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Cited by 40Alzheimer's disease research and treatmentsGut microbiota and healthMetabolomics and Mass Spectrometry Studies

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

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Qiu, Yunguang, Hou, Yuan, Gohel, Dhruv, Zhou, Yadi, Xu, Jielin, Bykova, Marina, Yang, Yuxin, Leverenz, James B. +5 more·2024·Cell Reports
DOI 10.1016/j.celrep.2024.114128PMC PMC11968202
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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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  • AI-assisted multi-omics integration has been increasingly applied to investigate how microbiome alterations affect host metabolism and immune signaling in AD.

    “AI-assisted multi-omics integration has been increasingly applied to investigate how microbiome alterations affect host metabolism and immune signaling in AD66, 67, 68.”

    From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [68]

    The Introduction and Results describe a machine-learning and multi-omics framework for studying gut microbial metabolites and host GPCRs in AD. The Results also examine GPCRs in inflammation-associated microglia, and the Discussion links gut-derived metabolites to mitochondrial metabolism. The paper supports this as an example of the approach, but does not establish that its use is increasingly widespread or directly investigate both host metabolism and immune signaling as outcomes. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Qiu, Y., Hou, Y., Gohel, D., Zhou, Y., Xu, J., Bykova, M., Yang, Y., Leverenz, J. B., Pieper, A. A., Nussinov, R., Caldwell, J. Z. K., Brown, J. M., & Cheng, F.
Affiliations
  • Cleveland Clinic (US)
  • University Hospitals of Cleveland (US)
  • Tel Aviv University (IL)
  • Lou Ruvo Brain Institute (US)
  • Cleveland Clinic Lerner College of Medicine (US)
Corresponding author
Cheng, Feixiong
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2024-05
Volume
43
Issue
5
Pages
114128
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2024.114128
PMC
PMC11968202
OpenAlex
W4394986450
Cited by
40
References
22
Citations by year
2026: 17 · 2025: 19 · 2024: 4
FWCI
11.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
Funders
  • Government of the United Kingdom
  • U.S. Department of Health and Human Services
  • Center for Cancer Research
  • American Heart Association (P20-AG068053, R01 DK130227, R01-AG070849, R01 DK120679, P01 HL147823, U01 AA026938, P50 AA024333, 19PABH134580006)
  • National Institute on Aging (3R01AG066707-02S1, U01AG073323, R21AG083003, R01AG084250, R01AG082118, R56AG063870, RF1AG082211, R01AG076448)
  • Voice Foundation
  • Case Western Reserve University
  • GE Healthcare
  • Office of Data Science Strategy
  • National Institute of General Medical Sciences (P20-GM109025)
  • NINDS (RF1NS133812)
  • National Cancer Institute (HHSN261201500003I)
  • National Institutes of Health
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
Keywords
Alzheimer's disease, gut microbiota metabolites, G protein-coupled receptors, GPR84, orphan G protein-coupled receptor, phenethylamines, agmatine, tau hyperphosphorylation, gut-brain axis, therapeutic target, iPSC-derived neurons, multi-omics integration
MeSH terms
Gastrointestinal Microbiome, Multiomics, Alzheimer Disease, Brain, Humans, Neurons, Phosphorylation, tau Proteins, Proteomics, Receptors, G-Protein-Coupled, Induced Pluripotent Stem Cells

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