L-carnitine: good for brains, bad for hearts?

Remember this study from a week ago, where researchers showed L-acetyl carnitine rapidly alleviating depression symptoms by changing DNA expression? Well, a new study in Nature Medicine now identified a compound in red meat that can be metabolized by our gut microbiota into TMAO, which promotes atherosceleosis. And the culprit? L-carnitine, the parent compound of L-acetyl carnitine.

Koeth RA et al (2013): Gut microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Medicine. Advanced online publication, doi:10.1038/nm.3145

It’s long been suspected that cholesterol and saturated fats in red meat are bad for the cardiovascular system, although a recent meta-analysis did not show a statistically significant association. This prompted the idea that environmental factors such as concurrent salt-intake, cooking of the meat or food-gut interactions may also be at play. The authors decided to look at the last factor: are the micro-critters in our gut converting SOMETHING in red meat into compounds toxic to our hearts?

 Previously, they discovered that choline – found in egg yolks- can turn into TMAO by gut flora. TMAO is correlated with future risk of heart disease in humans, and can cause heart problems when fed to mice (probably one reason why egg yolks have such a bad rep). Since L-carnitine is structurally similar to choline and abundant in red meat, researchers hypothesized L-carnitine may also be taken up by gut bugs and transformed into TMAO.

To test this, the authors fired up the grill and fed omnivore volunteers sirloin steaks together with an isotope-labeled L-carnitine capsule (an 8-ounce sirloin steak contains about 180mg of L-carnitine). Blood tests later revealed an increase in L-carnitine and TMAO radioactivity, meaning L-carnitine is being metabolized into TMAO. But by what? To pin this down, volunteers took broad-spectrum antibiotics to suppress gut flora for a week. They were then given another L-carnitine challenge. This time, there was virtually no TMAO in the blood and urine. After being off antibiotics for several weeks, allowing gut bacteria to grow back, the volunteers once again chowed down on steak and produced TMAO. This suggests the conversion only happens in the presence of gut bacteria.

However, your gut microbiome != my microbiome. Gut bacteria composition can be influenced by dietary habits. In fact, researchers found vegans and vegetarians produced markedly less TMAO after ingesting L-carnitine. A screen of their gut microbiome (extracted from poop) showed several gut bacteria types that were associated with lower ability to produce TMAO compared to meat-eating omnivores. This indicates that previous diet can be a major factor in gut flora composition and the ability to produce TMAO.

“Induction” is an important concept in biology. The more you consume some substances (like alcohol), the more your body increases the ability to break down that substance by switching necessary metabolism pathways into high gear (for example, by upregulating necessary enzymes and/or adjusting gut flora composition). To see if the ability to convert L-carnitine into TMAO is inducible, the researchers turned to mice. Indeed, specially raised germ-free mice were unable to produce TMAO initially, but gained the ability after living in conventional cages full of bacteria. In another group, mice supplemented with L-carnitine produced roughly ten times more TMAO compared to mice on a normal diet.

All of the above shows that in mice and men, gut flora is necessary to convert L-carnitine into TMAO and the composition determines the efficacy of the conversion. But is L-carnitine and/or TMAO actually BAD for heart health?

Mice supplement with L-carnitine showed more plagues in their arteries than normal mice after 15 weeks, and this was rescued when mice were given broad-spectrum antibiotics. So L-carnitine isn’t toxic per se, but its conversion into TMAO stresses the carodiovascular system. A correlational study in humans also found an association between L-carnitine and cardiovascular risk, but further analysis pointed to TMAO concentration as the main driving force.

Is L-carnitine the reason red meat is bad for our hearts? At this point it’s hard to say, but it may be an important contributing factor. Many questions remain unanswered. How does L-carnitine (or TMAO) cause plague buildup? How much and how often can a person consume red meat before TMAO reaches high enough concentration to be a hazard? Can supplementing L-carnitine for fitness goals ironically cause poorer heart health? L-carnitine is also present in fish, which is linked to lower cardiovascular risk. Are the omega-3s in fish counteracting TMAO’s effect? How does the co-consumption of other food substances alter L-carnitine absorption and TMAO conversion? Finally, even the link between red meat consumption and cardiovascular risk is still contentious. If the anti-cholesterol campaign has taught us anything, it’s that we must be cautious when pointing our finger at a single food chemical as the devil.

It would be very interesting to see if manipulating L-carnitine consumption can influence cardiovascular risk in a clinical setting. If so, tinkering with gut flora may be a new and exciting way to lower heart disease (a vegan-to-omnivore fecal transplant comes to mind, hah). Whether it also changes your brain function though, is an entirely different story that’ll have to be looked at.

Koeth, R., Wang, Z., Levison, B., Buffa, J., Org, E., Sheehy, B., Britt, E., Fu, X., Wu, Y., Li, L., Smith, J., DiDonato, J., Chen, J., Li, H., Wu, G., Lewis, J., Warrier, M., Brown, J., Krauss, R., Tang, W., Bushman, F., Lusis, A., & Hazen, S. (2013). Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis Nature Medicine DOI: 10.1038/nm.3145