Chronic Oral l-Carnitine Supplementation Drives Marked Plasma TMAO Elevations in Patients with Organic Acidemias Despite Dietary Meat Restrictions
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Recent studies have implicated trimethylamine N-oxide (TMAO) in atherosclerosis, raising concern about l-carnitine, a common supplement for patients with inborn errors of metabolism (IEMs) and a TMAO precursor metabolized, in part, by intestinal microbes. Dietary meat restriction attenuates carnitine-to-TMAO conversion, suggesting that TMAO production may not occur in meat-restricted individuals taking supplemental l-carnitine, but this has not been tested. Here, we mine a metabolomic dataset to assess TMAO levels in patients with diverse IEMs, including organic acidemias. These data were correlated with clinical information and confirmed using a quantitative TMAO assay. Marked plasma TMAO elevations were detected in patients treated with supplemental l-carnitine, including those on a meat-free diet. On average, patients with an organic acidemia had ~45-fold elevated [TMAO], as compared to the reference population. This effect was mitigated by metronidazole therapy lasting 7 days each month. Collectively, our data show that TMAO production occurs at high levels in patients with IEMs receiving oral l-carnitine. Further studies are needed to determine the long-term safety and efficacy of chronic oral l-carnitine supplementation and whether suppression or circumvention of intestinal bacteria may improve l-carnitine therapy.
KeywordsMaple Syrup Urine Disease Carnitine Supplementation Intestinal Microbiome Propionic Acidemia Methylmalonic Acidemia
We would like to thank the Rimoin family and the American College of Medical Genetics (ACMG) Foundation for recognizing this work with the inaugural Dr. David L. Rimoin Inspiring Excellence Award at the ACMG 2015 annual meeting. Thanks also to Drs. Mahim Jain and Robert Collins for technical assistance and to Dr. Brenden Lee for reviewing the manuscript. This work was funded, in part, by the T32 GM07526-37 Medical Genetics Research Fellowship Program (MJM).
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