Marked elevation in plasma trimethylamine-N-oxide (TMAO) in patients with mitochondrial disorders treated with oral l -carnitine

Abstract

Oral supplementation with l-carnitine is a common therapeutic modality for mitochondrial disorders despite limited evidence of efficacy. Recently, a number of studies have demonstrated that a gut microbiota-dependent metabolite of l-carnitine, trimethylamine oxide (TMAO), is an independent and dose-dependent risk factor for cardiovascular disease (CVD). Given the limited data demonstrating efficacy with oral l-carnitine therapy and the newly raised questions of potential harm, we assessed plasma TMAO levels in patients with mitochondrial disease with and without oral l-carnitine supplementation. Nine subjects were recruited and completed the study. Eight out of 9 subjects at baseline had plasma TMAO concentrations <97.5th percentile (<15.5 μM). One subject with stage 3 renal disease, had marked elevation in plasma TMAO (pre 33.98 μm versus post 101.6 μm). Following at least 3 months of l-carnitine supplementation (1000 mg per day), plasma TMAO levels were markedly increased in 7out of 9 subjects; overall, plasma TMAO significantly increased 11.8-fold (p < 0.001) from a baseline median level of 3.54 μm (interquartile range (IQR) 2.55–8.72) to 43.26 (IQR 23.99–56.04) post supplementation. The results of this study demonstrate that chronic oral l-carnitine supplementation markedly increases plasma TMAO levels in subjects with mitochondrial disorders. Further studies to evaluate both the efficacy and long term safety of oral l-carnitine supplementation for the treatment of mitochondrial disorders are warranted.

The bright and the dark sides of L-carnitine supplementation: a systematic review

“…Similar observations were noted in later human studies [ 56 , 57 ], with the peak serum TMAO observed within hours following oral administration of the tracer [ 56 ]. Prolonged LC treatment elevates fasting plasma TMAO [ 16 – 18 , 58 , 59 ]. Three months of oral LC supplementation in healthy aged women induced ten-fold increase of fasting plasma TMAO, and this level remained elevated for the further 3 months of supplementation [ 16 ].…”

“…Although the optimal dose of LC supplementation for myocardial infarction is 3 g/day in terms of all-cause mortality [ 90 ], even lower LC intake elevates fasting plasma TMAO [ 16 – 18 , 58 , 59 ], which is ten-fold higher than control after 3 months of supplementation [ 16 , 17 ]. It is worthy to mention that Bakalov et al [ 91 ] analyzing European Medicine Agency database of suspected adverse drug reaction, noticed 143 cases regarding LC.…”

“…On the other hand, it is also clear that prolonged LC supplementation elevates fasting plasma TMAO [ 16 – 18 , 58 , 59 ], compound supposed to be pro-atherogenic [ 61 ]. Therefore, additional studies focusing on long-term supplementation and its longitudinal effect on the TMAO metabolism and cardiovascular system are needed.…”

Aging-Related Disorders and Mitochondrial Dysfunction: A Critical Review for Prospect Mitoprotective Strategies Based on Mitochondrial Nutrient Mixtures

“…CARN transports long-chain fatty acids across the mitochondrial membrane for energy production and promotes the excretion of toxic organic acids in urine [ 120 ]. Some age-related metabolites (creatinine, creatine, glycine, betaine/trimethylamine N-oxide, citrate, succinate, and acetone) can be cleared from the body over a long period of time, which suggests their use in patients with mitochondrial disorders [ 121 , 122 ]. The role of CoQ10 in the metabolome is still unclear, since it is difficult to separate ubiquinone synthesized in eukaryotic cells from intestinal menaquinone in bacterial cells [ 123 ].…”

L-Карнітин І Його Властивості У Відновлювальний Період Після Інфаркту Міокарда

“…Натепер відомо, що L-карнітинвітаміноподібна речовина або амінокислота, споріднена з вітамінами групи В (карнітин також називають вітаміном B T та B 11 ), і він відіграє важливу роль в енергетичному обміні міокарда: переносить вільні жирні кислоти всередину УДК 615. 25 мітохондрій і, тим самим, підвищує доступність найкращого субстрату для окисного метаболізму в серці [5].…”