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

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

The mutual interplay of gut microbiota, diet and human disease

“…1) [171]. Clinical studies performed on cerebrospinal fluid samples have demonstrated that TMAO may be relevant to the neurodegenerative changes in AD-related tau pathology, thus confirming the role of the gut-brain axis in the pathophysiology of AD [172].…”

“…) . Clinical studies performed on cerebro‐spinal fluid samples have demonstrated that TMAO may be relevant to the neurodegenerative changes in AD‐related tau pathology, thus confirming the role of the gut–brain axis in the pathophysiology of AD . Comprehensive 16s rRNA sequencing of stool samples of AD patients demonstrated their microbiome has decreased microbial diversity, with an increased relative abundance of Lactobacillales , and decreased abundance of Bacteroidales and Selenomonadales .…”

Sex-Specific Associations of Trimethylamine-N-Oxide and Zonulin with Signs of Depression in Carbohydrate Malabsorbers and Nonmalabsorbers

“…The gut bacteria-derived metabolite trimethylamine-Noxide (TMAO) is a small organic molecule, which was recently shown to be associated with neurodegenerative diseases [2] and postoperative cognitive dysfunction [3]. The gut microbiome metabolizes phosphatidyl and L-carnitine containing nutrients (i.e., eggs, red meat, cheese, and seasalt fish) to trimethylamine (TMA), which is absorbed into the bloodstream and then oxidized by the hepatic flavincontaining monooxygenase (FMO) family members FMO-1 and FMO-3 [4,5].…”

Enzymatically Produced Trimethylamine N-Oxide: Conserving It or Eliminating It

“…High TMAO concentrations were also found in cerebrospinal fluids of patients with Alzheimer's clinical syndrome and TMAO is associated with biomarkers of Alzheimer's disease [100]. Further studies are needed to evaluate the role of TMAO in the development of the pathology.…”