Truth, Fiction or something in between? “Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis”
Author: Paul Anderson, NMD
Koeth, R. A., et.al. (2013). Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Medicine, 19(5), 576–585. http://doi.org/10.1038/nm.3145
Design: Review with updated in vitro and animal data.
I have written briefly about this topic in the past but see so many concerns posted on various health care practitioner sites about it that I decided it was worthy of a deeper review here. It was sometime in 2013 when, lecturing to a group of physicians about things like therapeutic uses of carnitine and choline, I had a few hands raised with a similar comment: “but it has been proven that carnitine and choline cause cardiovascular disease, why would we use them therapeutically?” I had read these papers and had relegated them to the “yes, when people are sick you have to get the whole system in balance or anything might make them sicker” file.
Trimethylamine N-oxide (aka TMAO) is a post oxidation metabolite of a few things in humans. Mostly from foods we eat that can go from trimethylamine (TMA) which is then converted to TMAO. Two studies from 2013 tried to show “association” between carnitine and lecithin (phosphatidylcholine – PTC) and cardiovascular risk., It is a classic example of people cherry picking both data and biologic situations (not likely intentionally) and creating ‘exciting’ news. Not getting any exciting press were the two other studies in the following years [3,4] that refuted the basis of these claims.,
In a recent review paper on the topic Tang and Hazen attempted to summarize “current understanding of the role of TMAO in the pathogenesis of cardiometabolic diseases and discuss current findings, controversies, and further perspectives in this new area of investigation.” Their work essentially underscores the more nuanced conclusions given below. The paper concludes that “better appreciation of the interactions between dietary nutrient intake with gut microbiota-mediated metabolism may provide clinical insights into defining individuals at risk for disease progression in cardiometabolic diseases, as well as additional potential therapeutic targets for reducing risks for cardiometabolic disease progression.”
The theme, which is biochemically true and likely to create results, where something seems to be a danger sometimes and not others is ‘context’. As with all things (tocopherols, glutathione, ascorbate, methyl donors, and a million others) in a biologic system there is never one outcome to the biochemical reactions they are involved in; all are based on innumerable related reactions and other balancing effects of cofactors, enzyme kinetics and other factors.
TMAO formed from carnitine, cholines and other substrates is created under oxidative conditions. Many factors increase this in the GI tract especially dysbiotic flora and other situations such as altered enterocyte redox. So of course, especially under experimental conditions, one could force substrate to product in an oxidative milieu. And as mentioned in regard to other substrates above, if you put them in an imbalanced and oxidative setting they can feed more of the same. Keep in mind that the typical biochemical outcome of carnitine and cholines are stabilizing, supportive of energy transport and cell membrane function as well as supporting antioxidant status overall.
In both studies in question, the situation was definitely set up to prove microbial activity and TMAO production. I often (in courses, writing and patient care) return to this concept to underscore the importance of balance of all systems, appropriate dosing strategies over time, variable kinetics (due to genomic effects) and thoughtful sequencing of therapies. In that context rarely would any of these things pose a single problem. Outside this balance, anything can be pushed into a potentially negative biochemical effect.
Is there any data looking at exactly how inflammation and ill health may predispose one to such imbalanced flora that these deleterious effects can flourish? There are actually a few researchers who took these ideas to the next level and outlined known and theoretical reasons why imbalance in the parameters above may occur. The authors of this paper used the well-studied model of kidney disease and elucidated the changes that occur not only in the kidney but also in the GI microbiota as well as the health of the GI epithelium. They show that the GI tract microbiota shifts (toward the unwanted flora that can cause this inflammatory chemistry) and also that the underlying disease creates dysfunctional tight junctions and “leaky gut”, further exacerbating the problem.
A few positives have come to light. One being this discussion and data pool have shed light on the importance and non-linear nature of the gut microbiota in human health. This is truly a positive. Also this all may lead to markers (such as TMAO and relatives) which will lead not only to risk assessment improvements in chronic cardiac and renal disease but also in the assessment of a truly dysfunctional GI microbiome. Interestingly many “older” ideas such as the central role of gut health in whole body health and the role of body wide inflammation in gut degradation and dysfunction are not only getting “press” but also some very nice mechanistic explanations as well.
In my clinical thinking with any nutrient being used beyond repletion levels (as in pharmacologic or therapeutic doses such as are required in the care of ill or imbalanced people) the following are points to consider. If then such potentials as microbial conversion of nutrients to damaging metabolites are minimized and (as I have experienced in my few decades treating sick people)one can create the safest and most efficacious use of the interventions:
- Work toward global health optimization in all patients addressing the core factors such as diet, microbiota, exercise, depuration, mental emotional work, endocrine and immune balance etc. Realize these factors are key to health overall and will not “fix everything quickly” in most cases – but also healing cannot happen without them.
- Know the nutrient or other agents general physiologic requirements and reasons for those requirements to be higher or lower (genomic, disease state, etc.)
- Know that increased doses of a few substances will require more of the cofactors and collateral nutrients used in the biochemical transformation of the substance being dosed at a higher level and adjust other supplements as required.
- Dose the therapy in the following steps:
- A test dose to assure tolerance
- An escalating dose to repletion / therapeutic or pharmacologic dose required
- A decreasing dose after therapeutic goal is met or repletion has occurred
- When the reason for the therapeutic dose is improving consider lowering the exogenous source and emphasizing dietary sources (supplementing if needed).
If the above are considered and implemented in a well-rounded treatment plan the potential for any nutritional substance being a cause of disease or dysfunction (or danger) is almost nil.
 Tang, W.H. et.al. (April 25, 2013). “Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk”. The New England Journal of Medicine. 368 (17): 1575–1584
 Koeth, Robert A. et.al. (April 7, 2013). “Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis”. Nature Medicine. 19 (5): 576–85.
 Collins, Heidi L. et.al. (2016). “L-Carnitine intake and high trimethylamine N-oxide plasma levels correlate with low aortic lesions in ApoE−/− transgenic mice expressing CETP”. Atherosclerosis. 244: 29–37.
 Johri, A.M. et.al. (2014). “Carnitine therapy for the treatment of metabolic syndrome and cardiovascular disease: Evidence and controversies”. Nutrition, Metabolism and Cardiovascular Diseases. 24 (8): 808–814.
 Tang WH, Hazen SL. Microbiome, trimethylamine N-oxide, and cardiometabolic disease. Transl Res. 2017 Jan;179:108-115.
 Vaziri ND, Zhao YY and Pahl MV. Altered intestinal microbial flora and impaired epithelial barrier structure and function in CKD: the nature, mechanisms, consequences and potential treatment. Nephrol Dial Transplant (2016) 31: 737–746.