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Title: Inflammatory biomarkers of colorectal neoplasia and their manipulation by an anti-inflammatory diet
Author: Basavaraju, Umesh
ISNI:       0000 0004 2721 8421
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2011
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Colorectal neoplasia (CRN) continues to be a leading cause of morbidity and mortality in the developed world and with westernisation, similar trends are now emerging in the developing world. Although secondary prevention through screening programmes has reduced mortality, uptake remains poor due to the invasive nature of colonoscopy, which also exerts increased costs to the health care system. Primary prevention remains the ultimate aim to reduce the morbidity and mortality associated with CRN. In this regard, chemoprevention strategies through regular use of aspirin and other NSAIDS have showed great promise but the associated significant side-effects of these drugs has prevented their routine clinical application for this purpose. Hence there is an urgent need for the identification of safer alternatives for primary prevention of CRN. In parallel to this search, better understanding of the molecular pathogenesis of CRN to identify biomarkers that aid in stratification of at risk individuals would also help. In this regard, the role of chronic inflammation and the influence of host genetics in the pathogenesis of CRN has been the focus of extensive research in recent years. However there is a lack of studies which have investigated these associations in an exclusively screened population, which confers some advantages for this type of investigation. Firstly, most of the screened subjects are relatively healthy, asymptomatic and with no significant co-morbidities, the factors which could otherwise influence the levels of inflammatory markers. Secondly, the screened population is in the 50 to74 year age group which represents the group with a high prevalence of CRN and hence increasing the possibility of finding associations which would be more relevant and generalisable. Thirdly, the selected controls match the cases in all important respects, apart from having CRN, thus increasing the validity of the findings in this population. The Grampian region was one of the first in the UK to participate in the National Colorectal Cancer Screening Programme and this resource gave the ideal opportunity to conduct research involving an exclusively screened population. Utilising this cohort, the current thesis addressed three important aspects of the association between inflammation and CRN. Firstly the investigation of the association of inflammatory genotype, inflammatory phenotype and CRN risk. Secondly the impact of environmental factors, specifically dietary antiinflammatory salicylic acid intakes on CRN risk. And finally assessing if inflammation, and hence in the long term risk of CRN, could be attenuated through a comprehensive anti-inflammatory dietary supplementation in the form of a randomised dietary intervention clinical trial. The study of the association of polymorphisms in key inflammatory genes (IL1B- 31, IL8-251, IL6-174, TNFα-308, IL10-1082, IL10-592, PTGS2-765, and IL1RN VNTR) and CRN risk showed some significant findings. A novel finding was that the homozygous IL1B-31C*C genotype was associated with statistically significant increased risk of CRN, OR 1.63 (95% CI 1.06-2.50) whilst the IL8-251 A*A genotype increased the propensity of having high risk lesions by two-fold (OR 2.04; 95% CI 1.02-4.07). The study of circulating inflammatory marker levels in subjects in whom the CRN was in-situ showed that increased CRP levels were associated with increased risk of CRN, OR 1.55 (95% CI 1.00-2.39). Increased levels of IL8 were associated with increased risk of having a high risk lesion, OR 2.57 (95% CI 1.03-6.44). In a sub group of subjects, it was observed that levels IL8 and CRP decreased following polypectomy (mean IL8 20.3 pg/ml to 14.9 pg/ml, p=0.05 and mean CRP 5.99 mg/l to 3.82 mg/l, p=0.07) raising an important question regarding the sequence of the inflammation-neoplasia cascade, “Is inflammation the cause or the effect of neoplasia?” The study of the association of dietary salicylic acid (SA) and CRN using the newly constructed SA database showed that high levels of total SA (aspirin and dietary SA) intakes were associated with a 75% and moderate levels with a 67% decreased risk of CRN. But dietary SA on its own showed no significant effect on CRN risk probably because of low intake levels in the current cohort. Applying the SA database to populations with higher dietary SA intake would help to further explore its association with CRN risk. The randomised clinical trial examining the effect of a combined antiinflammatory dietary supplement (curcumin, omega-3 PUFA and polyphenols rich fruit smoothie) on markers of inflammation in subjects who had adenomatous colorectal polyps removed showed that the inflammatory marker levels in the control group who just continued their habitual diet remained stable without any statistically significant changes at 6 weeks compared to the baseline. Whereas following 6 weeks of dietary intervention, there was marginally significant increase in IL8 and IL1B levels. One of the possible mechanisms for increase in pro-inflammatory marker levels in the intervention group was the weight gain seen in the intervention group. In the intervention group, the post-intervention mean weight (86.80kgs) was significantly higher than the pre-intervention mean weight (85.38 kgs). In summary, the findings from these investigations suggest that a proinflammatory genotype (IL1B-31C*C and IL8-251 A*A) and elevated circulating inflammatory marker levels (CRP and IL8) are associated with increased risk of CRN. And along with the findings that regular NSAID use and total dietary SA are associated with decreased risk of CRN, our data point to inflammation as an underlying pathogenetic mechanism in CRN. The pilot clinical trial has demonstrated that a clinical trial with combined dietary supplementation is feasible, but challenging. The anti-inflammatory dietary intervention strategy employed to reduce the inflammatory markers did not achieve the desired effect and hence more research is required to establish the ideal delivery strategy of the anti-inflammatory dietary agents. Once this is established, dietary chemoprevention of CRN as a safe alternative should be a realistic achievable goal in the future.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Colon (Anatomy) ; Rectum ; Biochemical markers ; Anti-inflammatory agents