Background Reported outcomes for colorectal cancer associated with Inflammatory Bowel Disease are inconsistent. We compared survival outcomes in colorectal cancer patients with and without Inflammatory Bowel Disease using a population-based cohort and elicited prognostic factors associated with survival Methods Adult patients with a diagnosis of colorectal cancer in 2007-2015 were identified from the Ontario Cancer Registry. Those with Inflammatory Bowel Disease were detected via the validated Ontario Crohn’s and Colitis Cohort. Primary outcome measure was overall survival from time of colorectal cancer diagnosis until the date of death. Secondary outcome measures included treatments received and publicly-provided health care costs. Results Colorectal cancer was diagnosed in 67,137 with Inflammatory Bowel Disease present in 783 (1.2%). The Inflammatory Bowel Disease-associated colorectal cancer patients were younger at diagnosis (median range 55-59 vs 70-74, p<0.001). Five-year survival in Inflammatory Bowel Disease-associated patients was 56.4% (95% CI 52.6-59.9) and 57.0% (95% CI 56.6-57.4) in sporadic colorectal cancer (p=0.8). Inflammatory Bowel Disease was a significant predictor of death (Hazard Ratio=1.45, 95% CI 1.29-1.63, p<0.001) after adjusting for other variables. In patients under 50, 5-year survival was significantly (p<0.001) reduced in the Inflammatory Bowel Disease population (56.8%, 95% CI 49.4-63.5) compared with the sporadic colorectal cancer population (71.4%, 95% CI 70.0-72.7). Similar results were observed in those 50-64 years old. Conclusion Young patients (<65) with Inflammatory Bowel Disease-associated colorectal cancer have worse survival outcomes than young (<65) patients with sporadic colorectal cancer. These findings inform prognostication and may direct future research for this high-risk population. / Thesis / Master of Science (MSc) / Background Reported outcomes for colorectal cancer associated with Inflammatory Bowel Disease are inconsistent. We compared survival outcomes in colorectal cancer patients with and without Inflammatory Bowel Disease using a population-based cohort and elicited prognostic factors associated with survival Methods Adult patients with a diagnosis of colorectal cancer in 2007-2015 were identified from the Ontario Cancer Registry. Those with Inflammatory Bowel Disease were detected via the validated Ontario Crohn’s and Colitis Cohort. Primary outcome measure was overall survival from time of colorectal cancer diagnosis until the date of death. Secondary outcome measures included treatments received and publicly-provided health care costs. Results Colorectal cancer was diagnosed in 67,137 with Inflammatory Bowel Disease present in 783 (1.2%). The Inflammatory Bowel Disease-associated colorectal cancer patients were younger at diagnosis (median range 55-59 vs 70-74, p<0.001). Five-year survival in Inflammatory Bowel Disease-associated patients was 56.4% (95% CI 52.6-59.9) and 57.0% (95% CI 56.6-57.4) in sporadic colorectal cancer (p=0.8). Inflammatory Bowel Disease was a significant predictor of death (Hazard Ratio=1.45, 95% CI 1.29-1.63, p<0.001) after adjusting for other variables. In patients under 50, 5-year survival was significantly (p<0.001) reduced in the Inflammatory Bowel Disease population (56.8%, 95% CI 49.4-63.5) compared with the sporadic colorectal cancer population (71.4%, 95% CI 70.0-72.7). Similar results were observed in those 50-64 years old. Conclusion Young patients (<65) with Inflammatory Bowel Disease-associated colorectal cancer have worse survival outcomes than young (<65) patients with sporadic colorectal cancer. These findings inform prognostication and may direct future research for this high-risk population.

The gluten-free diet is the only treatment available for gluten-related disorders, such as celiac disease, an autoimmune reaction to gluten, or non-celiac gluten or wheat sensitivity, a symptomatic reaction to wheat or gluten. However, gluten may not be the only culprit, and patients on a gluten-free diet have been suggested to symptomatically improve through the placebo effect, alterations in immune activity, and alterations in gut microbiota composition. It is unclear which of these mechanisms underlie symptoms in gluten-related disorders and well-designed clinical studies are needed to better understand them. This thesis aims to understand the mechanisms and symptomatic responses by which wheat and gluten affect individuals with gluten-related disorders. I hypothesize that patients with gluten-related disorders have increased psychological symptoms and immune reactivity which may be modulated by the gut microbiota. To test this, I conducted a clinical crossover trial to investigate whether whole wheat or gluten triggered symptoms versus gluten-free control, or nocebo, in irritable bowel syndrome patients adopting a gluten-free diet. Participants reacted similarly to each intervention, suggesting a strong 'nocebo effect' to be the main trigger of their symptoms. However, several participants did not comply to the protocol, muddying the results. Subsequent follow-up visits after disclosing personalized study results found no changes in participant beliefs, behaviours, and symptoms, and most remained on a gluten-free diet. Next, a systematic review of 65 observational studies found an elevated risk of IBD in celiac disease and vice versa. Finally, a systematic review of 6 RCTs found limited evidence that probiotics are safe and possibly therapeutic for ameliorating symptoms in celiac disease. Overall, the work presented in this thesis critically assesses the mechanisms by which gluten and wheat trigger symptoms in gluten-related disorders and highlights the importance of rigorous clinical trial design to control for psychological factors and patient compliance. / Thesis / Doctor of Philosophy (PhD) / Gluten, a wheat protein, is commonly associated with the autoimmune condition celiac disease, symptomatic worsening from gluten or wheat in non-celiac gluten/wheat sensitivity, and irritable bowel syndrome. This thesis strove to understand how gluten and other wheat proteins impact symptoms via psychological, immune, and/or bacteria-mediated pathways in gluten-related disorders. A clinical trial tested the effects of whole wheat, gluten, and gluten-free control on symptoms in irritable bowel syndrome patients on a gluten-free diet. We found no differences between interventions but discovered widespread diet non-compliance and that patient fears triggered symptoms. Informing patients of whether wheat, gluten, or gluten-free control triggered their symptoms did not change their dietary beliefs or behaviours. Additionally, two systematic reviews found a relationship between celiac disease and inflammatory bowel disease, and a possible therapeutic effect of probiotics in celiac patients. Our findings provided insights into the content and quality of the clinical evidence for gluten-related disorders.

The mucosal immune system encompasses a wide array of interactions that work in concert to protect an individual from harmful agents while retaining tolerance to molecules, microbes, and self-antigens that present no danger. The upheaval in the regulation-response balance is a critical aspect in both infectious and immune-mediated disease. To understand this balance and methods of its restoration, iterative and integrative modeling cycles on the pathogenesis of disease are necessary. In this thesis, I present three studies highlighting phases of a systems immunology cycle. Firstly, the thesis provides a description of the construction of a computational ordinary differential equation based model on the host-pathogen-microbiota interactions during Clostridium difficile infection and the use of this model for the development of the hypothesis that host-antimicrobial peptide production may correlate with increased disease severity and promote increased recurrence. Secondly, it provides insight into the necessity of trans-disciplinary analysis for the understanding of novel molecular targets in disease through the immunometabolic regulation of CD4+ T cell by NLRX1 in inflammatory bowel disease. Third, it provides the assessment of novel therapeutics in disease through the evaluation of LANCL2 activation in influenza virus infection. In total, the computational and experimental strategies used in this dissertation are critical foundational pieces in the framework of precision medicine initiatives that can assist in the diagnosis, understanding, and treatment of disease. / Ph. D.

<p dir="ltr">Approximately 2.39 million Americans suffer from inflammatory bowel disease (IBD), an autoimmune disorder that is characterized by chronic inflammation of the gastrointestinal (GI) tract. Current treatment options for IBD, which are limited, include oral medications, surgery, and supportive care. These therapeutics often times are not effective and are associated with high toxicity. Thus, there is a pressing clinical need for a therapy that can be delivered both locally and precisely, while also having an improvement in efficacy and lower toxicity.</p><p dir="ltr">This study introduces three novel microrobot designs fabricated using stereolithography (SLA) 3D printing, which aims to address the challenges seen in IBD treatment. The microrobots utilize a reservoir design to encapsulate the drug for an on-demand release, allowing for improved control and precision. The SLA microrobots were evaluated for cytotoxicity as well as drug release capabilities. We were able to demonstrate a local release of a protein on-demand at a biologically relevant temperature. The integration of microrobots in IBD therapy has the capability to significantly improve patient outcomes and quality of life, offering a more efficient and less toxic treatment approach.</p>

Noncanonical NF-KB is an alternative NF-KB pathway that is critically involved in the development and maturation of the adaptive immune system. As such, it has typically been studied in B and T cell biology without application to complex organ systems such as the gut. The following work explores the contribution of noncanonical NF-KB to inflammatory and neoplastic disease in the gastrointestinal (GI) system, as well as the effects of its loss on GI health. Chapter 1 opens with an overview of gastrointestinal homeostasis and inflammation, with emphasis on the particular diseases studied in this body of work. Chapter 2 focuses on a review of noncanonical NF-KB function and components, as well as its applications in inflammatory bowel disease (IBD), a quintessential example of disruption of intestinal homeostasis. In Chapter 3 we determine the role of noncanonical NF-KB in allergic disease of the upper gastrointestinal tract, namely a novel model of the disease eosinophilic esophagitis. Our studies revealed that loss of NF-KB-inducing kinase (NIK), the bottleneck molecule in noncanonical NF-KB signaling, results in targeted esophageal inflammation, remodeling, and gene expression changes that are comparable to the human disease. In Chapter 4, we examine the role of noncanonical NF-KB in inflammatory bowel disease using biopsy samples from human IBD patients, and compare the expression of various components of the pathway to inflammation status and treatment response. Noncanonical NF-KB is upregulated in IBD patients, and also appears to be specifically upregulated in patients that have lost response to anti-TNF inhibitors, which are potent drugs that are widely used to treat IBD. In Chapter 5 we focus on NIK and its effects on stem cell function, growth, and inflammation-induced cancer in the gut. Loss of NIK in mice results in alterations in colonic stem cell function and changes in colonic microbiome, which predisposes them to the development of inflammation-induced carcinogenesis. Indeed, in human patients with colorectal cancer, noncanonical NF-KB is also suppressed. Overall, we have discovered multiple novel roles of noncanonical NF-KB signaling at multiple levels in the gut and in the context of a variety of diseases, and have greatly expanded the current body of knowledge as to the functions and effects of this pathway. / Ph. D. / The gastrointestinal system has a complex set of checks and balances to maintain overall health. If factors involved in the promotion or suppression of inflammation, the regulation of growth, or the prevention of tumor formation become dysregulated, there can be catastrophic consequences for the human body. The aim of this work is to investigate a pathway called noncanonical NF-κB in the development of various diseases in the GI tract. Noncanonical NF-κB is not a well understood pathway and to date has mostly been studied in the context of white blood cell development. However, we discovered that noncanonical NF-κB has several very important functions in the GI tract that have implications in conditions such as inflammatory bowel disease and colorectal cancer. First we explored the role of noncanonical NF-κB in the upper GI tract, namely the esophagus, and found that this signaling pathway is critically involved in the movement of white blood cells called eosinophils to the esophagus, resulting in throat inflammation in both mouse models and human patients. Secondly, we determined that this same pathway also has effects in the lower GI tract. Human patients with inflammatory bowel disease, especially those who develop resistance to popular medications, see an upregulation of this pathway in their colon tissue. Loss of this pathway in the colons of mice also causes changes in growth of the colonic epithelium, and predisposes them to the formation of colon cancer. Interestingly, in human colon cancer patients, we also see similar changes in expression of genes associated with this pathway. Overall, we have found many new and exciting roles for this underappreciated pathway in the gut.

Machine learning can provide insight and support for a variety of decisions. In some areas of medicine, decision-support models are capable of assisting healthcare practitioners in making accurate diagnoses. In this work we explored the application of these techniques to distinguish between two diseases in veterinary medicine; inflammatory bowel disease (IBD) and alimentary lymphoma (ALA). Both disorders are common gastrointestinal (GI) diseases in humans and animals that share very similar clinical and pathological outcomes. Because of these similarities, distinguishing between these two diseases can sometimes be challenging. In order to identify patterns that may help with this differentiation, we retrospectively mined medical records from dogs and cats with histopathologically diagnosed GI diseases. Since the pathology report is the key conveyer of this information in the medical records, our first study focused on its information structure. Other groups have had a similar interest. In 2008, to help insure consistent reporting, the World Small Animal Veterinary Association (WSAVA) GI International Standardization Group proposed standards for recording histopathological findings (HF) from GI biopsy samples. In our work, we extend WSAVA efforts and propose an information model (composed of information structure and terminology mapped to the Systematized Nomenclature of Medicine - Clinical Terms) to be used when recording histopathological diagnoses (HDX, one or more HF from one or more tissues). Next, our aim was to identify free-text HF not currently expressed in the WSAVA format that may provide evidence for distinguishing between IBD and ALA in cats. As part of this work, we hypothesized that WSAVA-based structured reports would have higher classification accuracy of GI disorders in comparison to use of unstructured free-text format. We trained machine learning models in 60 structured, and independently, 60 unstructured reports. Results show that unstructured information-based models using two machine learning algorithms achieved higher accuracy in predicting the diagnosis when compared to the structured information-based models, and some novel free-text features were identified for possible inclusion in the WSAVA-reports. In our third study, we tested the use of machine learning algorithms to differentiate between IBD and ALA using complete blood count and serum chemistry data. Three models (using naïve Bayes, neural networks, and C4.5 decision trees) were trained and tested on laboratory results for 40 Normal, 40 IBD, and 40 ALA cats. Diagnostic models achieved classification sensitivity ranging between 63% and 71% with naïve Bayes and neural networks being superior. These models can provide another non-invasive diagnostic tool to assist with differentiating between IBD and ALA, and between diseased and non-diseased cats. We believe that relying on our information model for histopathological reporting can lead to a more complete, consistent, and computable knowledgebase in which machine learning algorithms can more efficiently identify these and other disease patterns. / Ph. D.

Background and aims: This interdisciplinary thesis was designed to deepen understanding of the co-morbidity of anxiety and depression with chronic diseases of the digestive tract, and inflammatory bowel disease (IBD) in particular. The first part of the thesis aimed to explore the prevalence of psychological problems in IBD compared to irritable bowel syndrome (IBS) and chronic hepatitis C (HCV) groups. It also explored the relationship between the number of co-morbid functional gastrointestinal disorders and the severity of psychological problems in IBD and IBS. It also aimed to determine whether there is a relationship between psychological problems and the response to standard medical treatment/physical outcomes in patients with IBD, IBS and HCV. Furthermore, it aimed to explore whether disclosure of the psychological status of depressed and/or anxious IBD patients to their gastroenterologists influences doctors’ behaviour and affects patients’ responses to treatment/physical outcomes. The second part of the thesis aimed to investigate the potential role of antidepressants in IBD and to determine the feasibility of future randomised controlled trials on the role of antidepressants in IBD. Methods: Overall, a cohort of 139 outpatients (64 IBD, 41 HCV, and 34 IBS) and 18 gastroenterologists participated in the six studies comprising this thesis. A mixed methods design was applied. Two cross-sectional studies, an observational cohort prospective management study, a randomised controlled trial, a systematic review and an exploratory interview study were conducted. Differences between the groups for continuous variables were assesed with one way analysis of variance (ANOVA) and independent samples ttests. Differences in categorical variables were assessed with contingency tables with the Chi-Square test and the Fisher’s Exact Test. Propsective analyses were conducted with repeated measures ANOVA, logistic regression and Poisson regression. Qualitative data were analysed using content analysis. Results: Overall, 42% of participants were anxious and 19% were depressed. Participants with HCV had higher levels of psychological impairment compared with the IBS, the IBD group and the general population (p<0.05). Those IBD participants with fewer co-morbid functional disorders had better physical quality of life than participants with a greater number of these disorders (p=0.025). Moreover, depression/anxiety at baseline did not explain medical outcomes after 12 months in this cohort of patients with chronic diseases of the digestive tract. Doctors’ knowledge of patients’ psychological status was found to have no impact on IBD patients’ outcomes after 12 months. However, interestingly, the level of anxiety in IBD participants significantly dropped between the baseline and nine months indicating a possible benefit from participating in the study. In the literature review, insufficient evidence was found to conclude that antidepressants are efficacious for treatment of psychological co-morbidities or somatic complaints in IBD. However, the qualitative interview study indicated a potential positive impact of treatment with antidepressants on coping with disease symptoms and general wellbeing in patients with IBD. Conclusion: The thesis confirms that there is a significant burden of psychological co-morbidity in patients with chronic gastroenterological diseases. Interdisciplinary approaches to the management of these diseases are therefore warranted in Australian gastroenterology clinics. Anxiety targeted interventions and research in this setting are urgently needed, especially with respect to patients with HCV. Larger studies exploring the gastroenterologists’ role in treatment of co-morbid psychological problems in their patients are recommended. Longer prospective studies on homogenous samples of patients are also needed to clarify the nature of the relationship between psychological problems and relapse of somatic symptoms. Finally, randomised controlled trials exploring the efficacy of antidepressants in IBD are warranted. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1321006 / Thesis (Ph.D.) -- University of Adelaide, School of Population Health and Clinical Practice, 2008

Bakgrund: Avföringsproblemen förstoppning, avföringsinkontinens och irritabel tarm är vanliga åkommor hos människor i det västerländska samhället. Alla tre har liknande symtom och problematik. Åkommorna påverkar hela människan inte bara den fysiska kroppen. Få studier har fokuserat på människors upplevelse av att leva med avföringsproblem. Syfte: Syftet med litteraturstudien var att beskriva hur människor med avföringsproblem upplever sin livssituation. Metod: Studien var baserad på tio vetenskapliga artiklar med kvalitativ ansats. Resultat: Studien resulterade i tre huvudteman; upplevelsen av det egna lidandet, upplevelsen av det dagliga livet och upplevelsen av relationer med åtta underteman. Resultatet visade att människor som lider av avföringsproblemen förstoppning, irritabel tarm och avföringsinkontinens upplevde att hela deras livssituation påverkades av avföringsproblemen. Hela människan drabbades psykiskt, emotionellt, fysiskt och socialt. Människorna var tvungna att leva ett liv fullt av dagliga begränsningar. Slutsats: Att leva med avföringsproblem innebar för människorna att vara involverad i en evig kamp som de ofta var ensamma i. Resultatet indikerar på att avföringsproblem är ett dolt problem och tystnaden kring problemen gör att många människor inte får den hjälp och stöd som de behöver. / Background: Bowel movement problems as constipation, faecal incontinence and irritable bowel syndrome are common problems in the community. All three has similar symptoms and the same complex of problems. The disorders affect the whole human being not just the physical body. Few studies have been focusing on peoples experiences of living with bowel movement problems. Aim: The aim of this literature study was to describe how people with bowel movement problems experienced their life situation. Method: The study was based on ten scientific articles in qualitative approach. Results: The study resulted in three main themes; the experience of the own suffering, the experience of the daily life and the experience of relations with eight subthemes. The result showed that people suffering from bowel movement problems as constipation, irritable bowel syndrome and faecal incontinence experienced that their whole life situation was affected by the problems. The whole human being was affected psychological, emotional, physical and social. These people had to live a life full of daily restrictions. Conclusion: A life with bowel movement problems meant being involved in an everlasting fight, which they often fought alone. The result indicates that bowel movement problems are a hidden problem in the community and because of the silence many people does not get the help and support that they need.

Inflammatory bowel disease (including Crohn’s disease and ulcerative colitis) and coeliac disease are debilitating gastrointestinal diseases that seriously affect the quality of life of those affected. Under normal circumstances, the intestinal immune system is maintained in a state of controlled inflammation, whereby balance exists between protective immunity, mediated by effector cells, and tolerance mediated by cells with regulatory function. However, an aberrant immune response is believed to contribute to the intestinal inflammation present in individuals afflicted by these diseases. This thesis investigated the involvement of CD4⁺ CD25[superscript]high Foxp3⁺ Regulatory T cells (Treg) and Th17 Effector cells in both inflammatory bowel disease (IBD) and coeliac disease. The reciprocal relationship between Treg and Th17 cells under certain cytokine conditions, has prompted the exploration of these two cell types in IBD and coeliac disease. Previous studies have examined these factors individually in a range of diseases, however, to our knowledge the study of both Treg and Th17 in IBD and coeliac disease subjects represents a novel area of research. Crohn’s disease (CD), ulcerative colitis (UC) and coeliac disease subjects were recruited through the Department of Gastroenterology and Hepatology at The Queen Elizabeth Hospital (QEH) in Adelaide, South Australia. In total, one-hundred and seventeen subjects were enlisted in this study to donate blood samples. In addtion, intestinal biopsy samples were collected from fifty-six subjects undergoing colonoscopy at the QEH Department of Gastroenterology and Hepatology. All subjects participated, with informed consent and ethics approval. Treg and Th17 cell numbers were investigated in the peripheral blood of Crohn’s disease, ulcerative colitis, coeliac disease and control subjects using multi-colour, intracellular flow cytometry. A decrease in Treg cell numbers and an increase in Th17 cell numbers was observed in IBD, but not in coeliac disease. Closer investigation into the ratio of Treg and Th17 cells within patients identified a near 1:1 Treg/Th17 ratio in control subjects, but a lower Treg/Th17 ratio in IBD patients. This suggested a disturbance in regulatory and effector cell equilibrium. Furthermore, the excess of Th17 cells and deficiency of Tregs could contribute to the pathologies observed in IBD. The discovery of an imbalance in Treg and Th17 cell numbers in IBD prompted further investigation of these cells in intestinal biopsies collected from IBD, coeliac and control subjects. Real time RT-PCR of intestinal biopsy samples demonstrated increased expression of the Th17 cytokine, IL-17a, in both IBD and coeliac disease. Elevated levels of the Treg transcription factor Foxp3 were also identified in intestinal biopsies from IBD subjects. It was therefore hypothesised that Treg cells may have been actively recruited from the periphery in an attempt to control inflammation in the gut; however, the intestinal cytokine microenvironment may have restricted the regulatory function of these cells. Cytokines known to promote human Th17 differentiation, namely IL-1β, IL-6, TGF-β, IL-21 and IL-23, were explored in intestinal biopsy samples from IBD, coeliac and control subjects. High levels of IL-1β and IL-6 were detected in IBD patient samples, however, no change in levels of IL-21 or IL-23 were observed in IBD or coeliac disease subjects. Elevated levels of TGF-β were only identified in UC. No changes in cytokine expression were observed between control and coeliac subjects, except a significant decrease in IL-6 levels was identified in coeliac disease sufferers. The pro-inflammatory microenvironment identified in intestinal biopsies from IBD subjects may have promoted the continual differentiation and development of Th17 cells, whilst restricting Treg activity. Moreover, the observed deficiency of Treg in IBD patients may have impaired the ability of the immune system to limit excessive pathogenic Th17 driven immune responses in the intestinal mucosa. Therefore, therapeutic approaches that aim to re-establish regulatory and effector cell homeostasis by increasing Treg numbers in IBD patients, and specifically targeting Th17 cells, may prove effective in the treatment of IBD. Approaches such as these could provide greater focus to treatment strategies for IBD management compared to current broad-spectrum immunosuppressive therapies that could increase susceptibility to cancer or infection in IBD patients. In addition, the imbalance of regulatory and effector cells demonstrated in the peripheral blood of IBD patients may potentially provide new options for a noninvasive diagnostic tool. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1457580 / Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 2009

Background and aims: This interdisciplinary thesis was designed to deepen understanding of the co-morbidity of anxiety and depression with chronic diseases of the digestive tract, and inflammatory bowel disease (IBD) in particular. The first part of the thesis aimed to explore the prevalence of psychological problems in IBD compared to irritable bowel syndrome (IBS) and chronic hepatitis C (HCV) groups. It also explored the relationship between the number of co-morbid functional gastrointestinal disorders and the severity of psychological problems in IBD and IBS. It also aimed to determine whether there is a relationship between psychological problems and the response to standard medical treatment/physical outcomes in patients with IBD, IBS and HCV. Furthermore, it aimed to explore whether disclosure of the psychological status of depressed and/or anxious IBD patients to their gastroenterologists influences doctors’ behaviour and affects patients’ responses to treatment/physical outcomes. The second part of the thesis aimed to investigate the potential role of antidepressants in IBD and to determine the feasibility of future randomised controlled trials on the role of antidepressants in IBD. Methods: Overall, a cohort of 139 outpatients (64 IBD, 41 HCV, and 34 IBS) and 18 gastroenterologists participated in the six studies comprising this thesis. A mixed methods design was applied. Two cross-sectional studies, an observational cohort prospective management study, a randomised controlled trial, a systematic review and an exploratory interview study were conducted. Differences between the groups for continuous variables were assesed with one way analysis of variance (ANOVA) and independent samples ttests. Differences in categorical variables were assessed with contingency tables with the Chi-Square test and the Fisher’s Exact Test. Propsective analyses were conducted with repeated measures ANOVA, logistic regression and Poisson regression. Qualitative data were analysed using content analysis. Results: Overall, 42% of participants were anxious and 19% were depressed. Participants with HCV had higher levels of psychological impairment compared with the IBS, the IBD group and the general population (p<0.05). Those IBD participants with fewer co-morbid functional disorders had better physical quality of life than participants with a greater number of these disorders (p=0.025). Moreover, depression/anxiety at baseline did not explain medical outcomes after 12 months in this cohort of patients with chronic diseases of the digestive tract. Doctors’ knowledge of patients’ psychological status was found to have no impact on IBD patients’ outcomes after 12 months. However, interestingly, the level of anxiety in IBD participants significantly dropped between the baseline and nine months indicating a possible benefit from participating in the study. In the literature review, insufficient evidence was found to conclude that antidepressants are efficacious for treatment of psychological co-morbidities or somatic complaints in IBD. However, the qualitative interview study indicated a potential positive impact of treatment with antidepressants on coping with disease symptoms and general wellbeing in patients with IBD. Conclusion: The thesis confirms that there is a significant burden of psychological co-morbidity in patients with chronic gastroenterological diseases. Interdisciplinary approaches to the management of these diseases are therefore warranted in Australian gastroenterology clinics. Anxiety targeted interventions and research in this setting are urgently needed, especially with respect to patients with HCV. Larger studies exploring the gastroenterologists’ role in treatment of co-morbid psychological problems in their patients are recommended. Longer prospective studies on homogenous samples of patients are also needed to clarify the nature of the relationship between psychological problems and relapse of somatic symptoms. Finally, randomised controlled trials exploring the efficacy of antidepressants in IBD are warranted. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1321006 / Thesis (Ph.D.) -- University of Adelaide, School of Population Health and Clinical Practice, 2008