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Bowen, Joanne Wardill, Hannah Gladman, Marc Subramaniam, Courtney Brooke School of Biomedicine 2022 https://hdl.handle.net/2440/138276 The neuropsychological side effects of chemotherapy are consistently identified as some of the most significant complications of cancer treatment impacting the long-term health and daily functioning of people living with and beyond cancer. These complications typically include cognitive deficits affecting memory, executive function, concentration and processing speeds which often present in parallel with psychological symptoms related to anxiety, depression and fear of cancer recurrence. Importantly, these symptoms have been shown to persist long after cancer remission and treatment cessation, and so are associated with significant psychosocial burden due to their impact on employment capacity and quality of life. It is now recognised that chemotherapy causes both neuroinflammatory changes within the brain, a neuropathological hallmark shared by all neuropsychological symptoms, and significant compositional changes to the gut microbiota. However, the role of the microbiota-gut-brain axis in the development of neuropsychological complications remains unclear. Given that the gut microbiota has been shown to have profound control over neuroinflammatory processes in other clinical settings, the body of work presented in this thesis addresses this gap in knowledge by exploring the role of the gut microbiota as a potential mediator of neuroinflammation induced by chemotherapy and associated neuropsychological symptom development. The overarching hypothesis of this thesis is that the gut microbiota exerts profound control over the neuropathological consequences of chemotherapy treatment. Specifically, I hypothesise that there are distinct microbial traits differentiating individuals with and without cognitive symptoms following chemotherapy and that the gut microbiota can be augmented to modulate chemotherapy-induced neuroinflammation. These hypotheses were addressed across three main sections. Firstly, I aimed to characterise the longitudinal changes to gut microbiota composition in a cohort of women receiving chemotherapy for breast cancer, with and without cognitive impairment (Chapter 3). In undertaking this explorative study, I was the first to identify gut microbial taxa enriched and depleted in women with breast cancer stratified by the presence or absence of cognitive impairment, positioning the gut microbiota as a potential mediator. The results of this study underscored the need to further explore the underlying pathophysiology related to dysfunctional microbiota-gut-brain axis communication. Given that neuroinflammation is recognised as a mechanism shared by all neuropsychological symptoms, I then aimed to develop a mouse model of chemotherapy-induced neuroinflammation (Chapter 4) and use this model to evaluate the effect of a high fibre dietary intervention in augmenting the gut microbiota and preventing neuroinflammation (Chapter 5). Collectively, these in vivo studies characterised the temporal dynamics of neuroinflammatory changes in the brain caused by chemotherapy and established the beneficial effects of dietary fibre in decreasing markers of neuroinflammation following chemotherapy. Taken together, the body of work described within my thesis established the role of the gut microbiota in both chemotherapy-induced cognitive impairment and neuroinflammation, providing a strong rationale for the continued investigation into the gut microbiota as a potential therapeutic target for the neuropsychological complications of chemotherapy treatment. Thesis (Ph.D.) -- University of Adelaide, School of Biomedicine, 2023 en neuropsychological complications, chemotherapy-induced cognitive impairment, microbiota-gut-brain axis, microbiome, neuroinflammation, neurotoxicity The Microbiota Gut Brain Axis in the Neuropsychological Complications of Chemotherapy Treatment Thesis 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/legalsopen.access