Increased consumption of L-carnitine is gaining popularity due to its beneficial effects on the human condition. However, the absence of side effects of excessive L-carnitine consumption has not been proven.
Heavy consumption of meat products in developed countries is associated with an increased risk of cardiovascular disease, attributing this to the high saturated fat and cholesterol content of meat. But is this true? Research in 2013 did not confirm the link between saturated fat consumption and increased risk of cardiovascular disease, which prompted scientists to search for other factors leading to pathology. That's when they remembered about another feature of meat products - the abundant content of L-carnitine.
L-carnitine was first isolated by two Russian scientists in 1905. Consequently, it is now the second century since the discovery and the beginning of the study of the role of this molecule in the human body. It is one of the most researched components of food. Food, namely red meat, is the main source of carnitine in omnivorous animals; however, a little L-carnitine is synthesized from lysine in the body itself.
In addition, more and more people are consuming L-carnitine as dietary supplements. In addition to online stores, sports nutrition stores and pharmacies, carnitine is now even found on the shelves of grocery stores in our country, including vitamins, energy drinks, chocolate bars and more. Anyone can buy L-carnitine or products containing it. In most cases, L-carnitine is taken apparently in the hope of intensifying the destruction of fats, as it is believed that it transports fatty acids into the mitochondrial matrix, where they are destroyed with the release of energy.
L-carnitine advertising promises rapid weight loss, increased muscle mass, improved mental and physical fitness, stress resistance, detoxification of the body and much more. It must be said that many of the positive effects of carnitine are indeed scientifically proven, but we should not forget that it is still unknown whether excess carnitine is harmful to health.
The norm of L-carnitine consumption for an adult is 300 mg, while doses from 500 mg to 2 g per day are considered optimal for losing weight and improving sports performance. In the hope of gaining an ideal body with minimum effort, people exceed the norm several times, without thinking about the possible consequences. And for nothing. After all, we know that metabolic pathways in the body are not sufficiently studied, and that almost all medicines - and what is there, even vitamins have side effects in case of their excessive use. L-carnitine is no exception! A 2013 study found that a metabolite of L-carnitine, trimethylamine oxide (TMAO), is a substance that promotes atherosclerosis.
Insidious bacteria, or a new look at L-carnitine metabolism
The discovery in 2011, which showed the connection between the metabolism of choline, a structural analog of L-carnitine, and the pathogenesis of cardiovascular diseases, made us think about the possible connection between L-carnitine and the development of atherosclerosis. The main source of choline is phosphatidylcholine, one of the most common molecules of cell membranes, in large quantities contained in food of animal origin.
Choline has been shown to be used by some intestinal bacteria to synthesize the intermediate trimethylamine (TMA). In turn, TMA is rapidly absorbed and oxidized by enzymes of the FMO family (flavin monooxygenase, FMO3 is the main enzyme of the process) in the liver to TMAO, which causes the development of atherosclerosis.
The use of the trimethylamine group of choline by bacteria to synthesize TMA raises the question of the existence of similar metabolic pathways for similar compounds that include this group. One such molecule is precisely carnitine. The emerging assumption that TMAO production from L-carnitine is linked was confirmed by a 2013 study, although previous experiments in rats did not reveal such a link.
A metabolite of L-carnitine is one of the causes of cardiovascular disease
Two independent clinical studies have shown an association between plasma concentrations of L-carnitine and TMAO and the development of coronary and peripheral insufficiency, as well as cardiovascular disease in general. The first study involved a group of 2,595 participants, while the second study involved three-year cardiac follow-up of 4,000 patients.
Studies in mice also confirm the correlation of high levels of L-carnitine and TMAO with the development of cardiovascular pathologies. From four weeks of age, four groups of mice were fed a particular type of diet: 1) normal, 2) carnitine-enhanced, 3) antibiotic-supplemented, or 4) carnitine-enhanced and antibiotic-supplemented. Comparison of aortic root tissue in mice after reaching 19 weeks of age revealed a twofold increase in the area of atherosclerotic damage when L-carnitine was added to the feed. No abnormalities occurred in mice receiving L-carnitine in combination with antibiotics. Consequently, the culprits in the development of cardiovascular disorders are bacteria involved in the formation of TMAO, the level of which increases significantly with the consumption of L-carnitine and correlates with the development of atherosclerosis.
Let's think about vegans (radical vegetarians who do not consume any animal products) and vegetarians who do not consume red meat high in L-carnitine and wonder if they have a group of bacteria in their intestines responsible for the formation of TMA oxidized to TMAO?
It's no secret that food preferences determine the composition of the microbiota. For example, prolonged excess carnitine in the diet leads to changes in the composition of the gut flora, favoring the flourishing of bacteria involved in the synthesis of TMAO. In contrast, reduced intake of L-carnitine and choline in vegans and vegetarians prevents them from developing. There are virtually no bacteria synthesizing TMAO, and even when L-carnitine is included in the diet of people on a long-term plant-based diet, plasma and urine levels of TMAO remain low.
The synthesis of TMAO (or its d3-labeled analog) after consumption of meat steak and L-carnitine (or d3-methyl carnitine) is negligible in vegans (more than 5 years of avoiding animal products), in contrast to people who regularly consume red meat. The findings were further tested and confirmed on people following a regular diet and people leading a vegan or vegetarian lifestyle for more than a year.
From this we can assume that low TMAO levels are the main reason for the good cardiovascular health of vegans and vegetarians. After all, statistics show us a rarer incidence of cardiovascular disease and a 29% reduced risk of death from cardiac ischemia for people in this group.
Experiments also suggest that following a balanced plant-based diet leads to lower blood pressure, blood cholesterol levels and risk of atherosclerosis. Thus, avoiding animal foods may reduce medication for cardiovascular disorders. In one study, a group of patients with atherosclerosis was offered a complete switch to plant-based foods. After one year, 82% of the group had already shown improvement. Repeating the experiment produced similar results.
But maybe the benefits of a plant-based diet are not due to the absence of TMAO synthesis, but to the low saturated fat and cholesterol content in the diet? After all, it is widely believed that the consumption of high amounts of saturated fat and cholesterol is the main risk factor for atherosclerosis. However, a 2013 study did not confirm this link. It is also noteworthy that the development of atherosclerotic lesions in mice occurred in the absence of changes in the composition and content of lipids, lipoproteins, glucose and insulin levels. Moreover, no signs of obesity could also be detected in these mice.
So perhaps gut bacteria involved in the synthesis of TMAO is one of the important causes of atherosclerosis. If so, the use of antibiotics is a new possible way to combat cardiovascular disease as well as prevent it. For both humans and mice, bacterial genera presumably involved in the synthesis of TMAO have already been identified. Although the findings are not yet sufficient to identify a common taxon responsible for TMAO synthesis, further studies will soon clarify the situation.
How dangerous is atherosclerosis and what is the role of TMAO in its development?
Cardiovascular disease causes the highest number of deaths of any disease each year. The World Health Organization (WHO) estimates that about 17.3 million people died of cardiovascular disease in 2008; this represents 30% of the total number of deaths worldwide. Of these, 7.3 million were deaths from coronary heart disease and its acute manifestation, heart attacks; 6.2 million were deaths from stroke. Both develop mainly due to the obstruction of blood flow caused by atherosclerosis.
Most researchers tend to believe that the development of atherosclerosis is an inflammatory process in the vascular wall, with macrophages playing a key role. In the development of atherosclerosis are involved mainly fats, which are part of low and very low density lipoproteins (LDL and VLDL). If they penetrate the arterial walls, LDL and VLDL are oxidized, attracting macrophages, which normally absorb the oxidized fats and transfer them to high-density lipoproteins (HDL), promoting their utilization.
However, hyperactivation of phagocytosis of oxidized fats by macrophages is possible: so-called foam cells are formed that continue to accumulate oxidized fats in the intracellular space without transferring them to HDL. Eventually, such macrophages die and rupture; platelet aggregation is activated, leading to increased blood clotting. At the same time, previously absorbed fats are poured outward, which promotes the activation of more and more macrophages. Fibrous plaques are formed, in which dead tissue accumulates; subsequently, these plaques calcify. This leads to deformation of vessels and narrowing of the lumen up to complete occlusion.
One of the factors contributing to inflammation is the inhibitory effect of TMAO on reverse cholesterol transport and stimulation of expression of SRA and CD36 receptors on their outer membrane, which leads to impaired uptake of modified lipoproteins. Another factor induced by TMAO is inhibition of bile accumulation in the liver and decreased expression of proteins responsible for bile acid synthesis and transport. Both the first and the second factors are associated with the development of atherosclerosis, but the details of the mechanisms of action of TMAO on reverse cholesterol transport, synthesis and transport of fatty acids remain unknown.
Conclusion
The metabolic pathway of L-carnitine involving the gut microbiota is probably the main reason for the long-observed relationship between heavy consumption of red meat and the occurrence of atherosclerosis. Antibiotics that inhibit the synthesis of TMA by gut flora could be a new weapon to combat and prevent cardiovascular disease. In addition, the discovery of TMAO synthesis from L-carnitine challenges the public's belief in the absolute harmlessness of L-carnitine for health and shows the need for further research