期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：32
DOI：10.1073/pnas.2101498118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Trimethylamine (TMA) is a disease-associated metabolite produced in the human body exclusively by microbes. Gut microbes generate TMA from essential nutrients consumed in the human diet, including
l-carnitine. However, our understanding of the biochemical mechanisms involved in these transformations is incomplete. In this work, 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 TMA-producing 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.
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.
