Introduction: Early growth response 1 (EGR1) is a zinc-finger transcription factor involved in the regulation of cell growth. It can act as either a tumour suppressor or a tumour promoter with a role in the induction of apoptosis in cancer cells by various pathways and is likely to play a role in colorectal cancer (CRC). EGR1 also appears to play a significant role in inflammatory pathways, therefore a possible role in Inflammatory Bowel Disease (IBD) is hypothesised. Patients with IBD have a greater risk of developing CRC, which is increased with duration of symptoms and severity of inflammation and dysplasia. The aim of this study is to determine whether EGR1 is differentially expressed in diseased colon tissue and to investigate novel EGR1-protein interactions in CRC cell lines. Methods: The relative EGR1 expression in CRC cell lines and in normal mucosa and tumours of colorectal cancer patients was determined by qRT-PCR. IBD patient samples were also examined for differential EGR1 expression levels by qRT-PCR, before and after stimulation with inflammatory mediators. Statistical analysis of the data was performed using ‘R’ statistical package, with the mixed-model ANOVA. Statistical significance was set at < 0.05. The genotype of three EGR1 variants was determined in the samples using PCR and sequencing, and the methylation status of regions of the EGR1 promoter was determined using bisulfite sequencing. A yeasttwo hybrid screen was conducted with EGR1 as bait, and screened against a SW480 CRC cell line library. Interesting novel interactions were investigated using immunocytochemistry and immunoprecipitation, as was the novel interaction between EGR1 and NOD2 and between EGR1 and components of the cytoskeleton. Results: Investigation into the relative EGR1 mRNA expression in CRC has shown that there is differential expression of EGR1 between matched normal mucosa and tumour. EGR1 expression is decreased in IBD patients compared with healthy controls. Induction of EGR1 by inflammatory stimuli also appears to be aberrant in these patients. The differential expression of EGR1 was not associated with aberrant methylation of a large region of the EGR1 promoter in either the CRC or IBD patients or with the genotype of EGR1 variants. EGR1 localises to both the cytoplasm and the nucleus in CRC cell lines and this study demonstrate interactions with the IBD susceptibility protein NOD2 and with components of the cyotskeleton. A yeast-two hybrid screen conducted with EGR1 as bait using a CRC cell line library has identified several other novel protein interactions of EGR1 in CRC cell lines. Conclusion: EGR1 is differentially expressed in both CRC and IBD, and in the case of IBD shows aberrant activity, suggesting that EGR1 may play a role in both colorectal diseases. EGR1 interacts with the IBD protein NOD2, and components of the cytoskeleton in CRC cells. Several novel protein interactions with EGR1 have been identified and warrant further study.

Fecal microbiota transplantation (FMT) is the process by which fecal suspension from a healthy individual is transferred into the gastrointestinal tract of another individual in an attempt to cure certain diseases. This transplantation process has been accredited as being a potential remedy for a growing number of diseases that have been associated with gut microbial imbalances. Interest in FMT has largely been driven by the science community’s increasing interest in the gut microbiome and its role in potentially regulating a multitude of different functions and processes within the human body. One disease that has been found to respond exceptionally well to FMT treatments is Clostridium difficile infection (CDI). However, while FMT has demonstrated high cure rates for CDI, this transplantation process is no panacea. In fact, the results from FMT treatments on other diseases, such as Inflammatory Bowel Disease (IBD), have not been as impressive as CDI’s. This review will examine the existing literature surrounding FMT usage on IBD and will propose a series of experiments and studies needed to truly test the safety and efficacy of FMT for IBD patients. This review will also reference current literature documenting FMT treatments for CDI as a comparative tool for investigating if this form of bacteriotherapy is indeed a viable therapeutic option for treating IBD.

Peritoneal adhesions occur in up to 93% of adults after peritoneal trauma during surgery. Most adhesions are asymptomatic but can cause female infertility, small bowel obstruction (SBO) and chronic abdominal pain. Adhesion prophylaxis is needed to reduce the significant morbidity and increased health care costs resulting from peritoneal adhesions. This thesis aims to establish a relevant and reproducible experimental adhesion model to simultaneously study the healing processs and adhesion formation and later to examine whether carbazate-activated polyvinyl alcohol (PVAC), an aldehyde-carbonyl scavenger, can reduce adhesion formation or not; and, in a long-term follow-up, to investigate the incidence of and identify risk factors for adhesive SBO requiring surgical treatment after laparotomy during infancy and to survey the prevalence of self-reported chronic abdominal pain and female infertility. Male Sprague-Dawley rats were subjected to laparotomy, cecal abrasion, and construction of a small bowel anastomosis and examined at various time points after surgery. Early elevation of IL-6, IL-1β and TNF-α concentrations in peritoneal fluid but not in plasma correlate to adhesion formation in this rodent adhesion model, indicating that anti-adhesion treatment should be early, local and not systemic. The animals were treated with either peritoneal instillation of PVAC, or the anastomosis was sutured with PVAC-impregnated resorbable polyglactin sutures. At day 7, bursting pressure of the anastomosis was measured and adhesions were blindly evaluated using Kennedy- and Nair scoring systems. PVAC-impregnated sutures reduced adhesion formation without reducing bursting pressure. Infants who underwent laparotomy between 1976 and 2011 were identified (n=1185) and 898 patients were included with a median follow-up time of 14.7 (range 0.0-36.0) years. The median age at first laparotomy was 6 (range 1.0-365.0) days. There were 113 patients (12.6%) with adhesive SBO, with the highest incidence found in patients with Hirschsprung’s disease (19 of 65, 29%), malrotation (13 of 45, 29%), intestinal atresia (11 of 40, 28%) and necrotizing enterocolitis (16 of 64, 25%). Lengthy duration of surgery (hazard ratio (HR) 1.25, 95% CI, 1.07 to 1.45), stoma formation (HR 1.72, 1.15 to 2.56) and postoperative complications (HR 1.81, 1.12 to 2.92) were independent risk factors. Chronic abdominal pain was reported in 180 (24.0%) of 750 patients, and 17 (13.8%) of 123 women reported infertility. The morbidity after laparotomy in neonates and infants is high. Awareness of the risk factors may promote changes in surgical practice.

Aryl Hydrocarbon Receptor (AhR) is a ligand-actviated receptor known as the dioxin receptor. Environmental pollutants called dioxin-like toxicants are found in food, cigarette smoke, automobile exhaust and air. Therefore, they could chronically amplify the pathology of numerous chronic inflammatory diseases. AhR is a well known target of these environmental chemicals that disrupt endocrine signaling. By the year 2020, the number of people older than 60 years is expected to top 1 billion. The burden of treating chronic disease is significant both in dollars spent and in lost productivity. The need to identify risk factors for chronic diseases must be evaluated along with diet and lifestyle factors that will promote healthy aging. The studies presented in this dissertation tested the hypothesis that habitual exposure to dioxin-like contaminants contributes to chronic inflammatory disease states through activation of AhR pathway. Due to their lipophilicity, dioxin like toxicants (like PCB 77) accumulated in mice' visceral adipose tissue and induced adipocytes maturation and ectopic fat deposition. Exposure to persistent organic pollutants, such as polychlorinated biphenyls (PCB 77) can cause endothelial cells activation and inflammation by inducing pro-inflammatory signaling pathways. In our studies, PCB 77 had cumulative effects in Angiotensin II - induced Abdominal Aortic Aneurysm (AAA) by exacerbating inflammation in and around the aortic wall. More, PCB 77 increased mortality in mice that developed AAA. In order to appreciate the AhR involvement in inflammation we used a mouse model of Inflammatory Bowel Disease(IBD). Mice that had a reduced Ahr Receptor expression developed a less severe colitis and had a decreased general inflammatory status. These data provide evidence that exposure to environmental toxicants could augment inflammation and contribute to the social burden of obesity and obesity related chronic inflammatory diseases.

Introduction: Inflammatory pouch complications, including pouchitis, chronic pouchitis (CP) and a Crohn’s disease-like phenotype (CDL) of the pouch following ileal pouch-anal anastomosis (IPAA), are relatively common, and arise via unknown mechanisms. The phenotypic similarities between pouch inflammation and inflammatory bowel disease (IBD) suggest there may be common pathways involved in both disorders. The aim of this thesis is to investigate the serological, genetic and microbial factors contributing to the development of pouch inflammation in a large, well characterized patient cohort. Methods: Subjects with IPAA were recruited, and clinical and demographic information was obtained through medical chart review and patient questionnaire, allowing patients to be grouped based on post-surgical phenotype. Blood and tissue was collected for genetic, serological and microbial analyses. Anti-microbial antibodies were detected using enzyme-linked immunosorbent assay (ELISA), genotyping was carried out using the Illumina Goldengate custom SNP assay and Sequenome iPLEX platform, and tissue-associated microbial communities were assessed using 454 pyrosequencing. Results: Among our cohort, smoking was associated with CDL (P=0.003) and Ashkenazi Jewish heritage with CP (P<0.008). NOD2insC (rs2066847) (P=7.4x10-5), anti-CBir1 (P<0.0001) and ASCA (IgG) (P=0.03) were significantly associated with inflammatory pouch outcomes. Additional SNPs in NOX3, DAGLB, and NCF4 were also marginally associated with pouch outcome. A multi-variable risk model combining clinical, serologic and genetic markers was constructed and could differentiate between chronic pouch inflammatory phenotypes and no pouchitis. Genus level microbial analysis demonstrated that several organisms (Bacteroides, Parabacteroides, Blautia and Moryella) were detected less frequently among the inflammatory outcome groups (P<0.05). These associations remained significant even following adjustment for antibiotic use, smoking, country of birth and gender. Conclusions: CD-associated anti-microbial antibodies and genetic markers are associated with chronic inflammatory pouch phenotypes. Additionally, changes in the composition of the pouch associated microbiome are associated with inflammation. These observations suggest that similar mechanisms may be involved in non-surgical IBD and pouchitis.

Background and objectives: Physical fitness and stress resilience may influence the risk of gastrointestinal (GI) disease. High physical fitness level may reduce levels of systemic inflammation while psychosocial stress exposure can increase inflammation levels and intestinal permeability. The main objectives are to evaluate if poorer physical fitness and stress resilience in adolescence are associated with a raised risk of inflammatory bowel disease (IBD), peptic ulcer disease (PUD) and GI infections in adulthood and to assess evidence of causality. Materials and methods: Swedish registers provided information on a cohort of approximately 250,000 men who underwent military conscription assessments in late adolescence (1969 –1976) with follow-up until December 2009 (up to age 57 years). Cox regression evaluated the associations of physical fitness and stress resilience in adolescence with subsequent GI disease risk in adulthood. Results and conclusions: IBD: Poor physical fitness was associated with an increased risk of IBD. The association may be explained (in part) by prodromal disease activity reducing exercise capacity and therefore fitness. Low stress resilience was associated with an increased risk of receiving an IBD diagnosis. Stress may not be an important cause of IBD but may increase the likelihood of conversion from subclinical to symptomatic disease. PUD: Low stress resilience was associated with an increased risk of PUD. This may be explained by a combination of physiological and behavioural mechanisms that increase susceptibility to H. pylori infections and other risk factors. GI infections: Low stress resilience was associated with a reduced risk of GI infections, including enteric infections rather than the hypothesised increased risk.

Ulcerative colitis (UC) and Crohn’s disease (CD) are the two common forms of inflammatory bowel disease (IBD). They share similar clinical and demographic features as well as harbor key differences in tissue damage and prognosis. Previous studies indicated that they contributed to the increased rick to Colorectal cancer (CRC). However, whether UC and CD share inflammatory signatures still remains controversial. In addition, no inflammatory signatures have been reported on CRC. To answer these questions, a comprehensive study has been conducted on collected microarray datasets. Our analysis suggests that although CD and UC share common inflammatory pathways, they also present difference. Especially, CD patients are likely to have type I response, while UC patients are inclined to undergo type II response. Pathway enrichment analysis on CRC uncovered two potential CRC-specific inflammatory pathways.

Innate immune activation is thought to play a central role in IBD pathogenesis because genetic polymorphisms in NOD2 and NLRP3, cytosolic innate immune receptors belonging to the NLR family, have been associated with IBD susceptibility. However, the mechanisms through which NLR mutations predispose to IBD remain unclear. The aim of this project was to dissect the functional roles of different NLRs in intestinal inflammation. Using the well-established DSS-induced colitis model as well as experimental models of IBD based on infection with Helicobacter hepaticus, we found that Nod2 expression was significantly increased at the peak of intestinal inflammation, and remained elevated throughout the resolution process. This observation suggests a possible role for Nod2 in the resolution of inflammation. Conversely, upon infection with the acute intestinal pathogen Citrobacter rodentium, Nlrp3-/- mice suffered from increased bacterial colonization as early as 3 days post infection, resulting in exacerbated intestinal inflammation and severe weight loss. Analysis of irradiation bone marrow chimeras showed that the protection required Nlrp3 activation in the non-haematopoietic compartment. Furthermore, this protective mechanism was independent of the inflammasome-associated cytokines IL-1β or IL-18. Therefore, this study implicates Nlrp3 activation in intestinal tissue cells as having a crucial role in controlling pathogenic bacterial colonization, providing a potential mechanism by which NLRP3 polymorphisms could lead to increased susceptibility to IBD.

Bakgrund: Inflammatorisk tarmsjukdom (IBD) innefattar sjukdomarna Ulcerös kolit och Morbus Crohn. Miljöfaktorer och förändrade kostvanor tros vara anledningar till att IBD-fallen ökat i USA och västra Europa på kort tid. I Sverige drabbas cirka 500 personer av Morbus Crohn varje år och Ulcerös kolit drabbar ca 900 personer per år. Sjukdomen yttrar sig i fysiska symtom som diarré, smärta och viktnedgång men påverkar även individen psykosocialt. Syfte: Syftet var att beskriva människors upplevelser av att leva med inflammatorisk tarmsjukdom samt att presentera vilken undersökningsgrupp som beskrivits i de inkluderade vetenskapliga artiklarna. Metod: Studien är en beskrivande litteraturstudie där 11 kvalitativa artiklar användes. Databaserna PubMed och Cinahl användes för att söka artiklar. Sökorden som användes var: Inflammatory Bowel Diseases, Qualitative, Everyday life och Lived experiences. Huvudresultat: IBD är en kronisk sjukdom. Fysiska symtom som illamående, viktnedgång, smärta och trötthet vilket även ses som ett psykiskt symtom. Oro, depression och dålig självkänsla upplevdes också. Sjukdomen visade sig påverka individens vardagsliv, kostvanor, familjeliv, och sociala relationer. Alla inkluderade artiklar presenterade undersökningsgruppen. Slutsats: IBD blir allt vanligare i världen. Symtomen är både fysiska och psykosociala och påverkar den drabbades vardagsliv, sociala liv och kosthållning. Sjuksköterskan möter en stor utmaning i att kunna bemöta och vårda dessa patienter då varje enskild individ har olika upplevelser av samma diagnos. / Background: Inflammatory bowel disease (IBD) includes the diseases Ulcerative Colitis and Morbus Crohn. Environmental factors and changing diets are thought to be reasons for IBD cases has increased in the US and Western Europe in a short time. It is in Sweden about 500 people affected of Morbus Crohn every year and Ulcerative colitis affects about 900 people per year. The disease has physical symptoms such as diarrhea, pain and weight loss, but also affects an individual psychosocial. Aim: The aim was to describe people's experiences of living with inflammatory bowel disease, and to present the study group as described in the included articles. Methods: This study is a descriptive literature study and 11 qualitative articles were used. PubMed and Cinahl were used to search for articles. Keywords used were: Inflammatory Bowel Diseases, Qualitative, Everyday Life and Lived Experiences. Main results: IBD is a chronic disease. Physical symptoms such as nausea, pain and fatigue which is also seen as a mental symptoms. The disease was found to influence the individual's daily life, eating habits, family life, and social relationships. All included articles presented the study group. Conclusion: IBD are becoming more common in the world. The symptoms are both physical and psychosocial and affects the afflicted person everyday life, social life and diet. Nurses face a big challenge in being able to confronting and care for these patients, since each individual has different perceptions of the same diagnosis.

Gut microbiota is important for our health and well-being, but when its composition is disrupted, it can induce or perpetuate several chronic inflammatory disorders, including inflammatory bowel diseases (IBD). The mechanisms which distinguish protective microbes from the deleterious or indifferent ones are largely unknown. The aim of this thesis was to study the interaction of the immune system with microbes that have different relationships to IBD pathogenesis. Escherichia coli is a predominant aerobic microorganism of the gastrointestinal tract. This species includes microbes implicated in induction of IBD as well as in its therapy. Four E. coli strains with different relations to IBD were selected for our experiments: E. coli Nissle 1917 (EcN), which has been successfully used in IBD therapy, E. coli strains LF82 and p19A, which have been implicated in the pathogenesis of IBD, and E. coli strain K6, which has neither been implicated in pathogenesis nor in protection from this disease. The experiments were performed both with living bacteria and inactivated ones. As the mode of inactivation may change the microbial antigenic structure, we measured how different methods of inactivation, i.e. 1% formaldehyde, exposure to heat or UV irradiation, influence the microbe's immunogenicity. First, we...