Abstract
Trimethylamine (TMA) is an important gut microbial metabolite strongly associated with human disease. There are prominent gaps in our understanding of how TMA is produced from the essential dietary nutrient l-carnitine, particularly in the anoxic environment of the human gut where oxygen-dependent l-carnitine-metabolizing enzymes are likely inactive. Here, we elucidate the chemical and genetic basis for anaerobic TMA generation from the l-carnitine-derived metabolite γ-butyrobetaine (γbb) by the human gut bacterium Emergencia timonensis We identify a set of genes up-regulated by γbb and demonstrate that the enzymes encoded by the induced γbb utilization (bbu) gene cluster convert γbb to TMA. The key TMA-generating step is catalyzed by a previously unknown type of TMA-lyase enzyme that utilizes a putative flavin cofactor to catalyze a redox-neutral transformation. We identify additional cultured and uncultured host-associated bacteria that possess the bbu gene cluster, providing insights into the distribution of anaerobic γbb metabolism. Lastly, we present genetic, transcriptional, and metabolomic evidence that confirms the relevance of this metabolic pathway in the human gut microbiota. These analyses indicate that the anaerobic pathway is a more substantial contributor to TMA generation from l-carnitine in the human gut than the previously proposed aerobic pathway. The discovery and characterization of the bbu pathway provides the critical missing link in anaerobic metabolism of l-carnitine to TMA, enabling investigation into the connection between this microbial function and human disease.
Highlights
Trimethylamine (TMA) is an important gut microbial metabolite strongly associated with human disease
Gut microbial production of TMA from dietary L-carnitine has been recognized for decades, but our knowledge of the reactions, enzymes, and organisms involved in the O2-independent pathway has remained incomplete
We used RNA-seq to identify a substrateinducible bbu gene cluster that is responsible for anaerobic γbb metabolism in the gut microbe E. timonensis
Summary
Trimethylamine (TMA) is an important gut microbial metabolite strongly associated with human disease. The discovery and characterization of the bbu pathway provides the critical missing link in anaerobic metabolism of L-carnitine to TMA, enabling investigation into the connection between this microbial function and human disease. Trimethylamine (TMA) is a gut microbial metabolite that has been strongly associated with human disease It is derived from gut microbial transformations of dietary nutrients including phosphatidylcholine, choline, L-carnitine, betaine, and TMA N-oxide (TMAO) [4,5,6,7,8,9]. We define the biochemical pathway and genetic components in gut bacteria required for anaerobic production of TMA from γ-butyrobetaine, a metabolite derived from L-carnitine This discovery identifies a new type of TMAproducing enzyme and fills a critical gap in our knowledge of L-carnitine metabolism to TMA in the anaerobic environment of the human gut. This knowledge will enable evaluation of the link between L-carnitine metabolism and human disease and the design of potential therapeutics
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