Chronic Oral l-Carnitine Supplementation Drives Marked Plasma TMAO Elevations in Patients with Organic Acidemias Despite Dietary Meat Restrictions

  • Marcus J. Miller
  • Bret L. Bostwick
  • Adam D. Kennedy
  • Taraka R. Donti
  • Qin Sun
  • V. Reid Sutton
  • Sarah H. ElseaEmail author
Research Report
Part of the JIMD Reports book series (JIMD, volume 30)


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.


Maple Syrup Urine Disease Carnitine Supplementation Intestinal Microbiome Propionic Acidemia Methylmalonic Acidemia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



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).


  1. Backhed F (2013) Meat-metabolizing bacteria in atherosclerosis. Nat Med 19(5):533–534CrossRefPubMedGoogle Scholar
  2. Cross AJ, Major JM, Sinha R (2011) Urinary biomarkers of meat consumption. Cancer Epidemiol Biomarkers Prev 20(6):1107–1111CrossRefPubMedPubMedCentralGoogle Scholar
  3. Davies SE, Iles RA, Stacey TE, de Sousa C, Chalmers RA (1991) Carnitine therapy and metabolism in the disorders of propionyl-CoA metabolism studied using 1H-NMR spectroscopy. Clin Chim Acta 204(1–3):263–277CrossRefPubMedGoogle Scholar
  4. Koeth RA, Wang Z, Levison BS et al (2013) Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19(5):576–585CrossRefPubMedPubMedCentralGoogle Scholar
  5. Kolker S, Christensen E, Leonard JV et al (2011) Diagnosis and management of glutaric aciduria type I--revised recommendations. J Inherit Metab Dis 34(3):677–694CrossRefPubMedPubMedCentralGoogle Scholar
  6. Lang DH, Yeung CK, Peter RM et al (1998) Isoform specificity of trimethylamine N-oxygenation by human flavin-containing monooxygenase (FMO) and P450 enzymes: selective catalysis by FMO3. Biochem Pharmacol 56(8):1005–1012CrossRefPubMedGoogle Scholar
  7. Magoulas PL, El-Hattab AW (2012) Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management. Orphanet J Rare Dis 7:68CrossRefPubMedPubMedCentralGoogle Scholar
  8. Mescka CP, Guerreiro G, Hammerschmidt T et al (2015) L-Carnitine supplementation decreases DNA damage in treated MSUD patients. Mutat Res 775:43–47CrossRefPubMedGoogle Scholar
  9. Miller MJ, Kennedy AD, Eckhart AD et al (2015) Untargeted metabolomic analysis for the clinical screening of inborn errors of metabolism. J Inherit Metab Dis 38(6):1029–1039CrossRefPubMedPubMedCentralGoogle Scholar
  10. Mori T, Tsuchiyama A, Nagai K, Nagao M, Oyanagi K, Tsugawa S (1990) A case of carbamylphosphate synthetase-I deficiency associated with secondary carnitine deficiency--L-carnitine treatment of CPS-I deficiency. Eur J Pediatr 149(4):272–274CrossRefPubMedGoogle Scholar
  11. Nasser M, Javaheri H, Fedorowicz Z, Noorani Z (2012) Carnitine supplementation for inborn errors of metabolism. Cochrane Database Syst Rev 2:CD006659Google Scholar
  12. Rebouche CJ (1991) Quantitative estimation of absorption and degradation of a carnitine supplement by human adults. Metabolism 40(12):1305–1310CrossRefPubMedGoogle Scholar
  13. Rebouche CJ (2004) Kinetics, pharmacokinetics, and regulation of L-carnitine and acetyl-L-carnitine metabolism. Ann N Y Acad Sci 1033:30–41CrossRefPubMedGoogle Scholar
  14. Sebastio G, Sperandeo MP, Andria G (2011) Lysinuric protein intolerance: reviewing concepts on a multisystem disease. Am J Med Genet C Semin Med Genet 157C(1):54–62CrossRefPubMedGoogle Scholar
  15. Tang WH, Wang Z, Levison BS et al (2013) Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 368(17):1575–1584CrossRefPubMedPubMedCentralGoogle Scholar
  16. Thompson GN, Chalmers RA, Walter JH et al (1990) The use of metronidazole in management of methylmalonic and propionic acidaemias. Eur J Pediatr 149(11):792–796CrossRefPubMedGoogle Scholar
  17. Tischner C, Wenz T (2015) Keep the fire burning: current avenues in the quest of treating mitochondrial disorders. Mitochondrion 24:32–49CrossRefPubMedGoogle Scholar
  18. Walter JH (2003) L-carnitine in inborn errors of metabolism: what is the evidence? J Inherit Metab Dis 26(2–3):181–188CrossRefPubMedGoogle Scholar
  19. Wang Z, Klipfell E, Bennett BJ et al (2011) Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472(7341):57–63CrossRefPubMedPubMedCentralGoogle Scholar
  20. Winter SC (2003) Treatment of carnitine deficiency. J Inherit Metab Dis 26(2–3):171–180CrossRefPubMedGoogle Scholar
  21. Zhang AQ, Mitchell SC, Smith RL (1999) Dietary precursors of trimethylamine in man: a pilot study. Food Chem Toxicol 37(5):515–520CrossRefPubMedGoogle Scholar

Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Marcus J. Miller
    • 1
  • Bret L. Bostwick
    • 1
  • Adam D. Kennedy
    • 2
  • Taraka R. Donti
    • 1
  • Qin Sun
    • 1
  • V. Reid Sutton
    • 1
  • Sarah H. Elsea
    • 1
    Email author
  1. 1.Department of Molecular and Human Genetics, Medical Genetics LaboratoryBaylor College of MedicineHoustonUSA
  2. 2.Metabolon Inc.DurhamUSA

Personalised recommendations