Emu oil in combination with herbal preparations provides a novel adjunctive approach to colitis-associated colorectal cancer prevention

Abstract

Ulcerative colitis (UC) is an incurable and unremitting disease that presents as chronic inflammatory damage in the large intestine. UC is a lifelong condition that is often diagnosed in adolescence. The current pharmaceutical treatments for UC result in undesirable side effects and place patients at an increased risk of developing colorectal cancer (CRC). Emu Oil, derived from the adipose tissue of the Australian Emu, comprises fatty acids and has displayed anti-inflammatory, anti-oxidant and reparative properties in rodent models of gastrointestinal conditions. Notably, mice administered Emu Oil displayed improved clinical indicators of disease and resulted in fewer small colorectal tumours compared with untreated controls in an azoxymethane (AOM)/dextran sulphate sodium (DSS) mouse model. However, the total number of colorectal tumours was unaffected by Emu Oil administration (Chapter 2). Experimental studies have indicated that other naturally-sourced compounds (nutraceuticals), including grape seed extract (GSE) and Japanese Kampo medicine, have anti-neoplastic potential. Consequently, such nutraceuticals may be beneficial in colitis-associated CRC (CACRC) and amplify the therapeutic potential of Emu Oil. In Chapter 3, the combination of Emu Oil and GSE was most effective at reducing clinical disease severity scores compared to each treatment alone in AOM/DSS mice. Furthermore, the number of colonic tumours was decreased by Emu Oil, GSE and the combined treatments. Additionally, impaired intestinal permeability was abrogated by Emu Oil and the combination of Emu Oil and GSE; however, GSE was ineffective when administered alone. This thesis also includes the first study to investigate Saireito, a Japanese Kampo medicine, in pre-clinical CA-CRC. Notably, the combination of Emu Oil and Saireito proved more effective at reducing colonoscopically-assessed inflammation than each treatment alone (Chapter 4). Importantly, mice administered a combination of Emu Oil and Saireito displayed greater reductions in the total number of colonic tumours compared to AOM/DSS controls. In pre-clinical investigations, it is necessary to monitor animal wellbeing and behaviour to ensure welfare and ethical standards are upheld. In this thesis, a number of methods were used, including burrowing (Chapters 2–4), clinical disease scores Chapters 2–6) and the mouse grimace scale (Chapter 5). Chapter 5 provides details of the first study conducted to compare and correlate retrospective and real-time grimace analyses. Though, the results obtained in this study were not significant. Thus, it was concluded that the clinical disease score was the most reliable method for welfare monitoring in CA-CRC mice. Further, Chapter 6 aimed to develop a modified AOM/DSS model whereby chemotherapy treatment causes intestinal mucositis, resulting in a more reliable method to test future treatments. However, in this chapter the chemotherapy dose administered was insufficient to induce mucositis coincident with CACRC. Overall, this thesis includes rigorous scientific investigations into alternative and adjunct treatment options relevant to patients with CA-CRC. Additionally, modifications to the AOM/DSS model are discussed and the need to include animal wellbeing techniques in preclinical investigations is emphasised. Finally, the therapeutic action of Emu Oil was potentiated when administered with either GSE or Saireito, indicating that combined nutraceuticals could be utilised in CA-CRC management.