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

Abstract

BackgroundAlzheimer’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 methodsWe 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.ResultsWe 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.ConclusionsEmploying 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.

Trimethylamine‐N‐oxide promotes brain aging and cognitive impairment in mice

“…However, the exact mechanisms underlying how microbial metabolites regulate brain function have not been fully elucidated. A recent study proposed that TMAO is highly associated with Alzheimer's disease, which provides new insight into the influence of microbial metabolites on brain aging and cognitive function (Xu & Wang, 2016). In our research, we observed that TMAO could induce neuron senescence (Figure 3c and d) and destroy mitochondria in the hippocampal CA3 region of mice (Figure 4c and d), leading to aggravated brain aging in mice.…”

“…In our research, we observed that TMAO could induce neuron senescence (Figure 3c and d) and destroy mitochondria in the hippocampal CA3 region of mice (Figure 4c and d), leading to aggravated brain aging in mice. Recent studies demonstrated that elevating the circulating TMAO level could impair mitochondria and induce cardiovascular events (Xu & Wang, 2016). Mitochondrial energy metabolism impairments can decrease ATP production and increase calcium buffer damage and H 2 O 2 generation, which is considered a crucial player in both aging and neurodegenerative disorders (Johri, Chandra & Beal, 2013).…”

“…Recently, trimethylamine‐ N ‐oxide (TMAO), a product of choline, which is metabolized by the gut flora, has attracted increasing interest in medical research. TMAO is involved in a variety of diseases, including cardiovascular events (Tang et al., 2013), atherosclerosis (Koeth et al., 2013), obesity, diabetes (Gao et al., 2014), chronic kidney disease (Missailidis et al., 2016), nonalcoholic liver disease (Chen et al., 2016), Alzheimer's disease (Xu & Wang, 2016), peripheral arterial disease (Senthong et al., 2016), and tumours (Guertin et al., 2017). However, the influence of TMAO in the aging process, including brain aging, has not yet been reported.…”

Advancing Systems Biology in the International Conference on Intelligent Biology and Medicine (ICIBM) 2015

“…In the second paper, Xu and Wang developed a computational approach to characterize which and how human gut microbial metabolites may contribute to various aspects of Alzheimer's disease (AD), a disease that is currently under extensive investigation [3]. They found metabolites were significantly associated with various aspects of AD, such as AD susceptibility, cognitive decline, biomarkers, age of onset, and the onset of AD, which provided evidence to support that human gut microbial metabolites might serve as an important mechanistic link between environmental exposure and AD symptoms.…”

Health and disease imprinted in the time variability of the human microbiome

“…The human microbiota is plausibly related to diseases such as type 2 diabetes (10), cardiovascular disease (11), irritable bowel syndrome (IBS) (12), and Crohn's disease (13) and some afflictions like obesity (14,15) and malnutrition (16), as well as many other diseases (17). Current studies have revealed that gut microbes also influence brain function and behavior and are related to neurological disorders like Alzheimer's disease through the gut-brain axis (18,19). Recently, chronic fatigue syndrome (CFS), a subtle but devastating condition often cited as a psychosomatic disease, has been associated with a reduced diversity and altered composition of the gut microbiome (20).…”