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?

meat

Gaah meat, Y U so good?

 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.

Screen Shot 2013-04-07 at 2.11.54 PM

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?

Screen Shot 2013-04-07 at 2.12.45 PM

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.

ResearchBlogging.org
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

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22 thoughts on “L-carnitine: good for brains, bad for hearts?

    • L-acetyl carnitine can be converted into L-carnitine in the body, so presumably yes. I couldn’t find anything on how efficient L-acetyl carnitine is metabolized to TMAO though.

      • What is the ratio of carnitine for like portions of red meat and fish? In other words is the relative amount of carnitine significantly lower in fish or about the same? — thanks

      • Hi John, here you go:
        “L-Carnitine is present in the human diet in a variety of food sources. The richest sources of dietary Lcarnitine (proximate L-carnitine content in brackets) are animal products, such as mutton (210 mg/kg), beef (60 mg/kg), pork (27 mg/kg) and fish (3–5 mg/kg). Lower levels of L-carnitine are found in dairy products (2 mg/l cow‟s milk), whereas most fruits and vegetables (0–5 mg/kg) contain minimal amounts of L-carnitine (for details see Mitchell, 1978; Rebouche 1984; Götz, 1989; Demarquoy et al.,
        2004; Knüttel-Gustavsen and Harmeyer, 2007).”
        So it looks like fish has way less L-carnitine than red meat sources.

      • The drastically lower levels in fish might be the key to why its generally thought that diets high in fish result in lower incidences of heart problems. I’m definitely going to follow this thread. Thanks Shelly. PS – can you find info on chicken?

  1. I do not eat mammals, only white meat chicken, fatty fish like salmon and char, low glycemic carbs such as oats, veggies. Among my daily supplements are l-acetyl carnitine and probiotics. My concern after reading recent reports is that I might be doing myself harm by combining probiotics with l-acetyl carnitine.

  2. Jj my concern at first too. Also supplementing with ALCAR recently myself. It sounds like we will still have to wait to know. But from the results from vegetarians it sounds highly related to the gut flora being in a particular state. Supplementing with the probiotics our gut flora may be in better shape than full on red meat eaters. It sounds like there is an imbalance in the meat eater gut, but will need more study to know.

    • Jj and Ted: I’ve been supplementing with ALCAR on and off for at least 3 years, which is one of the reasons this study caught my eye. I’m looking into ALCAR metabolism as compared to L-carnitine to see if TMAO is also a major metabolite.
      As for the probiotics point: probiotics commonly contain Lactobacillus and Bifidobacterium. According to the study, ” individuals with an enterotype characterized by enriched proportions of the genus Prevotella (n = 4) had higher (P < 0.05) plasma TMAO concentrations than did subjects with an enterotype notable for enrichment in the Bacteroides (n = 49) genus". Note this is CORRELATIONAL. It doesn't say higher Prevotella leads to more TMAO formation or that eating L-carnitine up regulates Prevotella. However there was nothing about Lactobacillus or Bifdobacterium, so it's hard to say if supplementing with those will change your TMAO production.

      • Interesting, I wonder if there will be a correlation to intake of carbs? I’m fascinated by this stuff. There’s so much we still don’t know about the gut flora and it seems to relate to our health in ways just being discovered.

      • Shelly , I myself have been supplementing with ALCAR.
        But if I look at the study I’m not to worried.
        1. It’s an observational study.
        2. Too many confounding variables. Look at Smoker rates, statins use tec. http://www.nature.com/nm/journal/vaop/ncurrent/extref/nm.3145-S1.pdf
        3. I find they jump to conclusions and have conflicting interests.
        Stanley L Hazen has been on the case for TMAO for years see choline study 2011 and he is has been paid as a consultant or speaker by the following companies: Cleveland Heart Lab., Esperion, Liposciences, Merck & Co. and Pfizer. Furthermore S.L.H. and J.D.S. are named as co-inventors on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics patents,

  3. While it is true that fish has very low levels of L-carinitin, quite ironically it has large quantities of ready-made TMAO – in fact TMAO is very substance that makes fish smell like, well, fish.

    Depending on the species, fish muscle contains between 1 and 5% TMAO. There is more TMAO in a can of tuna than cartitine in a pound of beef!

    Doesn’t make sense with regard to this study, does it? Either the TMAO from fish is metabolized very differently from that produced by our own intestinal bugs, or the authors conclusion is wrong and TMAO by itself doesn’t pose a cardiovascular risk.

      • Thank you timar for the link! Here’s the original study linking choline metabolism into TMAO to cardiovascular risk: http://www.nature.com/nature/journal/v472/n7341/full/nature09922.html
        At the moment we can only conclude that some chemical ingredients in red meat can be converted into TMAO, and that TMAO increases risk of plague formation in a special type of transgenic mice. These results are very difficult to translate to humans – humans most likely have a different threshold for TMAO’s effects. Also if you think about L-carnitine as a nutrabolic, distribution and excretion also come into play: if L-carnitine is rapidly converted into TMAO and excreted, it may not built up in the body for long enough to have an effect.
        It’s a bit unfortunate science tends to isolate factors and analyze them separately. While looking at a single variable can provide useful insight, it’s important to keep in mind that human diet really isn’t that simple. I don’t think this study is a conspiracy theory to make us eat less red meat, it’s just a reflection on how science works and how (social) media blows up findings when reporting to everyone else. /rant

  4. So the big question for me as a vegan is: Will long-term ALCAR supplementation eventually up-regulate Prevotella to the point where damaging levels of TMAO are produced? I look forward to an answer.

  5. I gut a feeling! – Neurorexia

  6. I kind of wonder if iron comes into play here. It seems this bacteria requires iron for growth. There are low levels of iron available in vegies, but lots of heme iron in red meat. There is also added iron to lots of the starchy foods in the US. Iron is noted for skewing bacterial growth, which is why iron chelators are often used in antibiotics.

  7. The skinny on gutbug-transplanted obesity – Neurorexia

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