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Inflammatory bowel disease (IBD) is a lifelong relapsing/remitting condition. Early diagnosis and treatment can have a considerable impact on disease course and quality of life. Traditionally, IBD is managed in a specialist outpatient setting, however outpatient review may not always coincide with times of greatest need. The growth of eHealth technology has led to the development of new interactive self-management websites or 'portals' which allow remote self- monitoring and communication between patients and health providers. New diagnostic technologies for IBD are also becoming increasingly available. Faecal calprotectin (FC) testing can sensitively detect bowel inflammation and is used to aid diagnosis of IBD and predict disease flare in existing IBD. Recently, home-testing kits have been developed which, combined with a smartphone app, can provide rapid assessment of IBD activity. The aim of this thesis is to present three projects which explore the development and use of new diagnostic and self-management technologies to enhance the traditional IBD outpatient pathway: piloting the use of FC testing in primary care and its impact upon general practitioners' plans to refer, assessing the feasibility and acceptability of using the My Medical Record (MyMR) digital patient portal and home FC testing for disease monitoring in patients who have stopped a treatment for IBD, and developing a digital Virtual Clinic for remote follow-up of more stable patients. These projects were informed by a systematic review of the literature exploring if interactive digital self-management interventions improve patient outcomes for IBD. The primary care pilot study confirmed the clinical utility of FC testing as a screening tool when differentiating IBD from irritable bowel syndrome (IBS). It was observed that a negative calprotectin appeared to reverse a significant proportion of initial GP plans to refer to secondary care. In the feasibility study, recruitment was challenging but qualitative work demonstrated that home monitoring using MyMR and FC testing was acceptable and provided significant reassurance to a potentially vulnerable group of patients at greater risk of disease flare. A novel fully digital Virtual IBD clinic was established to oversee monitoring and support for more stable IBD patients. Normalisation Process Theory helped to reflect on barriers and facilitators to developing and implementing this new technology, particularly the need for greater engagement of key clerical and nursing stakeholders in the project. These studies explore how both FC and supported self-management via a digital portal have the potential to modernise and enhance key areas in the IBD patient pathway from diagnosis through to monitoring, but also highlight the challenges of implementing new technologies into established models of care.

The inflammatory bowel diseases, Crohn's disease (CD) and Ulcerative colitis (UC) are chronic relapsing remitting inflammatory diseases of the gastrointestinal tract. Over the last 20 years significant advances in the scientific understanding of these complex diseases has been made and several new pharmacological therapies with new mechanisms of action are now available. It is accepted that the inflammatory bowel diseases result from a complex interaction between environmental factors, host genetics, the immune system responses and the intestinal microbiota. Evidence from genetic, animal and human studies have identified a key role for the innate immune system in the pathogenesis of these diseases. Although several mouse studies have implicated mechanisms by which intestinal macrophages may be involved in inflammatory bowel disease pathogenesis, data from humans with the disease is sparse. In this study we have recruited patients with ulcerative colitis and colonic Crohn's disease as well as a group of health controls. In these patients we have isolated intestinal tissue macrophages and subjected the RNA from these cells to high throughput RNA-Seq. We have demonstrated that the gene expression profiles of the IBD macrophages are profoundly altered. We have found that in IBD patients the macrophages promote inflammation, recruitment of T-cells through the release of chemokines such as CXCL9 & CXCL10 and that cellular metabolic process are down regulated in these cells. We were able to show that although the macrophages from UC and CD have similar gene expression there are important differences such as expression of the M2 phenotype, up-regulation of pathways associated with fibrosis and granuloma formation in CD but not the UC macrophages.

A STUDY OF THE ROLE OF MICRORNAS IN INFLAMMATORY BOWEL DISEASE: THE EFFECT OF MIR-31 DYSREGULATION IN THE EXPRESSION OF TSLP IN ULCERATIVE COLITIS By Andrew Cia ridge Our current understanding suggests that Inflammatory Bowel Disease (lBD) is an immunological mediated disease triggered by unknown environmental factors in those who are genetically susceptible. MicroRNAs (miRNAs) are a class of small non coding RNAs that play a critical role in many immunological pathways by regulating gene expression. To date over 70 miRNAs have been identified as having a differential expression in IBD although their roles remain unlmown. Using microarray and RT-qPCR we have identified the differential expression of 7 miRNAs; miR-31, -146b, -194, -200b, -223, -375 and -422a, in the sigmoid mucosa of treatment na'ive Ulcerative Colitis. Of these, the expressions of miR-31 and -223 are also increased in mucosal Iymphocytes and the CD4+CD25in •• rm.dia •• subfamily. Using in silica analysis, thymic stromal Iymphopoietin (TSLP) is identified as a target for 4 of the 7 miRNAs; miR-31, -223, -194 and -422a. TSLP has been shown to be increased in TH2 mediated disorders of the lung and skin and implicated in epithelial barrier homeostasis and Iymphocyte function in response to luminal flora. Here we show for the first time the expression of TSLP by healthy Iymphocytes and a decreased expression in mucosal biopsies and mucosal Iymphocytes in active uc. In addition, using a human Iymphocyte cell model we demonstrate an increased expression of miR-31 in stimulated Iymphocytes which is inversely related to a decreased expression of TSLP mRNA and an even larger Abstract effect on the expression of TSLP protein in the same cells. Selective inhibition of miR-31 prevents the decrease in TSLP in stimulated Iymphocytes. The increased expression of miR-31 in UC actively decreases the expression of TSLP, a factor associated ' with epithelial homeostasis and less destructive inflammation. Manipulation of the miR-31 / TSLP pathway offers a potential therapeutic strategy for uc.