Is Ergothioneine an Important Source of Plasma Trimethylamine N-Oxide in Humans?

High circulating levels of trimethylamine-N-oxide (TMAO), largely produced by hepatic oxidation of gut-microbiota-derived trimethylamine (TMA), are associated with increased risk of cardiometabolic and neurodegenerative diseases. In contrast, the diet-derived compound ergothioneine (ET) possesses cytoprotective and neuroprotective properties, and higher circulating ET levels have been linked to a lower risk of cardiovascular, neurodegenerative, and other age-related disorders. However, concerns have been raised that microbial degradation of ET may also contribute to the TMAO pool. In this study, we examined the relationship between ET and TMAO. Bioinformatic analyses indicated that ergothionase, the enzyme responsible for ET degradation to trimethylamine (TMA), is restricted to a limited number of bacterial genera and is far less prevalent than choline trimethylamine lyase, which generates TMA from choline. In a randomised, placebo-controlled human study, ET supplementation (25 mg/day for 7 days) significantly increased plasma ET levels but did not increase TMAO concentrations. Similarly, in a heart failure cohort, plasma ET showed no correlation with TMA or TMAO levels, whereas TMAO was clearly correlated with TMA. Collectively, these findings suggest that ET is unlikely to contribute significantly to systemic TMAO levels.