Abstract:
Inflammatory bowel diseases chiefly involving Crohn’s disease (CD) and Ulcerative colitis (UC) are currently deficient in management strategies to offer complete remission in all cases. There are inconsistencies and side effects associated with the present understanding and management of IBD. Therefore this thesis explores areas for improvement in IBD management. Concepts of personalized medicine are being proposed as an enhanced strategy for treating IBD, therefore in vitro techniques that can help shape personalized medicine according to the pathogenesis conditions relevant to IBD are beneficial as introductory evaluation systems to consequently aid IBD management. Hence, this thesis has aspects analyzing drug and phytochemical activity in in vitro conditions with factors involved in IBD pathogenesis. As important SNPs relevant to IBD could have the potential to affect drug activity, a NOD2 SNP impact on drug and phytochemical activity is studied in an in vitro system to scrutinize the differential effects caused in the wild type and NOD2-G908R mutant cell lines. Also, due to the potential prospects of natural products to aid IBD therapy and the insignifica nt understanding of complementary and alternative therapies (CAM) in IBD therapy presently, certain phytochemicals that have been associated with drug development in addition to CAM in IBD are also evaluated besides the conventional drugs in IBD management. This study has provided insight on the NOD2-G908R SNP impact, at least in vitro, with the activity of the drugs Cyclosporin A, Methotrexate and phytochemic a ls Arctigenin, Glabridin, Acetyl-keto-β-Boswellic acid (AKBA), Ellagic acid and ZGuggulsterone being affected due to the mutation, and phytochemicals Curcumin, Phenethyl isothiocyanate (PEITC), Epigallocatechin-3-gallate, Triptolide, and drugs Prednisolone, Mesalamine not significantly affected in this study. Not only are CD and UC debilitating diseases in their own right, individuals with these diseases have an increased susceptibility to colorectal cancer. Due to the associating of colon cancer with IBD, drug and phytochemical activity in the presence of a mutagen mitomycin C (MMC) is evaluated in Salmonella typhimurium TA102 for investigating the effects of these chemicals on DNA repair mechanism and screen for any anti-mutage nic potential. An assessment for the anti-mutagenic potential of the drugs and phytochemic a ls to challenge MMC-induced free radical mutagenesis in this in vitro system revealed the potential impacts of drugs such as Cyclosporin A, and phytochemicals like Curcumin, Ellagic acid, PEITC. These may be affecting the DNA repair mechanism, and thus consequently having an anti-mutagenic impact in this system. In the eukaryotic HT-29 colon cancer cell line, the drugs Methotrexate, Cyclosporin A and the phytochemic a ls Triptolide, Curcumin and AKBA were able to influence MMC induced cell cycle alterations. Investigations of the intestinal microbiome in IBD conditions manifesting dermatologica l complications due to the anti-TNFα biologics treatment, were studied to analyze potential areas for therapeutic microbiome modulation. This study has revealed a higher abundance of proteobacteria, particularly the bacterial genus Proteus in infliximab-induced dermatological complications in UC, and a lower abundance of the butyrate producer Lachnospira pectinoschiza in CD with dermatological complications. This implicates a possible association of these microbes in the pathogenesis of dermatological complicatio ns in infliximab treated childhood-onset IBD. This microbial dysregulation may represent an alternative target for a potential therapeutic modulation. The overall results from the various aspects of this thesis could aid in understanding aspects associated with enhancing IBD management.