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α-Synuclein Overexpression and the Microbiome Shape the Gut and Brain Metabolome in Mice.
Morais, Livia H; Boktor, Joseph C; MahmoudianDehkordi, Siamak; Kaddurah-Daouk, Rima; Mazmanian, Sarkis K.
Afiliação
  • Morais LH; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
  • Boktor JC; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815.
  • MahmoudianDehkordi S; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
  • Kaddurah-Daouk R; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815.
  • Mazmanian SK; Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA.
bioRxiv ; 2024 Jun 10.
Article em En | MEDLINE | ID: mdl-38915679
ABSTRACT
Pathological forms of the protein α-synuclein contribute to a family of disorders termed synucleinopathies, which includes Parkinson's disease (PD). Most cases of PD are believed to arise from gene-environment interactions. Microbiome composition is altered in PD, and gut bacteria are causal to symptoms and pathology in animal models. To explore how the microbiome may impact PD-associated genetic risks, we quantitatively profiled nearly 630 metabolites from 26 biochemical classes in the gut, plasma, and brain of α-synuclein-overexpressing (ASO) mice with or without microbiota. We observe tissue-specific changes driven by genotype, microbiome, and their interaction. Many differentially expressed metabolites in ASO mice are also dysregulated in human PD patients, including amine oxides, bile acids and indoles. Notably, levels of the microbial metabolite trimethylamine N-oxide (TMAO) strongly correlate from the gut to the plasma to the brain, identifying a product of gene-environment interactions that may influence PD-like outcomes in mice. TMAO is elevated in the blood and cerebral spinal fluid of PD patients. These findings uncover broad metabolomic changes that are influenced by the intersection of host genetics and the microbiome in a mouse model of PD.

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: BioRxiv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: BioRxiv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos