Bakgrund: Kroniska inflammatoriska tarmsjukdomar (IBD) innefattar i första hand Ulcerös kolit (UC) och Crohns sjukdom (CD) vilka är de vanligast förekommande inflammatoriska tarmsjukdomarna. IBD karaktäriseras av symtom som smärta i mag-tarmkanalen, diarré, blod i avföringen och att symtomen går i skov. Syfte: Syftet med denna litteraturstudie var att belysa patienters upplevelser av att leva med en kronisk inflammatorisk tarmsjukdom. Metod: Metoden som användes i studien var allmän litteraturstudie. Vidare användes en induktiv ansats i denna litteraturstudie. Resultat: Resultatet visade att IBD påverkar patienter på flera nivåer. Nivåerna delades in i fyra kategorier: Psykisk hälsa vid IBD, Fysisk aktivitet och energinivåer vid IBD, Samverkan med sjukvårdspersonal vid IBD samt Kosthållning och nutrition vid IBD. Konklusion: Patienter som led av IBD upplevde att sjukdomen har en negativ påverkan på den psykiska hälsan. Dessutom påverkade IBD patienters energinivåer till att patienter hade svårt att utföra vardagliga aktiviteter, främst när de genomgick skov. De patienter som fick möjligheten att vara delaktiga i sin vård upplevde i högre grad minskad ångest relaterat till vald behandlingsmetod. Vidare upplevde patienter att sjukvården inte gav den hjälp gällande kostrådgivning som de själva kände sig behöva. / Background: Inflammatory bowel disease (IBD) primarily includes ulcerative colitis (UC) and crohn's disease (CD), which are the most common forms of inflammatory bowel diseases. IBD are characterized by symptoms such as bowel pain, diarrhea, blood in the stool, and that the symptoms often manifest in flares. Aim: The aim of the study was to illustrate patients experiences of living with inflammatory bowel disease. Method: The method used in this study was a general literature study. Furthermore an inductive approach was used in the study. Results: The result showed that IBD affects patients on different levels. The levels were divided into four categories: Mental health and IBD, Physical health and energy levels and IBD, Collaboration with healthcare personnel and IBD, and Diet and nutrition and IBD. Conclusion: Patients that suffered from IBD experienced a negative affect on their mental health. Additionally, the diagnosis affected the patients energy levels, which led to struggles in the day to day life, foremost when they went through a flare. The patients that participated in their own treatment, experienced lower anxiety in relation to their treatment. Moreover, the patients described that they did not get the help they required when it came to their diet changes.

Inflammatorisk tarmsjukdom blir allt vanligare. Sjukdomen är kronisk och kommer följa patienten för resten av livet. Sjuksköterskan behöver kunskap om patientens upplevelser av att leva med inflammatorisk tarmsjukdom för att kunna ge stöd och god omvårdnad. Syftet med litteraturstudien var att belysa patientens upplevelser av att leva med inflammatorisk tarmsjukdom. Metoden för litteraturstudien utformades efter niostegsmodellen av Polit och Beck (2012). En systematisk litteratursökning gjordes i databaserna Cinahl, PsycInfo och PubMed. En urvalsprocess i tre steg gjordes, där artiklarna bearbetades och kvalitetsgranskades. Elva artiklar inkluderades till resultatet, varav åtta kvalitativa studier, en kvantitativ studie och två kvalitativ-kvantitativ mixade metoder. Resultatet framställdes i sju kategorier som belyser patientens upplevelser av att leva med inflammatorisk tarmsjukdom. Kategorierna presenterar maktlöshet och frustration, social isolering, oro och rädsla, upplevelse av smärta, upplevelse av fatigue, att känna skuld och att känna kontroll över sin sjukdom. Litteraturstudiens slutsats beskriver att inflammatorisk tarmsjukdom bidrar till begränsningar i vardagen. Sjuksköterskan behöver kunskap om patientens upplevelse av att leva med inflammatorisk tarmsjukdom för att kunna ge stöd, och på så sätt bidra till att patienten lär sig leva med sin sjukdom.

Les MICI (maladies inflammatoires chroniques de l'intestin) invalident 200 000 personnes en France. La région Nord-Pas-de-Calais est particulièrement touchée par ces affections et les traitements disponibles pour ces pathologies demeurent coûteux et peu nombreux. Des études récentes ont suggéré que le système endocannabinoïde, exprimé au seing du tractus gastro-intestinal, est une cible thérapeutique prometteuse pour le traitement des MICI. Ce système se compose des récepteurs aux cannabinoïdes CB1 et CB2, des ligands endogènes de ces récepteurs, notamment l'anandamide et le 2-arachidonoylglycérol et des protéines impliquées dans l'anabolisme et le catabolisme des ligands. L'anandamide a présenté des capacités à prévenir la colite induite par le TNBS à des rongeurs. Toutefois, in vivo ce composé possède un temps de demi-vie court et est rapidement dégradé par une amidase à sérine, la FAAH (Fatty Acid Amide Hydrolase). Nous avons ainsi envisagé la conception, la synthèse et l'évaluation pharmacologique de nouveau inhibiteurs de la FAAH. L'une de nos molécules, le composé 95, présentant une CI50 sur l'enzyme de 88 nM a ensuite été injectée par voie intrapéritonéale à des souris dont la colite a été induite trois jours plus tard par l'injection intrarectale de TNBS. L'évaluation des scores macroscopiques et microscopiques des dommages causés sur le côlon par l'agent irritant a ensuite été effectuée. L'inflammation du côlon a été significativement réduite chez le groupe de souris ayant été traité par le composé 95, montrant que l'inhibition de la FAAH est une stratégie thérapeutique efficace dans le traitement des MICI. / IBD (Inflammatory Bowel Diseases) invalidate 200 000 persons in France. Nord-Pas-de-Calais region is particularly touched by these diseases and the available treatments for these pathologies are few and expensive. Recent studies have suggested that endocannabinoid system expressed in the gastrointestinal tract, was a promising therapeutic target for the IBD treatment. This system is made up of cannabinoids receptors CB1 and CB2, endogenous ligands of these receptors, notably anandamide and 2-arachidonoylglycerol, and proteins involved in ligands metabolism. Anandamide has shown properties to prevent TNBS-induced colitis in mice. However, in vivo, anandamide possesses a short life time and is rapidly hydrolyzed by a serine amidase, the FAAH (Fatty Acid Amide Hydrolase). In this context, we have considered the design, the synthesis and the pharmacological evaluation of new FAAH inhibitors. One of our molecules, compound 95, inhibiting the enzyme with an IC50 value of 88 nM has been injected intraperitonally to mice which the colitis was induced three days later by intrarectal TNBS-administration. The assessment of macroscopic and microscopic scores of colonic damages was undergone. Colonic inflammation was significatively reduced in the group of mice which has been treated by 95, showing evidence that FAAH inhibition was an effective therapeutic target for the treatment of IBD.

Introduktion: Inflammatorisk tarmsjukdom blir allt vanligare i Sverige och skapar stort lidande hos de som drabbas. Syfte: Syftet med litteraturstudien var att belysa faktorer som främjar den hälsorelaterade livskvaliteten hos patienter med inflammatorisk tarmsjukdom mätt med mätinstrumentet IBDQ. Metod: Detta är en litteraturstudie som genomförts på ett systematiskt sätt baserat på Polit och Becks nio-stegsmodell. Resultaten från de granskade artiklarna kategoriserades genom en induktiv process. Resultat: Litteraturstudiens resultat består av tre kategorier som på olika vis genererar en främjad hälsorelaterad livskvalitet. Den första kategorin innehåller faktorer som patienten själv kan påverka så som motion och olika avslappningsövningar. Den andra kategorin speglar patientens inställningar och uppfattningar och den tredje kategorin innehåller faktorer som kräver sjukvårdsinsatser så som läkemedelsbehandling eller kirurgi. Slutsats: Det finns en rad olika faktorer som leder till främjan av den hälsorelaterade livskvaliteten. Kännedom om dessa faktorer är en förutsättning för att sjuksköterskan skall kunna verka för en god hälsa och främja den hälsorelaterade livskvaliteten. Denna litteraturstudie lyfter fram att IBD drabbar hela individen och dennes fysiska- sociala- och emotionella dimensioner där av vikten att se till hela individen och tillgodose individens alla individuella och specifika behov.

The inflammatory bowel diseases (IBD) are chronic, relapsing and remitting diseases of the gastrointestinal tract. There are two main types of IBD: Crohn’s disease (CD) and ulcerative colitis (UC). The prevalence of IBD is highest in the western world, approximately 100-200 people per 100,000 are affected. In recent years there has been a marked increase in the incidence of CD and UC, in both adults and children (Henderson et al., 2012; Molodecky et al., 2012). This is particularly relevant in Scotland where recent research shows that there has been a 79% increase in the number of cases of paediatric IBD since the 1990’s (Henderson et al., 2012). A yeast 2 hybrid screen identified TLE1as an interacting partner of the known CD susceptibility gene; Nucleotide- binding oligomerisation protein 2 (Nod2). An initial genome wide association study (GWAS) also found an association between the rs6559629 SNP, located in Tle1 and ileal CD (p =3.1 x 10-5) and showed that carriage of the Tle1 risk allele increases the effects of Nod2 mutations in CD. TLE1 functions as a transcriptional co repressor in a variety of different cellular and developmental pathways The work presented in this thesis investigates the potential role of TLE1 in CD. This has been approached using four different strategies: sequencing TLE1 in CD patients and controls, analysing the effects of knocking down TLE1 on genome wide expression, investigating whether the known IBD susceptibility protein XBP1 binds to a predicted binding site in TLE1 and investigating TLE1 levels and localisation in human intestinal samples from CD patients and controls Sequencing TLE1 exons and introns 15/16 and 16/17 in a Scottish cohort of 24 CD patients and healthy controls identified a number of potentially pathogenic exonic and intronic SNPs. Two exonic SNPs and thirteen intronic SNPs were identified and these were further investigated in larger Scottish (203 CD cases, 190 HC) and European cohorts (6,333 CD cases and 15,056 HC) but were not present at statistically significantly different frequencies. Secondly, the effects of TLE1 knock down on genome wide expression were analysed using an Illumina HT12 expression chip. The results showed that TLE1 knock down significantly altered expression of 19 loci (Bonferroni) and 526 loci (FDR). Four of the 19 Bonferroni significant loci are potentially involved in CD: RIOK1 (p=4.3×10-3), SGPL1 (p=4.3×10-3), TUSC3 (p=1.8×10-2) and CCND1 (p=2.7×10-3). Furthermore, expression of SGPL1 and RIOK1 were shown to be differentially expressed at the mRNA level between inflamed patients and controls. The third approach investigates a predicted binding site for the known IBD susceptibility gene, XBP1 in TLE1 which was identified using the Haploreg program. This work shows, using chromatin immunoprecipitation, that exogenous XBP1 does not appear to bind to this predicted binding site. Finally, TLE1 expression was analysed in human intestinal resection samples from patients of known NOD2 status. This work shows that TLE1 and NOD2 are expressed in Paneth cells, however TLE1 expression is not altered in patients carrying CD associated NOD2 variants. In this work TLE1 sequence, expression and potential interacting proteins have been analysed. The results presented suggests multiple mechanisms by which TLE1 may be influencing susceptibility to CD including: the unfolded protein response (TUSC3), S1P signalling and ribosome biogenesis. They also implicate TLE1 in Paneth cell function alongside NOD2. The exact means by which TLE1 may play a role in IBD pathogenesis has yet to be fully elucidated.

BACKGROUND: During the mid to late 20th century, parts of Europe and North America began experiencing increasing incidence of inflammatory bowel disease for unknown reasons. Epidemiological studies carried out at the time determined that incidence rates and disease severity were higher in the northern latitudes than in the southern latitudes. LITERATURE REVIEW: In the ensuing years, an inverse association was established between ultraviolet radiation and incidence of Crohn’s disease, a finding that has not proven to be as robust for ulcerative colitis. This association was explored further and vitamin D was implicated to be the factor of ultraviolet radiation which was associated with increased incidence. Currently, all evidence implicating vitamin D in the pathogenesis of Crohn’s disease comes from epidemiological, animal, and in vitro studies, providing strong evidence for an association, but none of which can prove causality. Causality must be proven in prospective clinical trials, which, at present, have come up short in providing statistically significant findings. METHODS: The proposed trial outlined below provides a method of studying the question at hand in a way that has not been previously studied. This is a randomized, double blind, controlled trial which assesses the effect of supplementation of vitamin D in patients with active Crohn’s disease. DISCUSSION: Acceptance of the alternative hypothesis would be a big step forward in the management of Crohn’s disease. It would have wide-ranging implications, resulting in decreased healthcare costs, decreased use of toxic medications, and increased quality of life.

Introduction. Inflammatory bowel disease (IBD) is a condition affecting more than 3 million people in Europe and the USA combined. Patients report pain as one of the most severe and debilitating symptoms leading to a lower quality of life. Current analgesics lack efficacy for the treatment of visceral pain or produce unacceptable side effect profiles. New targets are needed. Aims and methods. The aim of this thesis was to examine the activation of primary visceral afferents in C57BL/6 mice in response to biopsy supernatants from paediatric patients with IBD (Crohn's disease and ulcerative colitis) and functional abdominal pain syndrome (FAPS). By comparing the expression of pro-inflammatory and pro-nociceptive mediators in these biopsy samples with patient pain scores and afferent nerve recording activation, we identified putative mediators likely to be responsible for causing pain. The ability of inflammatory mediators to drive visceral nociception was then examined by their exogenous application in recordings of mouse and human visceral nociceptor activity. Results. Nerve activation increased significantly in response to biopsy supernatants from FAPS, CD, and UC patients, when compared to controls. Supernatant IL-8, TNFα, IL-6 and IL-1β, levels were increased in IBD samples compared with control patients. Analysis of mRNA expression also showed high levels of pro-inflammatory cytokines and raised MMP-1, MMP-3, MMP-9, MMP-12, and MMP-19 in IBD samples. The expression of MMP-12 in biopsy samples from Crohn's patients significantly correlated with afferent firing suggesting a causative role. This was confirmed by exogenously application of MMP-12 stimulated afferent firing and sensitised responses to mechanical stimulation and inflammatory mediators. UC samples showed TIMP-1 as an effective inhibitor of afferent firing. Conclusion. Data from this study demonstrates that the bowel of patients with IBD and FAP releases pro-nociceptive mediators which stimulate visceral afferents. MMP's play an important role in the afferent activation mediated by IBD samples suggesting that exploiting the endogenous inhibitor TIMP-1 could be a key target for future therapeutic strategies.

Background: Not only does IBD lead to nutritional deficiencies, but also nutrients influence its pathophysiology: exclusive enteral nutrition (EEN) is an effective primary treatment in Crohn's disease; and vitamin D (VitD) is involved in its pathogenesis and course. Aims: We hypothesised that nutrients impact on the course of IBD. We therefore studied the effect of EEN i) on long term clinical course in children; ii) on CD58, a costimulatory molecule at the intestinal epithelial cell (IEC) lines, iii) adults with Crohn's disease. We examined the possible effect of serum vitamin D levels on the course of IBD and also the possible role of ethnicity in our paediatric and adult populations that were treated with EEN but also in our general adult population. Results Chapter II: 56 paediatric patients with Crohn's disesase were followed up for 5 years. 57% of patients achieved remission after 6 weeks of EEN. Achievement of clinical remission within 6 weeks of EEN was significantly associated with a longer time to relapse and to treatment escalation. VitD deficiency was common; and those patients who were deficient were significantly more likely to require corticosteroids and also needed thiopurines sooner. Chapter III: CD58 was expressed in the IEC isolated from IBD patients and healthy controls. EN down-regulated the expression of CD58 on IEC lines. Chapter IV: 22 adult patients with Crohn's disease with a mean age of 30.8 years were given EEN and followed up for a mean time of 1.9 years. 22.7% of patients went into clinical remission and 77.3% experienced a clinical response. By the end of follow up 63.6% (14/22) of patients had clinically relapsed and 36.4% required surgery during their follow up. There was no difference between South Asian and Caucasian patients in the disease outcomes after administration of EEN. Chapter V: Bangladeshis were more often vitamin D deficient than white Caucasian patients; however vitamin D status was not associated with the course of IBD. Bangladeshis developed perianal disease and required thiopurines earlier in their disease course. Bangladeshi patients with UC had more extensive disease. Conclusions: EEN, when successful, improves the long term outcome of Crohn's disease in children, possibly in part, by down-regulating CD58 on the IEC. VitD deficiency may influence the clinical course of IBD; however our results were contradictory between children and adults and significantly limited by the assessment of the vitamin D level at a single time point.

In this thesis, I explore the meanings and experience of health and well-being in the lives of individuals with Inflammatory Bowel Disease (IBD). Taking an auto/biographical approach and utilising in-depth qualitative online interviews, I draw on the experience and narratives of seventeen individuals with IBD, including myself. The three main themes addressed are 'Living with IBD', 'Becoming a Patient', and 'Coping and Control'. I explore how IBD influences individuals' experience of personal relationships, and their medical encounters and treatments. I reflect on how and why these factors arise and the effect they may have upon the disease and its management and on individuals' feelings of well-being more generally. I look at the resulting illness narratives and the impact of IBD on the daily life experience and the identity of the individual. I interrogate existing research and add to it from my analysis. Throughout, the research highlights the importance of acknowledging the impact of biographical disruption on the life experience and identity of individuals along with changing illness narratives. There are implications for future research and for policy, including the time taken to reach diagnosis, the use of IBD guidelines in diagnosis and treatment, and patient control and choice as a contributing factor to influence future guidelines and treatment plans.

Les protéases sont impliquées dans de nombreux processus biologiques et ont des origines très variées (cellules immunitaires, cellules épithéliales...). Leur activité est régulée par des inhibiteurs de protéases. Cette étude s'intéresse a` la balance entre les protéases épithéliales et leurs inhibiteurs dans le contexte de pathologies affectant l'intégrité´ de l'épithélium intestinal. Les conséquences d'un déséquilibre de la balance protéolytique ont été étudiées dans deux maladies chroniques aux composantes différentes, les Maladies Inflammatoires Chroniques de l'Intestin (MICI) (cycles de poussées inflammatoires) et le Syndrome du Côlon Irritable (SCI) (cycles de douleur). La muqueuse colique de patients atteints de SCI sécrète une activité de type trypsine dont l'origine et les fonctions sont mal définies. Cette étude s'intéresse à la source de cette activité trypsique dans le côlon des patients atteints de SCI, sa nature et son rôle dans l'activation neuronale. L'activité trypsique chez les patients atteints de SCI est augmentée majoritairement dans les cellules épithéliales (CEI). La stimulation de monocouches de cellules épithéliales avec du LPS ou de l'épinéphrine induit une augmentation de la quantité de trypsine-3 et de sa sécrétion au pôle basal de la cellule épithéliale stimulée, en corrélation avec une augmentation de l'activité trypsique. L'hyperactivité de la trypsine-3 au pôle basal entraine une perte de la fonction barrière de l'épithélium, anomalie retrouvée aussi chez les patients atteints de SCI. De plus, nous avons mis en évidence que la trypsine-3 est capable d'activer les neurones humains myentériques et les neurones sensitifs murins. In vivo, son administration intra-rectale à des souris induit une hypersensibilité viscérale dépendante du récepteur PAR2 (Protease Activated Receptor-2). Ainsi, les cellules épithéliales intestinales des patients atteints de SCI produisent et sécrètent de la trypsine-3 spécifiquement au pôle basal. Cette activité trypsique active des neurones sensitifs, participant à l'hypersensibilité viscérale, symptôme majeur dont souffrent les patients atteints de SCI. Les pathologies inflammatoires peuvent aussi être source d'un dérèglement protéolytique. Les patients atteints de MICI présentent une dérégulation de la balance élastolytique colique. Notre équipe a montré que l'apport d'ELAFINE (un inhibiteur d'élastase) par la bactérie génétiquement modifiée L.lactis au contact de la muqueuse inflammatoire protège les souris traitées en réduisant l'inflammation intestinale. Cependant les mécanismes protecteurs médiés par L'Elafine restent encore à déterminer. L'ELAFINE est un inhibiteur d'élastases mais possède aussi des propriétés antimicrobiennes. Afin de mettre en lumière quelles fonctions de L'Elafine portent les propriétés anti-inflammatoires des mutants de L'Elafine ont été générés et insérés dans la bactérie L.lactis: une mutation pour annuler sa fonction inhibiteur de protéase, un second mutant de son domaine antimicrobien et un dernier mutant ayant perdu ces 2 fonctions. Dans des monocouches de cellules intestinales épithéliales, l'apport d'ELAFINE protège de l'inflammation médiée par un déséquilibre de l'activité élastolytique : on observe une restauration de la fonction barrière de l'épithélium et une diminution des cytokines pro-inflammatoires (CXCL8 et IP10). La mutation du domaine antimicrobien n'affecte pas ces propriétés. Cependant, l'absence de la boucle inhibitrice annihile les propriétés anti-inflammatoires de L'Elafine. Ces travaux ont pu mettre en évidence l'importance de l'équilibre protéolytique au sein de la cellule épithéliale dans les pathologies intestinales. La balance entre les protéases et leurs inhibiteurs joue donc un rôle dans l'homéostasie épithéliale et les pathologies inflammatoires. / Proteases are involved in some biologic processes and their origins are variable (immune cells, epithelial cells...). Their activity is regulated by antiproteases. This study investigates the balance between proteases and their inhibitors in pathologies which modify epithelium integrity. Consequences of an unbalance in proteolytic activity was studied in two chronic pathologies with different components: Inflammatory Bowel Disease (IBD) (cycles of inflammatory boost) and Irritable Bowel Syndrome (IBS) (cycles of pain symptoms). Colonic mucosa from IBS patients releases trypsin activity. The origin and the functions of this activity are not well defined. This study investigated the source of this trypsin activity in the côlon of IBS patients, its nature and its role in neuronal activation. Trypsin activity from IBS patients is increased mostly in epithelial cells. Stimulation of epithelial cell monolayers with LPS or epinephrine induces an increase of trypsin-3 quantity and its secretion specifically in the basal side of epithelial cells. This is in correlation with the increase of trypsin activity. Trypsin-3 hyperactivity at the basal side provokes a loss of epithelium barrier function, which is also found in colons of IBS patients. Then, we have highlighted that trypsin-3 is able to activate human myenteric neurons and murine sensitive neurons. In vivo, its intra-rectal administration to mice induces a visceral hypersensitivity dependent of PAR2 (Protease Activated Receptors 2). Thus, intestinal epithelial cells from IBS patients produce and release trypsin-3 specifically on their basal side. This trypsin activity activates sensitive neurons which participate to visceral hypersensitivity, a major symptom of IBS patients. Inflammatory pathologies could be a source of proteolytic malfunction. IBD patients have a dysregulation of elastolytic balance in the colon. Our team has shown that ELAFIN (an elastase inhibitor) delivered by the bacteria genetically modified L.lactis near the inflamed mucosa, protects mice from intestinal inflammation. However, the protective mechanisms induced by ELAFIN need to be investigate. ELAFIN is an elastase inhibitor but have also antimicrobial properties. With the aim to highlight what function of ELAFIN owns anti-inflammatory properties, mutants of ELAFIN have been generated and were insered into L.lactis: a first mutant lacked its antiprotease function, a second lacked antimicrobial properties and a last mutant lacked both properties. In intestinal epithelial monolayers, ELAFIN delivered by L.lactis protects against inflammation: a restauration of epithelial barrier function and a decrease of pro-inflammatory cytokines (CXCL8 and IP10) are observed. Mutation of antimicrobial domain doesn't affected these properties. Nevertheless, the absence of inhibitory loop annihilates anti-inflammatory functions of ELAFIN. This work highlights the importance of proteolytic balance inside the epithelial cell in intestinal pathologies. The balance between proteases and antiproteases plays an important role in epithelial homeostasis.