New Insight into the Dietary Cause of Atherosclerosis: Implications for Pharmacology

Abstract

At present, the guideline approach to the medical treatment and prevention of atherosclerotic cardiovascular disease (ASCVD) is to classify patients by risk and treat the known risk factors (contributory causes), e.g., hypertension, diabetes, obesity, smoking, and poor diet, as appropriate. All high-risk patients should receive statins. This approach has had substantial success but ASCVD still remains the number one cause of death in the United States. Until recently, the underlying cause of ASCVD remained unknown, although a potential dietary cause was suggested by the fact that vegetarians, especially vegans, have a much lower incidence of ASCVD than animal flesh eaters. Recently, consistent with the vegetarian data, substantial evidence for a cause of ASCVD in animals and humans has been discovered. Trimethylamine (TMA)-containing dietary compounds in meat, milk, and other animal foods (e.g., lecithin, choline, and carnitine) are converted by closely related gut bacterial TMA lyases to TMA, which is absorbed and converted predominantly by flavin mono-oxygenase 3 to the toxic trimethylamine N-oxide (TMAO). TMAO causes atherosclerosis in animals and is elevated in patients with coronary heart disease. Inhibition of bacterial lyases in mice prevents TMA and secondarily TMAO formation and atherosclerosis, strong evidence for the TMAO hypothesis. At present, the challenge for the pharmaceutical industry is to discover and develop a potent "broad spectrum" bacterial lyase inhibitor that, along with diet and exercise, could, if the TMAO hypothesis is correct, revolutionize the preventive treatment of ASCVD.

Identification of Potential Biomarkers in the Cervicovaginal Fluid by Metabolic Profiling for Preterm Birth

“…Convincing evidence suggests an association between TMAO and inflammation with increased TNF-a, and IL-6 [ 44 ]. As we observed, the high level of TMAO in the PTB < 7 d group, with significant predictive value and correlated with GAB and CL, which might be the consumption of a choline or L-carnitine-containing diet during pregnancy [ 45 , 46 , 47 ].…”

Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target

“…Other studies propose the use of DMB, an analogue of choline that inhibits choline TMA lyase. DMB can be found in some foods like balsamic vinegars, red wines or extra-virgin olive oil and grapeseed oil [ 96 ]. Although it inhibits the transformation of choline, carnitine and crotonobetaine into TMA in mice and rats, DMB is not able to avoid the complete TMAO synthesis as it cannot inhibit the conversion of GBB to TMA [ 8 , 17 , 32 , 38 ].…”

Microbial trimethylamine-N-oxide as a disease marker: something fishy?

“…TMAO has been described as a toxic substance, and it has been suggested that broad-spectrum inhibitors of the bacterial TMA-lyase enzymes that generate TMA – the precursor of TMAO – may ‘revolutionize the preventive treatment’ of atherosclerotic cardiovascular disease [5]. The idea of enriching animal feeds with TMAO to improve their performance and growth [6] is, however, not in accordance with the assumption that TMAO is toxic.…”

“…Optimism has been expressed regarding the prospect of using TMA-lyase inhibitors as new pharmaceutical drugs against cardiovascular disease [5]. The concept is to reduce TMAO production in the liver by inhibiting the production of precursor TMA in the gut.…”