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Dawson, S 
ORCID: https://orcid.org/0000-0002-1637-9401,
2023.
Understanding the metabolism of trimethylamine N-oxide in human gut bacteria.
PhD, Nottingham Trent University.
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Abstract
Trimethylamine N-oxide (TMAO) is a dietary methylamine that has been implicated in the development of cardiovascular disease and metabolic disease, but also in protective effects on the liver and blood-brain barrier. While some TMAO is directly ingested in foods such as fish and dairy products, most TMAO in the human body is the product of microbial metabolism. In the human gut microbes breakdown TMAO to trimethylamine, which is transported to the liver where it is converted back to TMAO by hepatic enzymes and excreted in the urine. Previous work reported the protein TorA, encoded by Escherichia and Klebsiella spp., as being the main source of TMAO to trimethylamine metabolism in the human gut. A thorough literature review found several non-TorA TMAO metabolism pathways that could be utilised by gut bacteria. A bioinformatics analysis of ~36,000 genomes found that TorA was not as prevalent as previously thought, with less than 1 % of Klebsiella genomes encoding TorA. A caecal K. pneumoniae isolate, L4-FAA5, was fully characterised to examine its TMAO metabolism activity. L4-FAA5 was found to carry non-TorA TMAO metabolism proteins and showed significantly increased growth in the presence of TMAO in anaerobic conditions. The molybdoenzyme BisC was found to be highly prevalent in Klebsiella spp. in the bioinformatic analysis. BisC was found to have high (63.3 %) amino acid sequence identity with the TMAO reductase TorZ and so work was carried out to characterise its TMAO reductase ability. Bioinformatic analysis showed a high (>90 %) structural similarity between BisC carried by L4-FAA5 and known TMAO reductases. This led to work to clone, express, and purify L4-FAA5 BisC to assess its TMAO reductase ability, with preliminary results suggesting that BisC can reduce TMAO. This work used extensive bioinformatic analysis to inform laboratory work that increases the understanding of microbial TMAO metabolism in the human gut.
| Item Type: | Thesis |
|---|---|
| Creators: | Dawson, S. |
| Contributors: | Name Role NTU ID ORCID |
| Date: | September 2023 |
| Rights: | The copyright in this work is held by the author. You may copy up to 5 % of this work for private study, or personal, non-commercial research. Any re-use of the information contained within this document should be fully referenced, quoting the author, title, university, degree level and pagination. Queries or requests for any other use, or if a more substantial copy is required, should be directed to the author. |
| Divisions: | Schools > School of Science and Technology |
| Record created by: | Laura Borcherds |
| Date Added: | 08 Jul 2025 11:59 |
| Last Modified: | 08 Jul 2025 11:59 |
| URI: | https://irep.ntu.ac.uk/id/eprint/53896 |
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