Quintaneiro, Leonor Maximo (2020) Investigating the mechanisms of fluoropyrimidine anti-cancer drugs in the context of the holobiont. PhD thesis, Birkbeck, University of London.
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Abstract
The gut microbiota can be described as the large community of microorganisms that inhabit a host gastrointestinal tract. Host-microbe interactions have been linked to several aspects of host fitness and disease. However, very little is known about the effect of host-targeted drugs on gut-residing microbes and, consequentially, on host metabolism. Colorectal cancer (CRC) is the second deadliest cancer worldwide and, although the aetiology of this disease is now better understood, there is an increased need in improving therapeutic outcome. In addition, the role of gut microbes on the development and treatment outcome of CRC patients has not been properly explored. 5-Fluorouracil (5-FU) is a fluoropyrimidine that inhibits cell division by acting as a uracil analogue that inhibits nucleotide synthesis. We use the nematode C. elegans to unravel the mechanisms at play between the host, the gut microbes, nutritional cues and 5-FU. Via a host-microbe-drug model, we performed high-throughput screens and used metabolomic approaches to reveal that microbes can activate fluoropyrimidines via direct metabolic conversion through the salvage ribonucleotide pathway and, consequently, modulate drug efficacy on the host. The metabolic conversion of fluoropyrimidines was also found to be influenced by bacterial vitamin B6 and B9 metabolism. Furthermore, we have explored the role of dietary cues in regulating host response to 5-FU. We used high-throughput methods that allow the screening of hundreds of different nutrients while taking into account host-microbe-drug dynamics. We found that sugar compounds, such as glucose or galactose, can negatively affect drug efficacy on the host. The mechanisms underlying this effect were further explored in detail using a combination of phenotypic screening and metabolomic approaches. We found that sugars increase bacterial-mediated bioconversion of 5-FU, but in this nutritional context, UMP and UTP pools increase further, thereby impeding drug toxicity in C. elegans. Crucially, we discovered that blocking the de novo ribonucleotide pathway in the context of glucose, increases the abundance of IMP and GMP, which increases 5-FU toxicity on the host. Lastly, we found that nutrient-dependent impairment of the tricarboxylic acid cycle in bacteria, rewired pyruvate flux through the 2-methylcitratepathway for the production of 2-methylisocitrate - a metabolite that decreased drug efficacy on the host. Overall, the work presented in this thesis explores the mechanisms by which gut microbes regulate 5-FU toxicity in C. elegans. Further knowledge in these processes highlight the importance of understanding complex host-microbe interactions in response to drug treatment and nutrition to further improve medical treatment of cancer patients.
Metadata
| Item Type: | Thesis |
|---|---|
| Copyright Holders: | The copyright of this thesis rests with the author, who asserts his/her right to be known as such according to the Copyright Designs and Patents Act 1988. No dealing with the thesis contrary to the copyright or moral rights of the author is permitted. |
| Depositing User: | Acquisitions And Metadata |
| Date Deposited: | 25 Nov 2021 16:04 |
| Last Modified: | 01 Nov 2023 15:06 |
| URI: | https://eprints.bbk.ac.uk/id/eprint/46802 |
| DOI: | https://doi.org/10.18743/PUB.00046802 |
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