Abstract
BackgroundThe 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.ResultsA 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.ConclusionsReduction 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.
Highlights
The dietary methylamines choline, carnitine, and phosphatidylcholine are used by the gut microbiota to produce a range of metabolites, including trimethylamine (TMA)
Hoyles et al Microbiome (2018) 6:73. Dietary methylamines such as choline, trimethylamine N-oxide (TMAO), phosphatidylcholine (PC), and carnitine are present in a number of foodstuffs, including meat, fish, nuts, and eggs
TMA diffuses into the bloodstream from the intestine via the hepatic vein to hepatocytes, where it is converted to trimethylamine N-oxide (TMAO) by hepatic flavin-containing monooxygenases (FMOs) [6]
Summary
The dietary methylamines choline, carnitine, and phosphatidylcholine are used by the gut microbiota to produce a range of metabolites, including trimethylamine (TMA). Little is known about the use of trimethylamine N-oxide (TMAO) by this consortium of microbes. Dietary methylamines such as choline, trimethylamine N-oxide (TMAO), phosphatidylcholine (PC), and carnitine are present in a number of foodstuffs, including meat, fish, nuts, and eggs. The bulk of TMAO, and lesser amounts of TMA, derived from dietary methylamines can be detected in urine within 6 h of ingestion, and both compounds are excreted in urine but not faeces [7, 8]. TMAO can be detected in human skeletal muscle within 6 h of an oral dose of TMAO [8]
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