An Expanded Genetic Code Enables Trimethylamine Metabolism in Human Gut Bacteria

Cardiovascular disease (CVD) has been linked to animal-based diets, which are a major source of trimethylamine (TMA), a precursor of the proatherogenic compound trimethylamine-N-oxide (TMAO). Human gut bacteria in the genus Bilophila have genomic signatures for genetic code expansion that could enable them to metabolize both TMA and its precursors without production of TMAO. We uncovered evidence that the Bilophila demethylation pathway is actively transcribed in gut microbiomes and that animal-based diets cause Bilophila to rapidly increase in abundance. CVD occurrence and Bilophila abundance in humans were significantly negatively correlated. These data lead us to propose that Bilophila, which is commonly regarded as a pathobiont, may play a role in mitigating cardiovascular disease. Human gut microbiomes have been shown to affect the development of a myriad of disease states, but mechanistic connections between diet, health, and microbiota have been challenging to establish. The hypothesis that Bilophila reduces cardiovascular disease by circumventing TMAO production offers a clearly defined mechanism with a potential human health impact, but investigations of Bilophila cell biology and ecology will be needed to fully evaluate these ideas. IMPORTANCE Links between trimethylamine-N-oxide (TMAO) and cardiovascular disease (CVD) have focused attention on mechanisms by which animal-based diets have negative health consequences. In a meta-analysis of data from foundational gut microbiome studies, we found evidence that specialized bacteria have and express a metabolic pathway that circumvents TMAO production and is often misannotated because it relies on genetic code expansion. This naturally occurring mechanism for TMAO attenuation is negatively correlated with CVD. Ultimately, these findings point to new avenues of research that could increase microbiome-informed understanding of human health and hint at potential biomedical applications in which specialized bacteria are used to curtail CVD development.