Journal of Food Bioactives, ISSN 2637-8752 print, 2637-8779 online
Journal website www.isnff-jfb.com

Review

Volume 3, Number , September 2018, pages 87-94

Potential effects of natural dietary compounds on trimethylamine N-oxide (TMAO) formation and TMAO-induced atherosclerosis

Figures

Figure 1.
Figure 1.

Biosynthesis of gut microbiota-dependent metabolites and atherosclerosis and the effects of DMB.

TMA-containing nutrients (L-carnitine and choline) are source of TMAO. Unabsorbed L-carnitine and choline are first metabolized to TMA by distinct gut flora enzymes, CntA/B (Zhu et al. 2014) and CutC/D (Craciun and Balskus 2012), respectively. γ-Butyrobetaine is produced as an intermediate metabolite from L-carnitine by microbial enzyme YeaW/X and then into TMA. Study also suggested that YeaW/X can catalyze TMA formation from multiple TMA-containing compounds (Koeth et al. 2014). TMA is subsequently metabolized by host hepatic phase I enzyme FMOs to TMAO. TMAO is identified to promote and accelerate atherosclerosis progression and cause CVD. DMB, an analogue of choline, reported to reorganize gut microbial community and inhibit some TMA lyase activity (Wang et al. 2015). TMA: trimethylamine; TMAO: trimethylamine-N-oxide; FMOs: flavin monooxygenases; CVD: cardiovascular disease; DMB: 3,3-dimethyl-1-butanol.
Figure 2.
Figure 2.

Schematic representation of pro-atherosclerotic ability of TMAO and the effects of resveratrol.

TMAO activates inflammatory gene expression of cyclooxygenase-2, IL-6, E-selectin, and ICAM-1 in aortas (Seldin et al. 2016). TMAO facilitates cholesterol influx into macrophages by scavenger receptors, CD36 and SR-A1 (Wang et al. 2011), and inhibits cholesterol efflux by hindering reverse cholesterol transport (Koeth et al. 2013). TMAO also reduces the levels of bile acid synthetic enzymes (CYP7A1 and CYP27A1) and hepatic bile acid transporters (OATP1, OATP4, MRP2, and NTCP) and intestinal cholesterol transporters (NPC1L1 and ABCG5/8) (Koeth et al. 2013). Resveratrol, a natural dietary compound, increased CYP7A1 expression through downregulating FGF15, which induced by choline (Chen et al. 2016). B: bile acids; C: cholesterol; CE: cholesteryl ester; oxLDL: oxidized LDL.

Table

Table 1. Three key TMA-generating enzymes and the corresponding TMA producers
 
EnzymePhylumClass or subclassGenus or species
CutC/D (Craciun and Balskus 2012; Falony et al. 2015; Martinez-del Campo et al. 2015; Romano et al. 2015)FirmicutesClostridia
Clostridium hathewayi
Clostridium asparagiforme
Clostridium citroniae
Anaerococcus hydrogenalis
Bacilli
Enterococcus
Proteobacteriaγ-Proteobacteria
Klebsiella variicola
Klebsiella
Escherichia coli
Escherichia fergusonii
Proteus mirabilis
Edwardsiella tarda
Providencia rettgeri
δ-Proteobacteria
ActinobacteriaCoriobacteridae
Collinsella tanakaei
Olsenella uli
FusobacteriaFusobacteriia
CntA/B (Falony et al. 2015; Rath et al. 2017; Zhu et al. 2014)Proteobacteriaγ-Proteobacteria
Acinetobacter baumannii
Escherichia coli
Klebsiella
Citrobacter
β-Proteobacteria
ε-Proteobacteria
Firmicutes
YeaW/X (Falony et al. 2015; Koeth et al. 2014)Proteobacteriaγ-Proteobacteria
Acinetobacter baumannii
Escherichia coli
Citrobacter
β-Proteobacteria
Firmicutes