Pharmacomicrobiomics in gastrointestinal cancer: the gut microbiome as modulator of anticancer therapy efficacy and predictor of therapy outcomes
File(s)
Author(s)
Chrysostomou, Despoina
Type
Thesis
Abstract
Chemotherapeutic regimens have been shown to significantly improve cancer survival rates. However, robust clinical evidence shows that inter-patient response rates are sub-optimal, and patients often experience severe therapy-derived adverse effects. It is now recognised that the gut microbiota can directly or indirectly mediate drug metabolism and therefore influence drug efficacy and toxicity.
In this work, a combination of metataxonomic and metabolomic approaches have been employed to establish associations between changes in microbiota composition and function, and gastroesophageal patients’ response to FLOT-A treatment (5-Fluorouracil, Leucovorin, Oxaliplatin, Docetaxel and anti-PD-L1). Additionally, a high-throughput ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) assay was developed to identify bacterial species that can metabolise chemotherapeutic agents in vitro. The effect of bacteria-derived drug metabolism on drug efficacy was explored by investigating the survival of colorectal cancer cell lines in vitro and identifying changes in the development and stress responses of Caenorhabditis elegans in vivo. We observed that Escherichia coli BW25113, Citrobacter freundii, Bifidobacterium longum and Enterococcus faecalis could metabolise 5-FU and the results of those interactions led to an increase in 5-FU efficacy. Conversely, reduction of 5-FU efficacy was mediated by a human stool-derived Escherichia coli strain. Interestingly, the drug metabolising abilities of bacteria are not drug specific. We showed that a human stool-derived Escherichia coli, Bacteroides vulgatus, Enterococcus faecalis and Ruminoccocus gnavus can metabolise oxaliplatin leading to inactivation of the drug. Although interesting, further investigation is required.
Our results highlight the importance of the functional capacity of microbiota in clinical practice. The metabolic function of microbiota could explain the variability in patient responses, hence investigating patients’ microbiome prior to treatment could assist in clinical decisions and improve therapeutic outcomes. Therefore, it is now time to leverage the microbiome for the development of novel personalised therapeutic approaches in cancer treatment.
In this work, a combination of metataxonomic and metabolomic approaches have been employed to establish associations between changes in microbiota composition and function, and gastroesophageal patients’ response to FLOT-A treatment (5-Fluorouracil, Leucovorin, Oxaliplatin, Docetaxel and anti-PD-L1). Additionally, a high-throughput ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) assay was developed to identify bacterial species that can metabolise chemotherapeutic agents in vitro. The effect of bacteria-derived drug metabolism on drug efficacy was explored by investigating the survival of colorectal cancer cell lines in vitro and identifying changes in the development and stress responses of Caenorhabditis elegans in vivo. We observed that Escherichia coli BW25113, Citrobacter freundii, Bifidobacterium longum and Enterococcus faecalis could metabolise 5-FU and the results of those interactions led to an increase in 5-FU efficacy. Conversely, reduction of 5-FU efficacy was mediated by a human stool-derived Escherichia coli strain. Interestingly, the drug metabolising abilities of bacteria are not drug specific. We showed that a human stool-derived Escherichia coli, Bacteroides vulgatus, Enterococcus faecalis and Ruminoccocus gnavus can metabolise oxaliplatin leading to inactivation of the drug. Although interesting, further investigation is required.
Our results highlight the importance of the functional capacity of microbiota in clinical practice. The metabolic function of microbiota could explain the variability in patient responses, hence investigating patients’ microbiome prior to treatment could assist in clinical decisions and improve therapeutic outcomes. Therefore, it is now time to leverage the microbiome for the development of novel personalised therapeutic approaches in cancer treatment.
Version
Open Access
Date Issued
2023-10-04
Date Awarded
2024-03-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Marchesi, Julian
Kinross, James
Sponsor
MRC Doctoral Training Programme
Servier Laboratories Ltd.
Publisher Department
Department of Metabolism, Digestion and Reproduction
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)