinson disease
title_fullStr Overexpression of human alpha-Synuclein leads to dysregulated microbiome/metabolites with ageing in a rat model of Parkinson disease
title_full_unstemmed Overexpression of human alpha-Synuclein leads to dysregulated microbiome/metabolites with ageing in a rat model of Parkinson disease
title_short Overexpression of human alpha-Synuclein leads to dysregulated microbiome/metabolites with ageing in a rat model of Parkinson disease
title_sort overexpression of human alpha-synuclein leads to dysregulated microbiome/metabolites with ageing in a rat model of parkinson disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10318726/
https://www.ncbi.nlm.nih.gov/pubmed/37403161
http://dx.doi.org/10.1186/s13024-023-00628-1
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