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. 2018 Dec 22;10(1):124.
doi: 10.1186/s13195-018-0451-2.

The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer's disease

Nicholas M Vogt  1 , Kymberleigh A Romano  2   3 , Burcu F Darst  4 , Corinne D Engelman  4 , Sterling C Johnson  1   5 , Cynthia M Carlsson  1   5 , Sanjay Asthana  1   5 , Kaj Blennow  6   7 , Henrik Zetterberg  6   7   8   9 , Barbara B Bendlin  10 , Federico E Rey  11
Affiliations

The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer's disease

Nicholas M Vogt et al. Alzheimers Res Ther. .

Abstract

Background: 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.

Methods: In 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).

Results: CSF 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).

Conclusions: These findings provide additional insight into gut microbial involvement in AD and add to the growing understanding of the gut-brain axis.

Keywords: Alzheimer’s disease; Amyloid; Biomarkers; Cerebrospinal fluid; Gut bacteria; Microbiota; Neurofilament light; Tau; Trimethylamine N-oxide.

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Conflict of interest statement

Ethics approval and consent to participate

The University of Wisconsin Health Science Institutional Review Board approved all study procedures, and all experiments were performed in accordance with relevant guidelines and regulations. All participants provided written informed consent to be involved in this study.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
CSF TMAO levels are elevated in individuals with AD dementia and MCI compared to cognitively-unimpaired individuals, after controlling for age, sex, and APOE ε4 genotype. Data presented as violin plots (displaying scaled distribution of data for each group) with inset Tukey boxplots showing median, interquartile range (IQR), and 1.5 × IQR. AD Alzheimer’s disease, CSF cerebrospinal fluid, MCI mild cognitive impairment, TMAO trimethylamine N-oxide
Fig. 2
Fig. 2
Relationship between CSF TMAO and CSF AD biomarkers (a–c) and biomarkers of neuronal degeneration (d–f). CSF TMAO is significantly positively correlated with phosphorylated tau (p-tau), p-tau/Aβ42, total tau (t-tau), and neurofilament light chain protein (NFL), after controlling for age and sex. Scatterplots show individual data points (n = 410) colored by 2D kernel density estimation. Hotter colors represent higher density; black line represents best linear fit between variables; shading represents 95% confidence interval of fit. CSF TMAO expressed as natural log-transformed scaled intensity units (SIU). Aβ, beta-amyloid CSF cerebrospinal fluid, TMAO trimethylamine N-oxide
See this image and copyright information in PMC

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