Suppression of the Gut Microbiome‐Derived Metabolite Trimethylamine N‐oxide Prevents Western Diet‐Induced Arterial Dysfunction

Abstract

Consumption of a Western‐style diet (WD; high fat, high sugar) is associated with impaired arterial function and increased risk of cardiovascular diseases (CVD). One possible link between WD and impaired arterial function may be the gut microbiome. WD induces adverse changes to the gut microbiome, and consequently, increased production of the gut‐derived metabolite trimethylamine N‐oxide (TMAO). TMAO is causally atherogenic in mice and predicts incident risk of major CV events in humans, but it is unknown whether TMAO mediates arterial dysfunction that precedes clinical CVD.PURPOSETo determine if inhibition of TMAO with 3,3‐dimethyl‐1‐butanol (DMB; inhibitor of microbial TMA lyase) prevents WD‐induced large elastic artery stiffening and endothelial dysfunction.METHODSTwenty‐four young (3 mo) male C57BL/6 mice were fed WD (40% fat, 25% sugar) for 5 months and were supplemented without (WD‐Control, WD‐C; N=11) or with 1% DMB (N=13) in drinking water for the last 8 weeks. Arterial stiffness was assessed as aortic pulse wave velocity (aPWV) following 3 mo of WD (intervention baseline, BL) and following 4 and 8 weeks on the intervention. Endothelial function and its suppression by oxidative stress were evaluated ex vivo as carotid artery endothelium‐dependent dilation (EDD) to increasing doses of acetylcholine (10−9 to 10−4M) alone and following pre‐incubation with the superoxide dismutase mimetic TEMPOL. Total whole‐cell superoxide production was assessed in aortic rings via electron paramagnetic resonance spectroscopy. The same assessments were made in a reference group of age‐matched C57BL/6 male mice fed standard rodent chow (Normal Chow, NC; N=10). Data are mean±S.E.RESULTSWD induced progressive increases in aPWV (BL: 346±15, 4wks: 363±14, 8wks: 420±23 cm/sec, p=0.01), which were prevented by DMB (BL: 347±10, 4wks: 349±20, 8wks: 355±16cm/sec, p=0.98; DMB vs. WD‐C at 8wks: p=0.02). WD impaired EDD (peak dilation: 83.0±1.1% vs. NC: 92.5±2.0%, p<0.01), which was prevented by DMB (93.4±1.5%, p<0.0001 vs. WD‐C, p=0.71 vs. NC). Group differences in EDD were no longer significant after inhibition of oxidative stress with TEMPOL (peak EDD: p=0.22). Aortic superoxide production tended to be lower in DMB (2.2±0.3 AU) vs. WD‐C mice (3.9±1.1 AU, p=0.12) and was not different from NC (2.5±0.6 AU, p=0.52).CONCLUSIONSDMB supplementation prevented WD‐induced arterial stiffening and endothelial dysfunction, possibly through attenuation of oxidative stress. These data establish a role of the gut microbiome and TMAO in mediating WD‐induced arterial dysfunction and provide initial evidence of a novel strategy for preventing arterial dysfunction and reducing CVD risk.Support or Funding InformationSupported by R01 HL134887 & T32 HL007822This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.