Medicine (St Vincent's) - Theses

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    Immunological and microbiological studies in post-operative Crohn's disease
    Hamilton, Amy Louise ( 2017)
    Crohn’s disease is a chronic, inflammatory condition of the bowel. The aetiology of Crohn’s has not been fully elucidated, but is believed to arise from the interaction between the gut microbiota, the host immune system and environmental factors. A majority of Crohn’s disease patients will require a bowel resection as a result of disease, which causes significant morbidity and impacts on quality of life. While surgery can ameliorate clinical symptoms, the disease often initially recurs at the site of the resection. This may be sub-clinical initially, and can be identified endoscopically. This thesis investigates the immunological and microbiological characteristics of post-operative Crohn’s disease recurrence in, addressing serologic markers, the faecal microbiome and the possible contribution of Proteus species to gastrointestinal disease. Serologic markers, while disappointing for prediction of disease recurrence, did have some utility for identifying patients at the highest risk of disease recurrence. I also demonstrated lower rates of antibody positivity in Crohn’s patients who smoke for the first time, indicating that these results should be interpreted with caution in current and past smokers. I have further evaluated the faecal microbiome in the setting of post-operative disease using metagenomic techniques. This work showed that after resection for Crohn's disease, enrichment of the bacterial family Lachnospiraceae is associated with maintenance of disease remission, while patients enriched for the Enterobacteriaceae are more likely to recur. Recurrence may result from a higher abundance of enteric pathobionts such as Proteus, Klebsiella, Serratia, and Escherichia. The Lachnospiraceae are an important family of butyrate producing bacteria in the gut, and depletion of this bacterial family may perpetuate the expansion of Enterobacteriaceae via environmental perturbation and ecologic shifts. These findings indicate possible protective and pathogenic bacteria in post-operative recurrence. Finally, I addressed the potential contribution of Proteus species (from the Enterobacteriaceae family) to gastrointestinal diseases including to inflammatory bowel disease. Proteus spp. are low-abundance commensals of the human gut that harbour significant pathogenic potential. Preliminary evidence of a pathogenic role in the gut should stimulate further investigation. I have elucidated some aspects of the microbiome and host immune factors involved, in the pathophysiology of post-operative Crohn’s disease recurrence. This work should encourage further work on a unifying hypothesis for the aetiology of disease recurrence after resectional surgery for Crohn’s disease.
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    Clinical and scientific features of post-operative Crohn's disease recurrence
    Wright, Emily Kate ( 2016)
    Crohn’s disease is a chronic relapsing inflammatory condition, primarily affecting the gut. It is associated with a significant reduction in health-related quality of life and significant healthcare costs. Up to 80% of patients will require surgery at some point in their life, but this is not curative, with Crohn’s disease recurring in most patients. The pathophysiology of Crohn’s disease relates to the mucosal immune response to antigenic stimulation of the gut microbiota, on a background in some patients of genetic susceptibility. “Dysbiosis” of the gastrointestinal microbiota has been implicated in the cause of Crohn’s disease but how the microbiota behaves in the post-operative state has not been examined in detail. This thesis involves a range of clinical and scientific studies that are part of the Post-operative Crohn’s Endoscopic Recurrence (POCER) platform of studies. These studies aimed to characterise the optimal management for patients after intestinal resection, with a view to preventing disease recurrence. My work has involved scientific studies aimed at identifying key microbial elements that may play a central role in recurrent disease, and further studies addressing optimised clinical management. I have studied gut tissue from patients taken longitudinally from the time of surgery till 18 months post-operatively, and from surgical and healthy controls. Using molecular microbial sequencing techniques I have defined a microbial profile associated with endoscopic recurrence of Crohn’s disease, identifying a novel association between the Proteus genus and recurrence. I have also confirmed that the presence of Faecalibacterium pruausnitzii is associated with a lesser rate of recurrence. Lastly I have shown that smoking, known to increase the rate of recurrence, is associated with a specific bacterial profile. The role of therapeutic monitoring of anti-tumour necrosis factor (TNF) drugs in the post-operative setting has been defined. Blood levels of anti-TNF drugs do not explain why the disease sometimes recurs on these medications. I have evaluated how the faecal biomarkers calprotectin, lactoferrin and S100A12 can be used to diagnose the presence and severity of post-operative Crohn’s disease recurrence. I have shown that calprotectin is a reliable marker of disease recurrence, and can be used as a substitute for colonoscopy. The effects of surgery, immunosuppression, routine early colonoscopy and disease activity on health-related quality of life and healthcare costs in the post-operative period have also been explored in this large and well-characterised post-operative cohort. This series of studies on post-operative Crohn’s disease treatment, monitoring and pathophysiology hold the prospect of changing the paradigm of post-operative care. They may also provide insights in the cause of disease recurrence.