Small molecules produced by gut microbes have important consequences for human health and disease. Trimethylamine <i>N</i>-oxide (TMAO) is a metabolite strongly associated with cardiovascular disease that is generated via host-microbial co-metabolism of dietary nutrients, such as l-carnitine found abundantly in red meat. Although gut microbial metabolism of l-carnitine has been recognized for decades, there remain critical questions about the pathways and microbes that are responsible for its conversion to trimethylamine (TMA), the direct precursor to TMAO. A complete understanding of the organisms, genes, and enzymes involved in l-carnitine metabolism is critical to assess its prevalence in human populations and to evaluate its contribution to the development of cardiovascular disease. We have elucidated a key missing step in the anaerobic pathway for metabolism of l-carnitine to TMA. This pathway goes through the intermediate metabolite gamma-butyrobetaine, which is produced by gut bacteria that possess the <i>cai</i> gene cluster and consumed by a distinct, exclusive subset of gut Clostridiales. We determined the biochemical steps involved in conversion of gamma-butyrobetaine to TMA, as well as identified and validated the gene cluster and enzymes responsible. We demonstrated that the TMA-producing reaction is catalyzed by a new type of flavin-dependent TMA-lyase. Finally, bioinformatic analyses of human meta’omic datasets suggest that anaerobic l-carnitine metabolism is functionally active and important in the human gut. This work resolves a longstanding mystery regarding the origins of TMA from dietary l-carnitine in the anoxic human gut and identifies new targets for manipulation of a disease-associated microbial activity.

Enzyme discovery completes the anaerobic pathway for gut microbial metabolism of l-carnitine linked to cardiovascular disease

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.