Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/134012
Type: Thesis
Title: Exploration of the gut microbiome as a predictive factor for cancer treatment-induced gastrointestinal toxicity
Author: Secombe, Kate Rebecca
Issue Date: 2021
School/Discipline: School of Biomedicine
Abstract: Gastrointestinal toxicity is a significant side effect of many cancer treatments. Characterised by diarrhoea, abdominal pain and bleeding, this toxicity can affect up to 80% of patients, depending on treatment regimen. Currently, there are no highly effective intervention strategies for the vast majority of people affected, thus more evidence is required to improve future management. This thesis focussed primarily on gastrointestinal toxicity stemming from two major types of cancer treatment. These are chemotherapy, the most common form of cancer treatment, and small molecule tyrosine kinase inhibitors (SM-TKIs), a class of targeted therapies, often used in combination with chemotherapy. There is a clear gap in knowledge in understanding how these different cancer treatments cause gastrointestinal toxicity, and how the population of microorganisms in the intestine, the gut microbiome, links to these responses. This thesis therefore aimed to investigate the role of the gut microbiome in influencing the development and exacerbation of gastrointestinal toxicity stemming from cancer treatment. This was investigated in three main sections. Firstly, I aimed to examine the interaction between the gut microbiome and the innate immune system (chiefly the innate immune receptor Toll-like receptor 4 (TLR4)), and determine how this interaction could be involved in the development of gastrointestinal toxicity following chemotherapy. In order to achieve this aim, I characterised the microbial composition of a TLR4 conditional knockout mouse model and assessed changes due to chemotherapy treatment. There were no clear differences in the microbiome of wild type and TLR4 conditional knockout mice. Secondly, I aimed to characterise the role of the gut microbiome in diarrhoea stemming from the SM-TKI treatment neratinib, which causes high levels of diarrhoea. I found that, in a pre-clinical model, neratinib treatment does cause changes to microbial composition, however it was unclear if these changes were a key driver of diarrhoea development or simply a side effect of this diarrhoea. Therefore I analysed diarrhoea development following an initial, antibiotic-induced perturbation, showing that addition of narrow-spectrum antibiotics caused a significant decrease in diarrhoea severity and timespan. Finally, I clinically appraised the use of the gut microbiome in predicting risk of cancer treatment-induced gastrointestinal toxicity in two defined patient cohorts. A retrospective cohort showed that participants who went on to develop diarrhoea had significantly lower amounts of the bacterial genera Blautia and significantly higher amounts of the genera Collinsella. A longitudinal study was then developed. Pilot results did not show clear microbial clustering based on diarrhoea status. The results of my thesis demonstrate the emerging role gut microbiome composition has on the development of diarrhoea following cancer treatment. However I was unable to definitively identify any particular bacterial type that is a key mediator of this effect. The results presented here however provide strong rationale for further research in this area using specific machine learning and metabolomic techniques to identify compositional features that may be important in accurately predicting diarrhoea development following cancer treatment.
Advisor: Bowen, Joanne
Coller, Janet
Gibson, Rachel
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Biomedicine, 2021
Keywords: Cancer
microbiome
mucositis
supportive care
Provenance: This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals
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