Potential of phenolic compounds and their gut microbiota-derived metabolites to reduce microbial TMA formation: Application of an in vitro fermentation high throughput screening model

10 February 2022, Version 3
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Trimethylamine N-oxide (TMAO) is a pro-atherosclerotic product of dietary choline metabolism generated by a microbiome-host axis. The first step in this pathway is enzymatic metabolism of choline to trimethylamine (TMA) by the gut microbiota. This reaction could be targeted to reduce atherosclerosis risk. We aimed to evaluate potential inhibitory effects of select dietary phenolics and their relevant gut microbial metabolites on TMA production via a human ex vivo-in vitro fermentation model. Various phenolics inhibited choline use and TMA production. The most bioactive compounds tested (caffeic acid, catechin and epicatechin) reduced TMA-d9 formation (compared to control) by 57.5 ± 1.3% to 72.5 ± 0.4% at 8 h and preserved remaining choline-d9 concentrations by 194.1 ± 6.4% to 256.1 ± 6.3% compared to control conditions at 8 h. These inhibitory effects were achieved without altering cell respiration or cell growth. However, inhibitory effects decreased at late fermentation times, which suggest that these compounds delay choline metabolism rather than completely inhibiting TMA formation. Overall, caffeic acid, catechin and epicatechin were the most effective non-cytotoxic inhibitors of choline use and TMA production. Thus, these compounds are proposed as lead bioactives to test in vivo.

Keywords

atherosclerosis
Food bioactives
Gut microbiota metabolites
Phenolic compounds
TMAO

Supplementary materials

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Supplementary figures and tables
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Individual choline-d9 and TMA-d9 kinetic curves, kinetic curves for endogenous substrate (unlabeled choline) and product (unlabeled TMA), cell density time course data, MTT assay interference data, qPCR data, two-way ANOVA main effects and interactions significance summary table, % inhibition of choline-d9 utilization and TMA-d9 production at individual time points.
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