Study under review: l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans
Trimethylamine N-oxide (TMAO) is a compound generated by gut microbial metabolism that has been implicated in increased disease risk. Two recent systematic reviews and meta-analyses from 2017 and 2018 (whose results are shown in Figure 1) determined that TMAO is associated with a significantly higher risk of both all-cause mortality and cardiovascular events. After those reviews were published, another prospective cohort study demonstrated that plasma TMAO levels were significantly associated with an increased risk of all-cause mortality among participants with chronic obstructive pulmonary disease. How TMAO affects cardiovascular disease is not fully understood, but it is thought that TMAO disrupts cholesterol transport by increasing forward transport and decreasing reverse cholesterol transport.
TMAO has been shown to be generated from substrates with a trimethylamine (TMA) moiety such as L-carnitine and choline. L-carnitine is found in a variety of both plant and animal sources. However, levels of free L-carnitine are highest in meat products and very low in fruits, vegetables, nuts, and grains. L-carnitine is also added into some popular energy drinks with the expectation that it increases performance and helps to burn fat, although the evidence for those expectations is not clear. While vegetarians and vegans have considerably lower dietary intake of carnitine, studies show that their circulating levels in the blood are not drastically lower than people who consume meat and remain generally within the normal range. This is because carnitine can be synthesized in the liver, kidney, and brain if not enough is consumed in the diet.
Several studies have now demonstrated that dietary L-carnitine can be converted in the gut to TMA, at which point TMA can then be converted to TMAO in the liver by the enzyme flavin monooxygenase. However, it was not until 2013 that many of the same authors as the present study under review discovered that a compound called γ-butyrobetaine (γ-BB) was formed as an intermediate between L-carnitine and TMA formation in mice. The present study is the first to examine γ-BB generation in humans in the context of the gut microbial metabolism of L-carnitine to TMAO. The study is also the first to characterize some of the microbes involved in the two-step reaction.
Studies have shown that dietary sources of substances such as L-carnitine, high levels of which are found in meat products, can be converted to the atherogenic compound trimethylamine N-oxide, or TMAO, by gut bacteria. While studies on TMAO generation by gut bacteria have been performed, only recently was the compound γ-butyrobetaine (or γ-BB) identified in mice as an intermediate between L-carnitine and TMAO. This is the first study to examine this intermediate in humans.
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