Year: 2016
Type: article
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.
Source: BMC Systems Biology
Authors: Rong Xu, QuanQiu Wang
Institution: Case Western Reserve University
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,290
Funders: American Cancer Society, Cleveland Clinic, Case Western Reserve University, Case Comprehensive Cancer Center, Case Western Reserve University, Georgia Clinical and Translational Science Alliance, National Institutes of Health, National Institute on Aging, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Computational Genomic Epidemiology of Cancer (CoGEC) Training Program, G1452406238, G1916324419, Case Western Reserve University/Cleveland Clinic CTSA (UL1), G2401222623, Mechanisms of Experimental Crohn's Disease, Rapid reverse translational drug repositioning, Combine computational prediction, network analysis and genetic screening in C elegans to uncover neurodegenerative causes in Alzheimer's Disease, Construct large-scale phenomes of disease and drugs and develop data-driven systems approaches to understand genetic links between Alzheimer's disease and Neuropsychiatric symptoms, G463728467, G6288433032, An Integrated Reverse Engineering Approach Toward Rapid drug Re positioning for Alzheimer's Disease, Clinical and Translational Science Collaborative of Cleveland, G9000241656, G9000281696, G9000283857
OpenAlex ID: W2508485654