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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.

Diversos trabajos reportan aumento en el número de linfocitos intraepiteliales (LIE), mastocitos y células enterocromafines en pacientes con Sindrome de Intestino Irritable (SII). Muchos de estos hallazgos se basan en el uso de inmunohistoquímica que son de poca disponibilidad en hospitales generales. El objetivo del presente trabajo es estudiar los hallazgos histológicos en la biopsia de colon sólo con histoquimica en pacientes con SII comparándolos con un grupo sin SII. Fueron incluidos 25 pacientes: 16 (64%), con criterios diagnósticos de SII y 9 (36%), sin SII. Se encontró un mayor número de LIE en el grupo de SII (p=0,002). Un grupo de pacientes con criterios Roma III (41,9%) presentó LIE en el rango de Colitis Linfocitica por lo que fueron excluidos de este estudio. No se encontró diferencia estadísticamente significativa en el número de mastocitos, células enterocromafines y eosinofilos. / Several studies have shown increased numbers of intraepithelial lymphocytes (IEL), mast cells, enterochromaffin cells in colonic mucosa of patients with Irritable Bowel Syndrome (IBS). Many of these findings are based is based on immunohistochemistry results, which is not available in general hospitals. Our objective is to study the histological findings observed in colon biopsies from patients with IBS compared with a group without IBS, using only histochemistry. Twenty five (25) patients were included: 16 with IBS and 9 without IBS. We found increased numbers of IEL in patients with IBS (p=0,002). A group of patients with IBS (41.9%) who fulfilled histological criteria for lymphocytic colitis were excluded. There was no significant difference in mast cells, enterochromaffin cells or eosinophils.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Umeå : Univ., 2003. / Härtill 5 uppsatser.

Irritable Bowel Syndrome är en vanlig kronisk mag-tarmsjukdom som medför konsekvenser i det vardagliga livet för den som lever med sjukdomen. Än idag är orsaken till sjukdomen okänd, likväl finns inga tydliga riktlinjer för hur den ska behandlas. Syfte: Att belysa upplevelsen av att leva med Irritable Bowel Syndrome. Metod: Studien genomfördes som en systematisk litteraturstudie med induktiv ansats. Resultat: Resultatet baserades på nio kvalitativa vetenskapliga artiklar. Utifrån meningsenheter framkom tre huvudkategorier; Ett begränsat liv, Emotionell påverkan och Behov av förståelse och stöd med tillhörande sex underkategorier; Social isolering, Brist på energi, Rädsla och oro, Frustration, Att inte bli tagen på allvar av hälso- och sjukvårdspersonal och Att förstå och acceptera sin sjukdom. Slutsats: Att leva med Irritable Bowel Syndrome medförde begränsningar i det vardagliga livet. Det handlade både om professionella och privata områden. Att leva med den kroniska sjukdomen påverkade de drabbade individerna emotionellt eftersom de uttryckte att de inte kunde leva ett ”normalt” liv på grund av de oförutsägbara och genanta symtomen. I möten med hälso- och sjukvårdspersonal var det viktigt att ett personcentrerat förhållningssätt användes. Resultatet visade att individer med IBS uttryckte frustration över att inte få information och kunskap om deras sjukdom samt brist på evidensbaserad behandling. Därför behöver forskning bedrivas inom området. / Irritable Bowel Syndrome is a common chronic gastroinestinal disease that has consequenses in the everyday life for persons living with the condition. Still the cause of the disease is unknown, yet there is no clear guidelines how to treat it. Aim: To highlight the experience of living with Irritable Bowel Syndrome. Method: The study was conducted as a systematic literature study with inductive approach. Result: The result was based on nine qualitative scientific articles. Based on meaningful extracts three main categories were formed; A limited life, Emotional impact and The need for understanding and support. Six related subcategories were formed; Social isolation, Lack of energy, Fear and worry, Frustration, Not to be taken seriously by healthcare professionals and To understand and accept the disease. Conclusion: Living with Irritable Bowel Syndrome caused limitations in everyday life. It limited both the professional life and the private life. To live with a chronic disease affected the individuals emotionally because they expressed that they could not live a ”normal” life because of the unpredicable and embarrassing symptoms. In the meeting with healthcare it was important that a person-centered approach was used. The results showed that individuals living with IBS expressed frustration about not getting information and knowledge about their disease and treatment options. Because of this research needs to be conducted about the chronic condition and potential treatments.

Le syndrome de l’intestin irritable (SII) est un trouble fonctionnel d’origine multifactorielle, impliquant des facteurs environnementaux tels que le stress, l’alimentation et met en jeu un dysfonctionnement de l’axe intestin-cerveau, une micro-inflammation, une dysbiose et une hyperperméabilité intestinale. Le rôle du protéasome dans la régulation de la barrière intestinale au cours du SII a été étudié. De plus, ces troubles fonctionnels intestinaux (TFI) ont également été décrits comme exacerbés chez des patients souffrant d’obésité, dont la physiopathologie est complexe. Néanmoins, les mécanismes impliqués dans cette association restent mal compris et ont donc été recherchés. Dans ce travail, des modèles murins « SII-like » comme le modèle de stress « water avoidance stress » ou WAS et le modèle post-inflammatoire « post-TNBS » ont été utilisés afin d’étudier l’impact d’une inhibition du protéasome sur la régulation de la perméabilité intestinale. L’inhibition pharmacologique du protéasome par le PR-957 ou l’utilisation de souris invalidées pour une sous unité β2i du protéasome limite l’hyperperméabilité intestinale. Une supplémentation orale en glutamine permet également de diminuer la perméabilité intestinale. Une étude protéomique au niveau colique des souris WAS et une étude de l’ubiquitome colique de patients souffrant de SII à profil diarrhéique confirment l’implication du protéasome dans la physiopathologie du SII. Nous avons ensuite cherché à comprendre le lien entre l’obésité et le SII en combinant des modèles d’obésité (génétique et induite par une alimentation riche en graisses ou HFD) et le modèle WAS. Seules les souris HFD présentent une exacerbation de l’hyperperméabilité intestinale et une corticostéronémie plasmatique élevée en réponse au modèle WAS. Des études complémentaires suggèrent que ces résultats sont indépendants de la leptine, de la glycémie et du microbiote intestinal. Nos travaux proposent donc de nouvelles pistes de prise en charge des patients souffrant de SII, par intervention nutritionnelle via la glutamine ou en utilisant le protéasome comme cible thérapeutique. Nous suggérons également un rôle de l’alimentation (riche en graisse) dans le développement des TFI au cours de l’obésité. / Irritable bowel syndrome (IBS) is a multifactorial functional disorder, involving environmental factors (stress and diet for instance), gut-brain-axis dysfunction, micro-inflammation, dysbiosis and an alteration of intestinal permeability. The role of the proteasome in the regulation of the intestinal barrier during IBS has been studied. In addition, these intestinal functional disorders have also been described in patients with obesity. Nevertheless, the mechanisms underlying an association of intestinal functional disorders in the obesity context, remain poorly understood and have therefore been investigated in this thesis. In this study, "IBS-like" mouse models such as water avoidance stress (WAS) and the post-inflammatory (post-TNBS) models, were used to study the impact of proteasome inhibition on the regulation of intestinal permeability. We found that the pharmacological inhibition of the proteasome (with PR-957) or the use of knock-out mice for a subunit of the proteasome (β2i -/-) limit intestinal hyperpermeability occured in IBS-Like models. Moreover, we found that oral supplementation with glutamine also reduces intestinal hyperpermeability, wich, thus, can be considered as a putative nutritional treatment for IBS. A colonic proteomic study of WAS mice and a study of colonic ubiquitoma in IBS patients with diarrheal profiles confirmed the involvement of proteasome in the pathophysiology of IBS. Therefore, the link between obesity and IBS was examined by combining models of obesity (ob/ob genetic and high-fat diet [HFD] models) with WAS model. Only HFD mice displayed enhanced intestinal hyperpermeability and higher plasma corticosterone levels in response to WAS. Further studies suggest that these results, themselve, are independent of leptin, glycaemia and gut microbiota. This study paves new ways of treating patients suffering from IBS, by nutritional intervention via glutamine or by using the proteasome as a therapeutic target. We also suggest a role of diet (high fat) in the development of intestinal functional disorders during obesity.

Bakgrund   Irritable Bowel Syndrome (IBS) är en mag- och tarmsjukdom som drabbar cirka 18 procent av den svenska befolkningen och som medför en lägre livskvalitet. Irritable bowel syndrome är en komplex sjukdom med en multifaktoriell etiologi där vanliga symtom är exempelvis magsmärtor, förstoppning och diarré. I vården blir personer med IBS ofta felaktigt bemötta och det finns ett ökat behov av kunskap hos sjuksköterskor kring IBS för att kunna erbjuda en god och personcentrerad vård. Syfte Syftet med litteraturöversikten var att beskriva vuxna personers erfarenhet att leva med irritable bowel syndrome. Metod En icke-systematisk litteraturöversikt valdes som metod för att besvara studiens syfte där 12 vetenskapliga artiklar av både kvantitativ och kvalitativ metodansats inkluderades. Sökningen av artiklar genomfördes i databaserna PubMed och CINAHL där valda artiklar kvalitetsgranskades i enlighet med Sophiahemmet Högskolas bedömningsunderlag. Resultatet sammanställdes genom en integrerad dataanalys. Resultat Två huvudkategorier framkom i resultatet; Utmaningar i det dagliga livet och Mötet med hälso- och sjukvården. Personer upplevde att IBS påverkade negativt den fysiska och psykiska hälsan, yrkes- och privatlivet samt att det fanns brister i sjukvården. Sjukdoms påverkan över det dagliga livet är dubbelriktad där psykosociala faktorer samspelar med symtomen. Personer som sökt vård för IBS besvär upplever att de inte får tillräckligt med stöd och att de inte blir tagna på allvar. Resultatet diskuterades sedan med stöd av Erikssons teori om lidande så kallad Caritativ vårdande. Slutsats Denna litteraturöversikt belyste vuxna personers erfarenheter av att leva med IBS. Resultatet påvisade att IBS har en komplex påverkan på personernas dagliga liv och brister i mötet med sjukvårdspersonal. Genom ökad kunskap kring detta skulle sjuksköterskor kunna arbeta mer personcentrerat för att kunna bemöta och stötta personer med IBS. / Background Irritable Bowel Syndrome (IBS) is a gastrointestinal disorder that affects approximately 18 percent of the Swedish population and leads to a lower quality of life. Irritable bowel syndrome is a complex disease with multifactorial etiology, where common symptoms include abdominal pain, constipation, and diarrhea. People with IBS are often wrongly treated in the healthcare system, where there is an increased need for knowledge among nurses about IBS in order to offer good and person-centered care.  Aim The aim of the literature review was to describe adults’ experiences of living with irritable bowel syndrome. Method  A non-systematic literature review was chosen as the method to answer the purpose of the study where 12 scientific articles with a quantitative and qualitative approach were included. The search for articles was carried out in the databases PubMed and CINAHL and selected articles were quality checked in accordance with Sophiahemmet University’s assessment document. The results were compiled through an integrated data analysis.  Results Two main categories emerged in the results: Challenges in their daily lives and The encounter with healthcare. People experienced that IBS negatively affected their physical and mental health, work and personal life, and that there were shortcomings in healthcare. The impact of the disease on daily life is bidirectional, where psychosocial factors interact with the symptoms. People seeking care for IBS problems often feel that they do not receive enough support and that they are not taken seriously. The result was discussed with the support of Eriksson´s theory about suffering, known as Caritative caring.   Conclusions This literature review emphasizes adult’s experiences of living with IBS. The results showed that IBS has a complex impact on a person’s daily life and can create challenges when interacting with healthcare professionals. By increasing knowledge about this, nurses could work more patient-centered in order to meet and support people with IBS.

Les bénéfices attribués aux probiotiques sont nombreux : effets bénéfiques sur le microbiote intestinal, confort digestif, modulation du système immunitaire et prévention des infections intestinales. Ces effets divers et variés sont souches-spécifiques. Actuellement, de nombreuses études visent à mieux caractériser ces effets probiotiques.Ces travaux avaient pour objectif de déterminer et d’analyser les effets probiotiques de trois souches de la collection Danone : la souche de Lactobacillus paracasei CNCM I-3689, la souche de L. rhamnosus CNCM I-3690 ainsi que la souche de Bifidobacterium animalis subps. lactis CNCM I-2494. Dans un premier temps, leurs effets ont été caractérisés dans des modèles in vitro pour des propriétés anti-pathogènes, des propriétés d’immuno-modulation ainsi que pour des propriétés de protection de la barrière épithéliale intestinale. Dans un second temps, leurs effets de la protection de la barrière ont été confirmés dans un modèle murin de faible inflammation.Une analyse des mécanismes sous-jacents à ces effets à la fois chez la souche probiotique et chez l’hôte a été initiée par la construction et l’analyse fonctionnelle de banques génomiques bactériennes ainsi que par l’étude de la modulation des gènes impliqués dans le maintien de la barrière intestinale chez l’hôte. / Health benefits of probiotic bacteria are numerous: beneficial effects on the intestinal microbiota, digestive comfort, modulation of the immune system and prevention of winter infection. These diverse and various effects are strain-specific. Nowadays, numerous studies aim at better characterizing those probiotics effects.This project aimed at identifying and analyzing the probiotic effects of three strains from Danone collection: Lactobacillus paracasei CNCM I-3689, L. rhamnosus CNCM I-3690 and Bifidobacterium animalis subsp. lactis CNCM I-2494. First, their effects were assessed in in vitro models for immunomodulation properties, antipathogens activity and intestinal barrier protection. Secondly, their beneficial effects were confirmed in low-grade inflammation murine model.The analysis of the underlying mechanisms has been initiated both in the bacterial strains by the construction and the functional analysis of genomic libraries and in the host by measuring the modulation of the genes involved in the intestinal barrier maintain.

<p>Denna uppsats behandlar den dolda folksjukdomen IBS och dess konsekvenser för individens sociala delaktighet. Syftet med studien är att studera individens upplevelse av delaktighet och erfarenhet av att leva med sjukdomen. IBS är en så kallad funktionell mag- och tarmsjukdom och står för Irritable Bowel Syndrome (Colon/Kolon irritabile), Irriterad tarm i svenskt tal och kännetecknas av återkommande eller kroniska symtom från mag- tarmkanalen. Medicinskt sett anses IBS vara en godartad sjukdom, men den kan vara besvärlig att leva med och ibland ge nästintill handlingsförlamande konsekvenser för individen och dennes sociala livsvärld. Forskarna vet inte orsaken bakom IBS och det finns inget medicinskt test som visar att det är IBS som en patient lider av, men man vet att individens sjukdomshistoria ofta är typisk och att sjukdomen är vanligast bland kvinnor. Av världens alla invånare lever det många människor med sjukdomen IBS, som kommit att bli en ny folksjukdom, då man beräknar att närmare 10-20 procent av den vuxna befolkningen har IBS. Individens upplevelse av vad som är normalt kontra avvikande när det gäller det friska och det sjuka visar en bild av hur samhället tycks vara skapat. Individens hälsotillstånd påverkar livskvaliteten och diagnosen bidrar till en förändrad identitet, och för varje individ som lever med IBS har begreppet delaktighet; att vara social med andra och i samhället i stort, fått en helt ny mening i och med deras sjukdom. <strong> </strong></p><p>Min förhoppning är att denna studie ska uppmärksamma läsaren kring den nya folksjukdomen IBS och hur den påverkar individens sociala liv.</p><p> </p> / <p>This essay deals with the new widespread disease IBS and its consequences for the social participation of the individual. The purpose of the study is to look at the experience of social participation of the individual and her experience of living with this disease. IBS is a so-called dynamic/functional belly- and intestinal disease, which stands for Irritable Bowel Syndrome, and is symbolized by recurrent or chronical symptom from the belly- and intestinal canal. From a medical view IBS is considered as a benign disease, but it can be tricky to live with and sometimes give heavy problems for the individual and its social life. The scientists doesn`t know what the cause is behind the disease and it doesn`t exist any medical test who can prove that a patient is suffering by IBS, but they do know that the case-history of the individual is very typical and that the disease is more common among women. From a social view studies show that the social life of the individual is strongly affected, and that the identity and how she look at normalcy/variation is no longer the same as it was when she was healthy. For every individual whos is living with this disease has also the concept of participation; to be social with other people and in society at large, got a whole new meaning as a result of their disease.</p>