Systematic characterization of multi-omics landscape between gut microbial metabolites and GPCRome in Alzheimer's disease

Yunguang Qiu; Yuan Hou; Dhruv Gohel; Yadi Zhou; Jielin Xu; Marina Bykova; Yuxin Yang; James B Leverenz; Andrew A Pieper; Ruth Nussinov; Jessica Z K Caldwell; J Mark Brown; Feixiong Cheng

doi:10.1016/j.celrep.2024.114128

Systematic characterization of multi-omics landscape between gut microbial metabolites and GPCRome in Alzheimer's disease

Cell Rep. 2024 Apr 21;43(5):114128. doi: 10.1016/j.celrep.2024.114128. Online ahead of print.

Authors

Affiliations

¹ Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
² Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA.
³ Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA; Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106, USA; Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Neurosciences, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA; Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
⁴ Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD 21702, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
⁵ Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA; Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Las Vegas, NV 89106, USA.
⁶ Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA; Department of Cancer Biology, Lerner Research Institute Cleveland Clinic, Cleveland, OH 44195, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
⁷ Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA. Electronic address: chengf@ccf.org.

PMID: 38652661
DOI: 10.1016/j.celrep.2024.114128

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.

Keywords: AlphaFold2; Alzheimer's disease; CP: Microbiology; CP: Neuroscience; G-protein-coupled receptors; Mendelian randomization; gut microbial metabolite; gut microbiota; machine learning; metabolite-protein interaction; multi-omics; orphan GPCR.