Does choline supplementation increase TMAO levels?

Trimethylamine N-oxide (TMAO) is a small colorless amine oxide generated from choline, betaine, and carnitine from gut bacteria. A positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events and death is reported. 

Choline/Carnitine /TMAO has been in discussion since 2013 when a series of articles first brought it to light. Till now, the production of TMAO, a cardiovascular risk factor, has been studied in meat/egg consumers vs vegan, choline, and carnitine supplement takers vs none and the blame has mostly rested on the shoulders of the gut microbiome composition. Meaning, if the gut bacteria were balanced and mostly composed of those healthy types that did not convert TMA to TMAO then one was ok.   

Antibiotic therapy was the first choice of therapy- however, with known drawbacks of antibiotic usage, the next ‘gut’ reaction resorted to has been decreasing intake of all forms of choline and carnitine whether food or supplements. This, with the assumption that decreasing the intake of these nutrients would subsequently quell the issue.

Weak links in this theory 

• While it cannot be negated that choline and carnitine are precursors to TMA and then TMAO - trying to reduce the production of TMAO by decreasing important nutrients like choline and carnitine can be counter-productive. 
• The amounts of TMA that metabolize to TMAO are not accurately predicted by the food source and are not proportional to the amount ingested. 
• While being implicated as a biomarker for cardiovascular risk, elevated levels of TMAO have not caused elevation in C-reactive protein or LDL levels, in whom carnitine supplementation would actually be highly beneficial. 
• Cruciferous vegetables inhibit the activity of the FMO3 enzyme which plays a vital role in converting TMA to TMAO. 
• Most of the research on TMAO's negative effects is with high chronic dosage amounts and mostly in animal studies. 
• TMAO is still considered a bystander and not a cause of disease. 

Most importantly, our findings reconcile contradictory data on TMAO. There was no direct association between plasma TMAO and the extent of atherosclerosis, both in mice and humans.

Listen to Dr. Jaffe, MD, PhD, discuss this topic here. 

References

1. Fennema D, Phillips IR, Shephard EA. Trimethylamine and Trimethylamine N-Oxide, a Flavin-Containing Monooxygenase 3 (FMO3)-Mediated Host-Microbiome Metabolic Axis Implicated in Health and Disease [published correction appears in Drug Metab Dispos. 2016 Dec;44(12 ):1949]. Drug Metab Dispos. 2016;44(11):1839–1850. 
2. Velasquez MT, Ramezani A, Manal A, Raj DS. Trimethylamine N-Oxide: The Good, the Bad and the Unknown. Toxins (Basel). 2016;8(11):326. Published 2016 Nov 8. doi:10.3390/toxins8110326
3. Martin FP, Wang Y, Sprenger N, et al. Probiotic modulation of symbiotic gut microbial-host metabolic interactions in a humanized microbiome mouse model. Mol Syst Biol. 2008;4:157. 
4. Hu Y, Zhao Y, Yuan L, Yang X. Protective effects of tartary buckwheat flavonoids on high TMAO diet-induced vascular dysfunction and liver injury in mice. Food Funct. 2015;6(10):3359–3372.
5. Yen Chin Koay, Yung-Chih Chen, Jibran A Wali, Alison W S Luk, Mengbo Li, Hemavarni Doma, Rosa Reimark, Maria T K Zaldivia, Habteab T Habtom, Ashley E Franks, Gabrielle Fusco-Allison, Jean Yang, Andrew Holmes, Stephen J Simpson, Karlheinz Peter, John F O’Sullivan, Plasma levels of trimethylamine-N-oxide can be increased with ‘healthy’ and ‘unhealthy’ diets and do not correlate with the extent of atherosclerosis but with plaque instability, Cardiovascular Research, Volume 117, Issue 2, 1 February 2021, Pages 435–449, https://doi.org/10.1093/cvr/cvaa094