Trimethylamine-N-oxide (TMAO) has been linked to increase atherosclerosis (fatty deposits that clog blood vessels). Gut bacteria in meat eaters has been shown to convert L-carnitine in meat to TMAO. In this study, both meat eaters and vegans/vegetarians were tested and TMAO levels were found to be significantly higher in meat-eaters. Thus, higher levels of TMAO production from carnitine in meat eaters may contribute to atherosclerosis.
Why this matters:
Several studies have shown that red meat is linked to heart disease. There have been several explanations for this including high saturated fat in red meat, salt added to meat, or heterocyclic compounds formed when cooking meat. This study adds another possible explanation to the list. In addition, the study suggests that reduction in dietary carnitine leading to reduction in TMAO may help with the cardiovascular health benefits seen in vegans/ vegetarians.
- First, the researchers gave the omnivore group 8-ounce sirloin steak as a dietary source of L-carnitine. They also gave a capsule with 250mg of heavy isotope labeled L-carnitine. As expected, levels of TMAO in plasma and urine increased.
- To show gut involvement, the researchers gave the omnivore group poorly absorbed broad spectrum antibiotics for 1 week. Then they repeated the L-carnitine challenge and saw NO change in TMAO in plasma or urine.
- Finally, they repeated the challenge several weeks after stopping the antibiotics and once again levels of TMAO in plasma and urine significantly increased. Thus, gut bacteria played a major role in production of TMAO from L-carnitine.
- The researchers also tested the same L-carnitine challenge in long-term (>5 years) vegans. They found that TMAO levels rose very little in plasma and urine.
- The researchers then examined 2595 participants undergoing elective cardiac evaluation. They found a dose dependent relationship among plasma L-carnitine levels and risk for coronary artery disease (CAD), peripheral artery disease (PAD) and overall cardiovascular disease (p<0.05). The researchers also found that plasma L-carnitine levels were elevated in participants with greater than 50% blockages of their vessels (p<0.001).
- The researchers found that plasma L-carnitine levels were associated with 3-year risk of major cardiac events (MACE = composite of death, heart attack, stroke and revascularization). However, after adjusting for comorbidities, the association disappeared. Only in participants who also had high levels of TMAO, were levels of L-carnitine still linked with major cardiac events (p < 0.001).
- The researchers showed that mice fed chow supplemented with L-carnitine had almost a doubling of atherosclerotic plaque burden as compared to normal chow fed mice. However, after placing mice on antibiotics to suppress gut bacteria, there was no L-carnitine dependent increase in plaque burden. Thus, it’s not the L-carnitine but a metabolite (TMAO) that is dependent on gut bacteria.
- The authors, in separate studies, showed that TMAO can cause macrophages to accumulate cholesterol by increasing 2 proatherogenic scavenger receptors.
- The authors also showed that mice on carnitine supplemented diets showed a ~30% decrease (p<0.05) in reverse cholesterol transport which moves cholesterol from tissues back to the liver.
- Carnitine plays several important roles in the body and is involved in the transport of long chain fatty acids from the cytoplasm into the mitochondria and fatty acid oxidation.
- It is not clear if TMAO is a directly linked to heart disease or is simply a marker in the pathway. More studies are needed in this area.
- Finally, it’s not clear what is the acceptable limit of eating red meat (once a month, once a week or never) that will keep the gut bacteria healthy and keep TMAO levels controlled.
Koeth R, Zeneng W, Levison B, Buffa J, Org E, Sheehy B,… Hazen S. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013; 19(5):576-585.