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

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 ?4 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/A?42) 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.

SUBMITTER: Vogt NM

PROVIDER: S-EPMC6303862 | biostudies-other | 2018 Dec

REPOSITORIES: biostudies-other

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

Vogt Nicholas M NM Romano Kymberleigh A KA Darst Burcu F BF Engelman Corinne D CD Johnson Sterling C SC Carlsson Cynthia M CM Asthana Sanjay S Blennow Kaj K Zetterberg Henrik H Bendlin Barbara B BB Rey Federico E FE

Alzheimer's research & therapy 20181222 1

<h4>Background</h4>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.<h4>Methods</h4>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 cl ...[more]

PMID: 30579367

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Project description:BACKGROUND:The dietary methylamines choline, carnitine, and phosphatidylcholine are used by the gut microbiota to produce a range of metabolites, including trimethylamine (TMA). However, little is known about the use of trimethylamine N-oxide (TMAO) by this consortium of microbes. RESULTS:A feeding study using deuterated TMAO in C57BL6/J mice demonstrated microbial conversion of TMAO to TMA, with uptake of TMA into the bloodstream and its conversion to TMAO. Microbial activity necessary to convert TMAO to TMA was suppressed in antibiotic-treated mice, with deuterated TMAO being taken up directly into the bloodstream. In batch-culture fermentation systems inoculated with human faeces, growth of Enterobacteriaceae was stimulated in the presence of TMAO. Human-derived faecal and caecal bacteria (n?=?66 isolates) were screened on solid and liquid media for their ability to use TMAO, with metabolites in spent media analysed by 1H-NMR. As with the in vitro fermentation experiments, TMAO stimulated the growth of Enterobacteriaceae; these bacteria produced most TMA from TMAO. Caecal/small intestinal isolates of Escherichia coli produced more TMA from TMAO than their faecal counterparts. Lactic acid bacteria produced increased amounts of lactate when grown in the presence of TMAO but did not produce large amounts of TMA. Clostridia (sensu stricto), bifidobacteria, and coriobacteria were significantly correlated with TMA production in the mixed fermentation system but did not produce notable quantities of TMA from TMAO in pure culture. CONCLUSIONS:Reduction of TMAO by the gut microbiota (predominantly Enterobacteriaceae) to TMA followed by host uptake of TMA into the bloodstream from the intestine and its conversion back to TMAO by host hepatic enzymes is an example of metabolic retroconversion. TMAO influences microbial metabolism depending on isolation source and taxon of gut bacterium. Correlation of metabolomic and abundance data from mixed microbiota fermentation systems did not give a true picture of which members of the gut microbiota were responsible for converting TMAO to TMA; only by supplementing the study with pure culture work and additional metabolomics was it possible to increase our understanding of TMAO bioconversions by the human gut microbiota.

Dataset Information

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

Publications

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

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