Understanding the role of infections in the pathogenesis of inflammatory bowel disease, and improving the quality and safety of treatment

Abstract

Inflammatory bowel disease (IBD), comprising Crohn’s disease and ulcerative colitis are chronic inflammatory diseases of the gastrointestinal tract. These conditions cause significant morbidity and reduced quality of life in patients who are often young. The pathogenesis of IBD is uncertain, however the current paradigm is that mucosal inflammation is caused by a dysfunctional interaction between the innate immune system and the bacterial microbiota within the gastrointestinal tract. Single nucleotide polymorphisms (SNPs) of genes related to innate immunity such as pattern recognition receptors, mucosal barrier and autophagy are likely to play an important role.

Despite the potential role of altered innate immunity, the mainstay of treatment of inflammatory bowel disease is immunosuppressive medications. This includes thiopurine drugs, which affect lymphocyte function, and monoclonal antibody therapy based on inhibition of tumour necrosis factor α. Although often effective, these medications have the potential to increase the risk of infections and malignancy.

This thesis examines the role of infections in inflammatory bowel disease, initially assessing the role of the bacterial microbiota through analysis for the putative pathogen Mycobacterium avium subspp. paratuberculosis, and attempts to correlate these findings with a multiplex analysis of SNPs previously associated with IBD. The microbiota is then analysed more broadly using a metagenomic type approach with a custom phylogenetic oligonucleotide microarray based on 16s ribosomal RNA probes.

Approaches to improving quality and safety in IBD are then examined. A survey of Australian gastroenterologists in relation to screening for latent infections and vaccination, with respect to immunomodulators and monoclonal antibody therapies was carried out and discussed. A comprehensive audit of the use of infliximab, an anti-TNF α agent at a tertiary metropolitan hospital was undertaken. A novel electronic clinical decision support system was designed with the aim of improving the clinical governance related to these agents, and the impact of this system was examined. A study to assess the use of pharmacogenetics and measurement of thiopurine metabolites to improve the safety of thiopurine use was conducted in addition.