Systematic characterization of multi-omics landscape between gut microbial metabolites and GPCRome in Alzheimer's disease.
Cell Rep
; 43(5): 114128, 2024 May 28.
Article
em En
| MEDLINE
| ID: mdl-38652661
ABSTRACT
Shifts in the magnitude and nature of gut microbial metabolites have been implicated in Alzheimer's disease (AD), but the host receptors that sense and respond to these metabolites are largely unknown. Here, we develop a systems biology framework that integrates machine learning and multi-omics to identify molecular relationships of gut microbial metabolites with non-olfactory G-protein-coupled receptors (termed the "GPCRome"). We evaluate 1.09 million metabolite-protein pairs connecting 408 human GPCRs and 335 gut microbial metabolites. Using genetics-derived Mendelian randomization and integrative analyses of human brain transcriptomic and proteomic profiles, we identify orphan GPCRs (i.e., GPR84) as potential drug targets in AD and that triacanthine experimentally activates GPR84. We demonstrate that phenethylamine and agmatine significantly reduce tau hyperphosphorylation (p-tau181 and p-tau205) in AD patient induced pluripotent stem cell-derived neurons. This study demonstrates a systems biology framework to uncover the GPCR targets of human gut microbiota in AD and other complex diseases if broadly applied.
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Base de dados:
MEDLINE
Assunto principal:
Receptores Acoplados a Proteínas G
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Doença de Alzheimer
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Microbioma Gastrointestinal
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article