ArticleCell reports2024
Systematic characterization of multi-omics landscape between gut microbial metabolites and GPCRome in Alzheimer's disease.
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Article in Cell reports, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 4 of them syntheses that pooled it.
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26citing papers in PubMed, 4 pooled it
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Who cites it
26 citing papers in PubMed, 4 syntheses or guidelines pooled it, 26 citations in OpenAlex.
- Leveraging artificial intelligence for analysis of the gut microbiome for dementia diagnosis: a scoping review and discussion.Frontiers in dementia · 2026Pooled it
- Microbiota-derived metabolite signatures in Alzheimer's disease across the cognitive aging continuum: a human-focused systematic review and evidence-weighted knowledge graph.Frontiers in microbiology · 2026Pooled it
- STROBE-causal machine learning for the human microbiome: systematic review on methodological innovations and validation frameworks.Frontiers in microbiology · 2026Pooled it
- Beyond just correlation: causal machine learning for the microbiome, from prediction to health policy with econometric tools.Frontiers in microbiology · 2025Pooled it
- Review
- Artificial intelligence driven diet-intestinal microbiota-host health integration: A four-dimensional paradigm for advancing host wellness research.iMetaOmics · 2026Review
- Expression of GPR34 in microglia remains stable in human Alzheimer's disease.Acta neuropathologica · 2026Article
- Illuminating proinflammatory myeloid cells with PET tracers targeting GPR84.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Microbiota-Gut-Brain Axis in Alzheimer's Disease: Linking Oxidative Stress, Mitochondrial Dysfunction and Amyloid Pathology-A Systematic Review.Biomedicines · 2026Review
- Multi-View Biomedical Foundation Models for Molecule-Target and Property Prediction.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The gut-brain axis in Alzheimer's disease: early detection, microbial metabolites, mechanisms, and therapeutic opportunities.Frontiers in molecular biosciences · 2026Review
- Artificial intelligence empowers gut microbiota research in neurodegenerative diseases molecular mechanisms and precision therapy.iScience · 2025Review
- Gut microbial-derived indole-3-propionate improves cognitive function in Alzheimer's disease.Science advances · 2025Article
- Gaultheria leucocarpa inhibits Aβ fibrillization and enhances mitophagy-mediated degradation of pathogenic proteins.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
- Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions.Acta pharmaceutica Sinica. B · 2025Review
- Systematic characterization of cell type-specific master metabolic regulators in Alzheimer's disease.Research square · 2025Article
- Gut microbial metabolites and the brain-gut axis in Alzheimer's disease: A review.Biomolecules & biomedicine · 2025Review
- Review
- Cell type-specific master metabolic regulators of Alzheimer's disease.bioRxiv : the preprint server for biology · 2025Article
- Decreased mitochondrial NAD+ in WRN deficient cells links to dysfunctional proliferation.Aging · 2025Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 1 country.
Yunguang QiuCleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Yuan HouCleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Dhruv GohelCleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Yadi ZhouCleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Jielin XuCleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Marina BykovaCleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Yuxin YangCleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
James B LeverenzLou 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.
Andrew A PieperBrain 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.
Ruth NussinovComputational 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.
Jessica Z K CaldwellDepartment 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.
J Mark BrownDepartment 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.
Feixiong ChengCleveland 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.
Cleveland Clinic Lerner College of Medicine · USFrederick National Laboratory for Cancer Research · USLou Ruvo Brain Institute · USUniversity Hospitals of Cleveland · US
Funding
Renewal of Centers of Biomedical Research Excellence (COBRE) (Phase 2) CNTN - ResubmissionP20GM109025 · NIGMS · CLEVELAND CLINIC FOUNDATION · PI Robert J. Fox, Jefferson Kinney · 2015 to 2026
$22.8MProject Two - Exercise Training Decreases Alcohol Drinking by an FGF21-Dependent MechanismP50AA024333 · NIAAA · CLEVELAND CLINIC LERNER COM-CWRU · PI Thomas M McIntyre · 2016 to 2026
$19.6MProject 3: Microbiota generated aryl sulfates and secondary bile acids in cardiometabolic diseaseP01HL147823 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI Stanley L Hazen · 2019 to 2026
$17.0MProtein Structure, Stability, and Amyloid FormationZIABC010440 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI NUSSINOV, RUTH · 2009 to 2025
$11.8MBiomolecular Recognition and Binding MechanismsZIABC010441 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI NUSSINOV, RUTH · 2009 to 2025
$9.4MChemical, Structural and Cell-Signaling Interrogation of 15-Prostanglandin Dehydrogenase in Tissue Repair and RegenerationRM1GM142002 · NIGMS · UT SOUTHWESTERN MEDICAL CENTER · PI MARKOWITZ, SANFORD D., PIEPER, ANDREW A · 2021 to 2025
$6.9MEndophenotype Network-based Approaches to Prediction and Population-based Validation of In Silico Drug Repurposing for Alzheimer's DiseaseR01AG066707 · NIA · CLEVELAND CLINIC LERNER COM-CWRU · PI Feixiong Cheng · 2020 to 2026
$4.9MTREM2 Genotype-Informed Drug Repurposing and Combination Therapy Design for Alzheimers DiseaseR01AG076448 · NIA · CLEVELAND CLINIC LERNER COM-CWRU · PI Feixiong Cheng, Li Gan · 2022 to 2026
$4.0MAlzheimer's MultiOme Data Repurposing: Artificial Intelligence, Network Medicine, and Therapeutics DiscoveryU01AG073323 · NIA · CLEVELAND CLINIC LERNER COM-CWRU · PI BEKRIS, LYNN, CHENG, FEIXIONG · 2021 to 2025
$4.0MNVEDARC Clinical CoreP20AG068053 · NIA · CLEVELAND CLINIC FOUNDATION · PI WINT, DYLAN · 2020 to 2022
$3.3MMetaorganismal Endocrinology in Cardiometabolic DiseaseR01DK130227 · NIDDK · CLEVELAND CLINIC LERNER COM-CWRU · PI Jonathan Mark Brown · 2021 to 2026
$2.8MAlzheimer's Disease and Related Dementia-like Sequelae of SARS-CoV-2 Infection: Virus-Host Interactome, Neuropathobiology, and Drug RepurposingRF1AG082211 · NIA · CLEVELAND CLINIC LERNER COM-CWRU · PI CHENG, FEIXIONG, PIEPER, ANDREW A · 2023 to 2023
$2.4MBLRD VA I01 BX005976NCI NIH HHS HHSN261201500003CNCI NIH HHS HHSN261201500003INHLBI NIH HHS P01 HL147823NIAAA NIH HHS P50 AA024333NIAAA NIH HHS U01 AA026938NIA NIH HHS K08 AG065463NIA NIH HHS P20 AG068053NIA NIH HHS R01 AG066707NIA NIH HHS R01 AG070849NIA NIH HHS R01 AG076448NIA NIH HHS R01 AG082118NIA NIH HHS R01 AG084250NIA NIH HHS R21 AG083003NIA NIH HHS R56 AG063870NIA NIH HHS R56 AG074001NIA NIH HHS RF1 AG082211NIA NIH HHS U01 AG073323NIDDK NIH HHS R01 DK120679NIDDK NIH HHS R01 DK130227NIGMS NIH HHS P20 GM109025NIGMS NIH HHS RM1 GM142002NINDS NIH HHS RF1 NS133812
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.
Indexed as
Alzheimer DiseaseGastrointestinal MicrobiomeReceptors, G-Protein-CoupledBrainHumansInduced Pluripotent Stem CellsMultiomicsNeuronsPhosphorylationProteomicstau ProteinsReceptors, G-Protein-Coupledtau ProteinsAlphaFold2Alzheimer's diseaseCP: MicrobiologyCP: NeuroscienceG-protein-coupled receptorsgut microbial metabolitegut microbiotamachine learningMendelian randomizationmetabolite-protein interactionmulti-omicsorphan GPCR
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