Intestinal microbiota, L-carnitine, and cardiovascular risk


Integrative Medicine

Intestinal microbiota have been increasingly recognized for their diverse roles in human health and disease. While important in diseases such as C. difficile diarrhea, their ability to metabolize diverse compounds has recently gained greater appreciation. In 2013, a report identified L-carnitine in red meat as contributing to atherosclerosis1 via metabolism by intestinal microbiota, contradicting clinical trials that suggested benefits in cardiovascular disease. 


L-carnitine


L-carnitine is an amino acid synthesized primarily in the liver and kidney from lysine and methionine. Among its roles is the transport of long-chain fatty acids (FA) into the mitochondria for FA oxidation. As a supplement, L-carnitine has been used for primary and acquired carnitine deficiencies, cardiovascular diseases, diabetic neuropathy and endocrine disorders, bodybuilding, and valproate toxicity.2

Link to atherosclerosis?


L-carnitine, along with phosphatidylcholine, are present in red meat and can be metabolized by intestinal microbiota into trimethylamine (TMA). Subsequently, TMA is oxidized to trimethylamine-N-oxide (TMAO), which has been proposed to be proatherosclerotic, potentially inhibiting reverse cholesterol transport.3

Concerns with L-carnitine were identified in a summary of nine studies in mice and humans.1 Intestinal microbiota were shown to be responsible for endogenous production of TMAO following ingestion of an 8-ounce sirloin steak and its formation inhibited when participants received a broad-spectrum antibiotic. 


In a separate study, vegans and vegetarians demonstrated limited capacity to generate TMAO from oral carnitine, presumably because of their differing microbiota. In addition, the association between plasma L-carnitine levels and incident/prevalent cardiovascular disease was assessed in a large cohort, with the relationship no longer significant when controlling for TMAO concentrations. Rodent studies using L-carnitine showed that antibiotic treatment decreased TMA and TMAO and suppressed the expected atherosclerosis.


The report was criticized on several points. First, sirloin steak is also a source of phosphatidylcholine, which can be metabolized to TMAO. In addition, the dose of l-carnitine administered to the mice were 1,000 times greater than the 180 mg of L-carnitine in a sirloin steak that a human might ingest.3 


Secondary CVD prevention


A meta-analysis of 13 studies involving more than 3,600 participants evaluated effects of L-carnitine on cardiovascular outcomes following acute myocardial infarction (MI). The outcomes included all-cause mortality, ventricular arrhythmias, MI, heart failure, and angina episodes. L-carnitine was associated with improvements in all-cause mortality (27% reduction), ventricular arrhythmias (65% reduction), and angina episodes (40% reduction). 


Six studies were of moderate to good quality, and most included only small numbers of participants. Although the results with L-carnitine were impressive, these studies were older. Treatments patients received do not reflect current standards of care, as fewer than 9% and 40% received ACE inhibitors and beta-blockers, respectively, in the largest study. 


The study also was conducted before the widespread use of percutaneous coronary intervention (PCI). A second meta-analysis indicated that the benefit was maximal at 2 to 3 g of L-carnitine per day.


What to tell patients


L-carnitine is used for diverse cardiac and other purposes, as well as by athletes. Cardiovascular studies in humans are outdated, and L-carnitine’s value may not be as important today given the use of statins and ACE inhibitors. The studies on intestinal microbiota are interesting, but their applicability to humans remains unclear. Pharmacists should continue to emphasize the adoption of an overall heart-healthy lifestyle.


References


  1. Nat Med. 2013;19:576–85
  2. Nutr & Metab. 2010;7:30
  3. Atherosclerosis. 2013;231:456–61
  4. Mayo Clin Proc. 2013;1–8
  5. BMC Cardiovasc Disord. 2014;14:88