Research Article: The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease

Date Published: December 22, 2018

Publisher: BioMed Central

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


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.

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).

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).

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

The online version of this article (10.1186/s13195-018-0451-2) contains supplementary material, which is available to authorized users.

Partial Text

The human gut is home to trillions of microbes, including bacteria, eukaryotes, and viruses, that participate in a lifelong symbiotic relationship with their human hosts. Resident gut microbes perform essential functions for human health ranging from regulating nutrition and metabolism to influencing immune system development and function [1]. Gut microbes impact human health and disease at least in part by metabolizing dietary and host-derived substrates, and generating biologically active compounds including signaling compounds (e.g., agonists of G-protein coupled receptors), biological precursors, and toxins [2–4]. The microbial-derived metabolite trimethylamine N-oxide (TMAO) has been implicated in metabolic [5], cardiovascular [6, 7], and cerebrovascular [8] disease. The production of TMAO occurs via a two-step process. First, gut microbes enzymatically generate trimethylamine (TMA) from dietary constituents such as choline or l-carnitine [9]. TMA then enters the circulation and is oxidized to TMAO in the liver by flavin-containing monooxygenase 1 and 3 (FMO1 and FMO3) [6]. A recent study [10] demonstrated that TMAO is measurable in cerebrospinal fluid (CSF), suggesting that this microbial-derived metabolite reaches the central nervous system (CNS), and may therefore be relevant to neurological function or disorders. Indeed, mice treated with dietary TMAO show increased brain aging and cognitive impairment, likely due to increased oxidative stress, mitochondrial dysfunction, and inhibition of mammalian target of rapamycin (mTOR) signaling in the brain [11].

Understanding the contributions of the gut microbiota to neurological function and disease is an expanding area of research, particularly with respect to neurodegenerative disorders. A recent study [16], which used publicly available databases and a data-driven hypothesis-free computational approach to address the links between gut microbiota and AD, proposed that the gut microbial-derived metabolite TMAO is highly associated with AD. In the present study, we provide biochemical evidence revealing that CSF TMAO is higher in individuals with MCI and AD dementia, and elevated CSF TMAO is associated with both increased AD pathology (as measured by CSF biomarkers) as well as markers of neuronal degeneration.

In this study, we demonstrate that the gut microbiota-derived metabolite TMAO is elevated in the CSF of individuals with MCI and AD dementia, and that levels of CSF TMAO are associated with CSF biomarkers of AD pathology and neuronal degeneration. These results provide additional evidence for an association between TMAO and AD, and further inform the role of gut microbiota in AD. Longitudinal studies are needed to determine whether elevated TMAO during mid-life predicts subsequent development or exacerbation of AD pathology. In this scenario, pharmacological agents designed to inhibit gut microbial TMAO production may be useful in slowing AD pathology [42].




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