Causal relationships between gut metabolites and Alzheimer's disease: a bidirectional Mendelian randomization study

Zhuang, Zhenhuang; Gao, Meng; Rui-xia, Yang; Z, Liu; Cao, Weihua; Huang, Tao

doi:10.1016/j.neurobiolaging.2020.10.022

Cited by 39 publications

(27 citation statements)

References 18 publications

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“… Zhang et al (2020) found that high educational attainment, but not cognitive performance, was causally associated with a reduced risk of amyotrophic lateral sclerosis. Meanwhile, MR studies have found that increased education could reduce the risk of ischemic stroke ( Gill et al, 2019 ; Xiuyun et al, 2020 ; Harshfield et al, 2021 ) and Alzheimer’s disease ( Larsson et al, 2017 ; Anderson et al, 2020 ; Andrews et al, 2021 ; Zhuang et al, 2021a ). Anderson et al (2020) recently examined whether educational attainment and cognitive performance had causal effects on the risk of Alzheimer’s disease, independently of each other.…”

Section: Discussionmentioning

confidence: 99%

Evaluating the Causal Association Between Educational Attainment and Asthma Using a Mendelian Randomization Design

Chen

Shiyao

et al. 2021

Front. Genet.

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Asthma is a common chronic respiratory disease. In the past 10 years, genome-wide association study (GWAS) has been widely used to identify the common asthma genetic variants. Importantly, these publicly available asthma GWAS datasets provide important data support to investigate the causal association of kinds of risk factors with asthma by a Mendelian randomization (MR) design. It is known that socioeconomic status is associated with asthma. However, it remains unclear about the causal association between socioeconomic status and asthma. Here, we selected 162 independent educational attainment genetic variants as the potential instruments to evaluate the causal association between educational attainment and asthma using large-scale GWAS datasets of educational attainment (n = 405,072) and asthma (n = 30,810). We conducted a pleiotropy analysis using the MR-Egger intercept test and the MR pleiotropy residual sum and outlier (MR-PRESSO) test. We performed an MR analysis using inverse-variance weighted, weighted median, MR-Egger, and MR-PRESSO. The main analysis method inverse-variance weighted indicated that each 1 standard deviation increase in educational attainment (3.6 years) could reduce 35% asthma risk [odds ratio (OR) = 0.65, 95% confidence interval (CI) 0.51–0.85, P = 0.001]. Importantly, evidence from other MR methods further supported this finding, including weighted median (OR = 0.55, 95% CI 0.38–0.80, P = 0.001), MR-Egger (OR = 0.48, 95% CI 0.16–1.46, P = 0.198), and MR-PRESSO (OR = 0.65, 95% CI 0.51–0.85, P = 0.0015). Meanwhile, we provide evidence to support that educational attainment protects against asthma risk dependently on cognitive performance using multivariable MR analysis. In summary, we highlight the protective role of educational attainment against asthma. Our findings may have public health applications and deserve further investigation.

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Section: Discussionmentioning

confidence: 99%

Evaluating the Causal Association Between Educational Attainment and Asthma Using a Mendelian Randomization Design

Chen

Shiyao

et al. 2021

Front. Genet.

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“…Indeed, fecal microbiota transplantation (FMT) from AD donor animals increases the progression of AD pathology in recipient mice, while FMT of healthy donors decreases its progression (Sun et al, 2019 ), suggesting that the gut microbiota abnormalities are causal in AD pathology and their restoration can ameliorate AD progression. Although the mechanisms by which the gut microbiota contributes to brain health remain largely unknown, emerging data show that microbial metabolites are a possible link (Vogt et al, 2018 ; Fujii et al, 2019 ; Konjevod et al, 2020 ; Zhuang et al, 2021 ; Doifode et al, 2021 ). For example, short chain fatty acids (SCFAs, such as acetate, propionate, and butyrate) are the major beneficial metabolites produced by healthy microbiota; they exhibit beneficial effects on the brain, including a reduction in AD pathology, in several animal models (Mishra et al, 2020 ; Sun et al, 2020 ; Wenzel et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Activation of Microbiota Sensing – Free Fatty Acid Receptor 2 Signaling Ameliorates Amyloid-β Induced Neurotoxicity by Modulating Proteolysis-Senescence Axis

Razazan

Karunakar

Mishra

et al. 2021

Front. Aging Neurosci.

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Multiple emerging evidence indicates that the gut microbiota contributes to the pathology of Alzheimer’s disease (AD)—a debilitating public health problem in older adults. However, strategies to beneficially modulate gut microbiota and its sensing signaling pathways remain largely unknown. Here, we screened, validated, and established the agonists of free fatty acid receptor 2 (FFAR2) signaling, which senses beneficial signals from short chain fatty acids (SCFAs) produced by microbiota. The abundance of SCFAs, is often low in the gut of older adults with AD. We demonstrated that inhibition of FFAR2 signaling increases amyloid-beta (Aβ) stimulated neuronal toxicity. Thus, we screened FFAR2 agonists using an in-silico library of more than 144,000 natural compounds and selected 15 of them based on binding with FFAR2-agonist active sites. Fenchol (a natural compound commonly present in basil) was recognized as a potential FFAR2 stimulator in neuronal cells and demonstrated protective effects against Aβ-stimulated neurodegeneration in an FFAR2-dependent manner. In addition, Fenchol reduced AD-like phenotypes, such as Aβ-accumulation, and impaired chemotaxis behavior in Caenorhabditis (C.) elegans and mice models, by increasing Aβ-clearance via the promotion of proteolysis and reduced senescence in neuronal cells. These results suggest that the inhibition of FFAR2 signaling promotes Aβ-induced neurodegeneration, while the activation of FFAR2 by Fenchol ameliorates these abnormalities by promoting proteolytic Aβ-clearance and reducing cellular senescence. Thus, stimulation of FFAR2 signaling by Fenchol as a natural compound can be a therapeutic approach to ameliorate AD pathology.

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Section: Discussionmentioning

confidence: 99%

“…Interpreting associations between circulating TMAO and cognition is further complicated by studies indicating that consumption of the TMAO precursors choline and L-carnitine can improve cognitive function 24,25,73 , evidence that patients with Parkinson's disease have lower circulating TMAO than healthy controls 74 , and more recent Mendelian randomisation analysis indicating that serum TMAO and Alzheimer's disease are not causally related 75 . Given this background, our data indicating that physiologically relevant concentrations of TMAO have positive effects upon both BBB integrity and cognition in vivo thus serve as a useful counterweight to population-level correlation studies.…”

Section: Tmao and Cognitive Functionmentioning

confidence: 99%

Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamineN-oxide

Hoyles

Pontifex

Rodríguez-Ramiro

et al. 2021

Preprint

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Communication between the gut microbiota and the brain is primarily mediated via soluble microbe-derived metabolites, but the details of this pathway remain poorly defined. Methylamines produced by microbial metabolism of dietary choline and L-carnitine have received attention due to their proposed association with vascular disease, but their effects upon the cerebrovascular circulation have not hitherto been studied. Here we use an integrated in vitro/in vivo approach to show that physiologically relevant concentrations of the dietary methylamine trimethylamine N- oxide (TMAO) enhanced and protected blood-brain barrier (BBB) integrity, acting through the tight junction regulator annexin A1. In contrast, the TMAO precursor trimethylamine (TMA) impaired BBB function and disrupted tight junction integrity. Moreover, we show that long-term exposure to TMAO has beneficial effects upon cognition in mice, improving visual recognition memory. Our findings demonstrate a direct interaction of microbiome-associated metabolites with the mammalian BBB, with consequences for cerebrovascular and cognitive function.

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Causal relationships between gut metabolites and Alzheimer's disease: a bidirectional Mendelian randomization study

Cited by 39 publications

References 18 publications

Evaluating the Causal Association Between Educational Attainment and Asthma Using a Mendelian Randomization Design

Evaluating the Causal Association Between Educational Attainment and Asthma Using a Mendelian Randomization Design

Activation of Microbiota Sensing – Free Fatty Acid Receptor 2 Signaling Ameliorates Amyloid-β Induced Neurotoxicity by Modulating Proteolysis-Senescence Axis

Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamineN-oxide

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