The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer\u2019s disease

Nicholas M Vogt,Federico E Rey,Burcu F Darst,Cynthia M Carlsson,Kymberleigh A Romano,Corinne D Engelman,Henrik Zetterberg,Kaj Blennow,Sterling C Johnson,Sanjay Asthana,Barbara B Bendlin

doi:10.1186/s13195-018-0451-2

Abstract

BackgroundTrimethylamine N-oxide (TMAO), a small molecule produced by the metaorganismal metabolism of dietary choline, has been implicated in human disease pathogenesis, including known risk factors for Alzheimer’s disease (AD), such as metabolic, cardiovascular, and cerebrovascular disease.MethodsIn this study, we tested whether TMAO is linked to AD by examining TMAO levels in cerebrospinal fluid (CSF) collected from a large sample (n = 410) of individuals with Alzheimer’s clinical syndrome (n = 40), individuals with mild cognitive impairment (MCI) (n = 35), and cognitively-unimpaired individuals (n = 335). Linear regression analyses were used to determine differences in CSF TMAO between groups (controlling for age, sex, and APOE ε4 genotype), as well as to determine relationships between CSF TMAO and CSF biomarkers of AD (phosphorylated tau and beta-amyloid) and neuronal degeneration (total tau, neurogranin, and neurofilament light chain protein).ResultsCSF TMAO is higher in individuals with MCI and AD dementia compared to cognitively-unimpaired individuals, and elevated CSF TMAO is associated with biomarkers of AD pathology (phosphorylated tau and phosphorylated tau/Aβ42) and neuronal degeneration (total tau and neurofilament light chain protein).ConclusionsThese findings provide additional insight into gut microbial involvement in AD and add to the growing understanding of the gut–brain axis.

Highlights

Trimethylamine N-oxide (TMAO), a small molecule produced by the metaorganismal metabolism of dietary choline, has been implicated in human disease pathogenesis, including known risk factors for Alzheimer’s disease (AD), such as metabolic, cardiovascular, and cerebrovascular disease
We found that cerebrospinal fluid (CSF) TMAO levels are elevated in individuals with AD dementia, and that elevated CSF TMAO is associated with elevated AD pathology and neuronal degeneration as measured in CSF
CSF TMAO is elevated in individuals with mild cognitive impairment (MCI) and AD dementia CSF TMAO levels were elevated in individuals with AD dementia (β = 0.50, p < 0.0001) and MCI (β = 0.29, p < 0.05) compared to cognitively-unimpaired individuals (Fig. 1; Table 2), controlling for age, sex, and APOE ε4 genotype

Summary

Introduction

Trimethylamine N-oxide (TMAO), a small molecule produced by the metaorganismal metabolism of dietary choline, has been implicated in human disease pathogenesis, including known risk factors for Alzheimer’s disease (AD), such as metabolic, cardiovascular, and cerebrovascular disease. Gut microbes impact human health and disease at least in part by metabolizing dietary and host-derived substrates, and generating biologically active. 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]. We investigated the relationships between CSF TMAO, AD biomarkers (Aβ and phosphorylated tau), and biomarkers of neuronal and synaptic degeneration (total tau, neurofilament light chain protein, and neurogranin). We found that CSF TMAO levels are elevated in individuals with AD dementia, and that elevated CSF TMAO is associated with elevated AD pathology and neuronal degeneration as measured in CSF

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