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Cited by 175Alzheimer's disease research and treatmentsGut microbiota and healthDementia and Cognitive Impairment Research

Towards understanding brain-gut-microbiome connections in Alzheimer’s disease

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Xu, Rong, Wang, QuanQiu·2016·BMC Systems Biology
DOI 10.1186/s12918-016-0307-yPMC PMC5009560
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Abstract

BACKGROUND: Alzheimer's disease (AD) is complex, with genetic, epigenetic, and environmental factors contributing to disease susceptibility and progression. While significant progress has been made in understanding genetic, molecular, behavioral, and neurological aspects of AD, relatively little is known about which environmental factors are important in AD etiology and how they interact with genetic factors in the development of AD. Here, we propose a data-driven, hypotheses-free computational approach to characterize which and how human gut microbial metabolites, an important modifiable environmental factor, may contribute to various aspects of AD. MATERIALS AND METHODS: We integrated vast amounts of complex and heterogeneous biomedical data, including disease genetics, chemical genetics, human microbial metabolites, protein-protein interactions, and genetic pathways. We developed a novel network-based approach to model the genetic interactions between all human microbial metabolites and genetic diseases. We identified metabolites that share significant genetic commonality with AD in humans. We developed signal prioritization algorithms to identify the co-regulated genetic pathways underlying the identified AD-metabolite (brain-gut) connections. RESULTS: We validated our algorithms using known microbial metabolite-AD associations, namely AD-3,4-dihydroxybenzeneacetic acid, AD-mannitol, and AD-succinic acid. Our study provides supporting evidence that human gut microbial metabolites may be an important mechanistic link between environmental exposure and various aspects of AD. We identified metabolites that are significantly associated with various aspects in AD, including AD susceptibility, cognitive decline, biomarkers, age of onset, and the onset of AD. We identified common genetic pathways underlying AD biomarkers and its top one ranked metabolite trimethylamine N-oxide (TMAO), a gut microbial metabolite of dietary meat and fat. These coregulated pathways between TMAO-AD may provide insights into the mechanisms of how dietary meat and fat contribute to AD. CONCLUSIONS: Employing an integrated computational approach, we provide intriguing and supporting evidence for a role of microbial metabolites, an important modifiable environmental factor, in AD etiology. Our study provides the foundations for subsequent hypothesis-driven biological and clinical studies of brain-gut-environment interactions in AD.

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  • The relationship between TMAO and AD pathology has not yet been fully investigated in humans with Alzheimer's clinical syndrome.

    “While it has been hypothesized that TMAO could be associated with AD pathology [16], this relationship has not yet been fully investigated in humans with Alzheimer’s clinical syndrome (AD dementia) [17].”

    From The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease (2018) · cites this paper as [16]

  • TMAO is a metabolite significantly associated with various aspects of Alzheimer's disease, and common genetic pathways underlie AD biomarkers and TMAO.

    “Xu and Wang (2016) [79] used several validated algorithms to identify TMAO as a metabolite significantly associated with various aspects of Alzheimer’s disease (AD). They also found common genetic pathways underlying AD biomarkers and TMAO.”

    From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [79]

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Cited by

Sorted by citations

Authors
Xu, R., & Wang, Q.
Affiliations
Case Western Reserve University (US)
Corresponding author
Xu, Rong
ORCID
Xu, Rong
Venue
BMC Systems Biology
Publisher
Springer Science and Business Media LLC
Published
2016-08
Volume
10
Issue
S3
Pages
63-63
ISSN
1752-0509 (ISSN-L)
DOI
10.1186/s12918-016-0307-y
PMC
PMC5009560
OpenAlex
W2508485654
Cited by
175
References
6
Citations by year
2026: 4 · 2025: 15 · 2024: 17 · 2023: 21 · 2022: 26 · 2021: 25 · 2020: 27 · 2019: 20 · 2018: 11 · 2017: 8 · 2016: 1
FWCI
10.73
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • BMC Systems Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • American Cancer Society (IRG91-022-18, DP2HD084068)
  • Cleveland Clinic
  • Case Western Reserve University (UL1RR024989)
  • Case Comprehensive Cancer Center, Case Western Reserve University
  • Georgia Clinical and Translational Science Alliance (UL1 RR024989)
  • National Institutes of Health (UL1TR000439, DK055812, RR024989, CA094186)
  • National Institute on Aging (R01AG061388, R56AG062272, R01AG057557)
  • National Cancer Institute (R25CA094186)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 055812, R01DK055812)
  • National Center for Research Resources (UL1RR024989)
  • National Center for Advancing Translational Sciences
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (DP2HD084068)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, gut microbiota, microbial metabolites, gut-brain axis, environmental risk factors, trimethylamine N-oxide, mannitol, succinic acid, cognitive decline, disease biomarkers, age of onset, network analysis
MeSH terms
Gastrointestinal Microbiome, Alzheimer Disease, Brain, Humans, Methylamines, Computational Biology, Genome-Wide Association Study

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