From the Bottom Up: Chemotherapy-Induced Gut Toxicity, Glial Reactivity and Cognitive Impairment

Patients with inflammatory disorders of the gut often experience central comorbidities, which include depression, anxiety and cognitive deficits. This is not surprising considering the gastrointestinal tract (GIT; gut) and the central nervous system (CNS, brain and spinal cord) are connected by a myriad of bidirectional pathways. The dialogue between the peripheral immune system and the brain (neuroimmune interactions) has been implicated in the development of sickness behaviours, which interestingly mimic the central comorbidities reported by patients with gut inflammatory disorders, particularly those with inflammatory bowel diseases and cancer. The neuroimmune system lies at the heart of this thesis and its overarching hypotheses. This stems from evidence implicating microglial and astrocyte cell reactivity/priming in contributing to central changes via peripheral inflammatory events. Once primed, glial cells undergo morphological and functional changes which often result in neurotoxicity and neuroinflammation due to their intimate relationship with the synapse. In their quiescent state, however, microglial and astrocytes are critical in central homeostasis, health and development. Reactive glia induce a destructive microenvironment via tissue damage and neuronal loss, contributing to pathological pain pathways and neurodegeneration. Whilst glial reactivity is initiated as an innate response aimed at assisting the host in healing, often microglia and astrocytes can remain primed after the peripheral inflammatory event subsides. Consequently, this thesis examined microglial and astrocyte dysregulation in the brain and spinal cord of rodents across a range of inflammatory conditions of the gut. This work compared acute and chronic models involving a commonly used chemotherapy drug and non-steroidal antiinflammatory drug. The chronic models assessed ulcerative colitis and colitis-associated colorectal cancer. Finally, this thesis explored the relationship between gut disturbances and cognitive impairment in an Australian breast cancer cohort. The findings from this thesis suggest that neuroimmunological manifestations occur in the spinal cord and brain of rodents across a range of acute and chronic inflammatory disorders of the gut. Importantly, this indicates that current investigations into the central side-effects associated with gut inflammatory conditions may be critically missing the direct and indirect influence of simultaneously occurring side-effects. Rather than focussing on an individual mechanism relating to a specific side-effect of chemotherapy treatment, perhaps we should be more accurately reflecting a clinical setting and develop our understanding of how multiple side-effects work in unison. The findings from the clinical trial assist us in further understanding the relationships between the perceived severity of side-effects associated with chemotherapy treatment and identify relationships between allergies, pain, gut disturbances and cognition. The mechanistic implications of these findings should be further explored to elucidate whether the gut-inflammatory-induced glial dysregulation described in this thesis has the potential to modulate brain function and behaviour. Ultimately, such studies may critically lead to the development of novel treatment approaches that target multiple side-effects and positively influence the central comorbidities associated with inflammatory disorders of the gut.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 201