Suppression of trimethylamine N-oxide with DMB mitigates vascular dysfunction, exercise intolerance, and frailty associated with a Western-style diet in mice

Abstract

Consumption of a Western-style diet (WD; high fat, high sugar, low fiber) is associated with impaired vascular function and increased risk of cardiovascular diseases (CVD), which could be mediated partly by increased circulating concentrations of the gut microbiome-derived metabolite trimethylamine N-oxide (TMAO). We investigated if suppression of TMAO with 3,3-dimethyl-1-butanol (DMB; inhibitor of microbial TMA lyase) in mice could prevent: 1) WD-induced vascular endothelial dysfunction and aortic stiffening; and 2) WD-induced reductions in endurance exercise tolerance and increases in frailty, as both are linked to WD, vascular dysfunction, and increased CVD risk. C57BL/6N mice were fed standard chow or WD (41% fat, ~25% sugar, 4% fiber) for 5 months beginning at ~2 months of age. Within each diet, mice randomly received (n=11-13/group) normal drinking water (control) or 1% DMB in drinking water for the last 8 weeks (from 5-7 months of age). Plasma TMAO was increased in WD-fed mice but suppressed by DMB. WD induced endothelial dysfunction, assessed as carotid artery endothelium-dependent dilation to acetylcholine, and progressive increases in aortic stiffness (measured serially in vivo as pulse wave velocity), both of which were fully prevented by supplementation with DMB. Endurance exercise tolerance, assessed as time to fatigue on a rotarod test, was impaired in WD-fed mice but partially recovered by DMB. Lastly, WD-induced increases in frailty (31-point index) were prevented by DMB. Our findings indicate DMB or other TMAO-lowering therapies may be promising for mitigating the adverse effects of WD on physiological function, and thereby reducing risk of chronic diseases.

Western diet augments metabolic and arterial dysfunction in a sex-specific manner in outbred, genetically diverse mice

“…Systolic BP continued to rise throughout the 12-week dietary intervention. These data are in contrast to other studies that have shown a minimal effect of WD on systolic BP in mice (14)(15)(16)(17)(18)(19). However, it is important to note that these studies used genetically identical, inbred mouse strains, such as C57BL/6.…”

“…However, the vast majority of these studies use inbred, genetically identical mice, such as the C57BL/6 strain that have strain specific phenotypes that may limit translation to humans. For example, in response to WD, C57BL/6 mice display sex-differences in body mass gain (11)(12)(13) and/or a lack of elevation in systolic BP (14)(15)(16)(17)(18)(19), which conflicts with observations in humans (20)(21)(22).…”

Research Progress on the Correlation Between Hypertension and Gut Microbiota

“…[66][67][68][69] Although the underlying mechanism between TMAO and hypertension is not fully understood, it has been confirmed that TMAO in the plasma can accelerate the formation of foam cells, enhance oxidative stress and proinflammatory responses, and reduce the production of anti-inflammatory cytokines. 70 In hypertensive patients, due to the decreased intestinal barrier function, the inflammation in the body also increases when the concentration of TMAO rises. 71,72 Multiple studies have shown that the level of plasma TMAO is associated with the risk of hypertension and other diseases, and there is a dose-dependent relationship.…”

Modulation of Endothelial Function by TMAO, a Gut Microbiota-Derived Metabolite

“…Together with diet, aerobic exercise has been shown to be one of the best lifestyle interventions to counteract endothelial dysfunction and promote the colonization of a healthy microbiota in the gut, especially in old age, where multiple cardiovascular risk factors coexist [ 36 ]. Indeed, the gut microbiota synthesizes a plethora of metabolites from dietary sources that could be beneficial or detrimental according to the host status, and the composition of the gut microbiota could be influenced by endurance exercise [ 37 , 38 , 39 , 40 , 41 ]; alterations in the microbiota diversity, named dysbiosis, is associated with metabolic disorders onset due to an imbalance in released metabolites. Among all, L-carnitine, choline, and other amine-containing molecules, and not fats, present in animal-derived foods can be metabolized by the gut microbiota to form trimethylamine, which is absorbed in the colon and then oxidized by the liver to trimethylamine N-oxide (TMAO), whose role in cardiovascular health is widely discussed as its involvement as a direct cause or a marker of pathology remains unclear [ 35 , 42 ].…”