The TULA-family consists of two proteins implicated in cellular regulation. TULA-1 is expressed in T-cells and is involved in apoptosis. TULA-2 is a ubiquitously expressed phosphatase that suppresses receptor-mediated signaling. T cells from mice lacking TULA-1 and 2 (double knockout, or dKO) are hypersensitive to TCR stimulation. This may be due to these proteins having a similar function working synergistically or dissimilar functions having a convergent effect. To understand functional interaction of these proteins we have characterized TULA-family knockout mice without and during an immune challenge. We show that CD4+ T cells of dKO mice have a characteristic CD45RB distribution, and that within the CD45RBlow subset effector/memory T cells are expanded only in dKO, but not in single knockouts (sKO) of either TULA-1 or TULA-2. However, CD4+ T cells of sKO and wild-type (WT) mice respond differently to TCR stimulation as seen using signaling and responses in vitro. To evaluate consequences of TULA deficiency in vivo, we utilized two mouse models of inflammatory bowel disease: TNBS-induced colitis and colitis induced by the adoptive transfer of CD45RBhigh CD4+ T cells. Studies utilizing TNBS indicate that deficiency of any TULA-family protein exacerbates TNBS-induced colitis. Likewise, dKO CD45RBhigh CD4+ T cells were significantly more colitogenic than cells from WT mice in the transfer model. Taken together, our data indicate that TULA-family proteins are key to the physiological regulation of T-cell reactivity that drives intestinal inflammation. / Microbiology and Immunology

Introduction: Intestinal obstruction is a common cause of hospital admissions and carries a mortality rate around 5%. We hypothesized that surgical intervention reduces mortality among these patients. Methods: We conducted a retrospective cohort study using the 2006 Nationwide Inpatient Sample (NIS) to analyze patients with a diagnosis of intestinal obstruction without hernia. We used multiple variable logistic regression to calculate the odds ratio for surgery as a predictor of death after adjusting for illness severity. Results: Among 38,931 patients, 17,544 (45.1%) underwent operative intervention for intestinal obstructions. Surgical patients were slightly younger than non-surgical patients (65 vs. 68 years), and had more severe illness, as measured by the disease staging: mortality scale (115.45 vs. 97.95, p<0.001). After adjusting for illness severity, surgery was protective from mortality (adjusted odds ratio 0.617, 95% CI 0.535-0.710, p<0.001). This finding was validated with 2 other methods of severity adjustment. Among surgery patients, there were fewer days to surgery among survivors (1 day) than non-survivors (2 days), p<0.001. The risk of bowel necrosis increased as time from admission to surgery increased. A greater percentage of surgical patients (77.5%) were discharged home compared to non-surgical patients (76.3%), p=0.007. Conclusion: Surgery is associated with a reduced odds of in-hospital mortality among patients urgently or emergently admitted with intestinal obstruction without hernia. Delaying operative intervention is associated with an increased odds of bowel necrosis and death in these patients. / Clinical Research and Translational Medicine

Serotonin (5-hydroxytryptamine [5-HT]) is a key enteric signaling molecule that is implicated in many gastrointestinal (GI) disorders, including inflammatory bowel disease (IBD). Enterochromaffin (EC) cells are a key subgroup of enteric endocrine cells and produce the majority of 5-HT via tryptophan hydroxylase 1 (Tph1) in the gut. Recently, we have identified a pivotal role of 5-HT in the pathogenesis of experimental colitis, whereby 5-HT plays as a pro-inflammatory molecule. Gut function as well as pathology rely on interactions with gut microbiota. The intestinal epithelial cells produce antimicrobial peptides (AMPs), maintaining the mucosal barrier by shaping gut microbiota composition. Among the AMPs, β-defensins are the most well investigated subtype in the colon. Aberrant β-defensin expression has been reported in association with various GI disease pathogenesis including IBD. As EC cells are dispersed throughout the intestinal epithelium, it seems possible that 5-HT can modify β-defensin production which can regulate gut inflammation by influencing gut microbial composition. Colitis was induced with dextran sulfate sodium (DSS) in Tph1+/+ and Tph1-/- (which have lower amounts of 5-HT in gut). Tph1-/- mice exhibited higher levels of β-defensin in the colon, compared with wild-type littermates post-DSS. In addition, increased expression of β-defensin in Tph1-/- mice was suppressed by 5-hydroxytryptophan (5-HTP; precursor of 5-HT) treatment. 5-HT treatment resulted in decreased human β-defensin (hBD) 1 and hBD-2 expression in HT-29 cells. Peroxisome proliferator-activated receptor gamma (PPAR-γ) is essential for maintaining β-defensin expression in the colon. GW-9662, PPAR-γ antagonist, reduced mouse β-defensin (mBD) 1 and mBD-3 (orthologue of hBD-2). Furthermore, disrupting 5-HT7 receptors, but not 5-HT3 or 5-HT4, led to enhanced expression of PPAR-γ via ERK1/2-dependent mechanism. These observations provide us with novel information on pivotal role of gut-derived 5-HT in innate immune response and highlight the potential benefits of targeting 5-HT signaling in various GI disorders such as IBD. / Thesis / Master of Science (MSc)

Yes / Our aim is to provide an understanding of the experience of women with IBD who have made the transition to motherhood. Twenty-two mothers with IBD were recruited from around the UK. Semi-structured interviews were conducted and analyzed using thematic analysis. The central concept – Blurred Lines – offers a novel frame for understanding the transition to motherhood with IBD through identifying parallels between having IBD and becoming, and being, a mother. Parallels clustered into three main themes: Need for Readiness, Lifestyle Changes, and Monitoring Personal and Physical Development. Hence, women with IBD are in some ways well prepared for the challenges of motherhood even though, as a group, they tend to restrict their reproductive choices. We recommend health professionals initiate conversations about reproduction early and provide a multidisciplinary approach to pregnancy and IBD in which women have confidence that their on-going treatment will be integrated successfully with their maternity care. / Crohn’s & Colitis UK [grant number SP2013/2].

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.

No / This session considers the double contrast barium enema examination (DCBE) in investigation of bowel pathology and discusses its place alongside other imaging modalities and alternative investigations. Tips on equipment use, technique and reporting will be offered.

Introduktion: Irritable bowel syndrome, IBS, är den vanligaste funktionella tarmsjukdomen och påverkar ungefär 11 % av befolkningen. Forskningsresultat antyder att förändringar i mikroorganismernas sammansättning i tarmen, känd som dysbios, kan spela en roll i uppkomsten och patofysiologin vid IBS. Detta har ökat intresset för behandlingar som fokuserar på att återställa balansen av dessa mikroorganismer genom probiotika. Det finns dock begränsad forskning om effekten av probiotika på förstoppningsdominerad IBS (IBS-c), vilket indikerar ett behov av ytterligare studier på området.  Syfte: Att utforska litteraturen angående effekten av probiotika som behandling vid IBS-c hos vuxna.  Metod: Studien genomfördes som en litteraturstudie baserad på sökning av vetenskapliga originalartiklar i Pubmeds sökmotor Medline. Datainsamlingen startade i februari 2024 med inklusionskriterierna RCT-studier om effekten av probiotika vid IBS-c hos vuxna. Sökningen resulterade i 212 artiklar, vars titlar och nyckelord först granskades efter dess relevans för syftet, d.v.s. om de studerade probiotikas effekt på symtomen vid just IBS-c eller inte, och där föll många bort då de bara verkade studera generell IBS. 35 artiklar valdes då för vidare läsning av abstrakt, och slutligen ansågs fem RCT-studier möta inklusionskriterierna för denna litteraturstudie. Resultat: Studie 1, som undersökte två probiotikakombinationer, hade bäst utfall med signifikant förbättring av samtliga IBS-symtom och med trestjärnig signifikansnivå. I studie 2 visades signifikanta förbättringar av buksmärta, uppblåsthet, avföringskonsistens och den sammansatta IBS-poängen men med enstjärnig signifikansnivå. Studie 3 visade en signifikant förbättring av den sammansatta IBS-poängen samt buksmärta men också med en enstjärnig signifikansnivå. Studie 4 visade en signifikant förbättring av buksmärta och livskvalitet med en enstjärnig signifikansnivå, och i studie 5 förbättrades endast avföringsfrekvensen blygsamt i de två olika probiotikagrupperna som testades. Diskussion: En signifikant symtomförbättring av buksmärta jämfört med placebo sågs i alla studier utom en. Bäst utfall hade studie 1 som studerade probiotikakombinationerna L. acidophilus och L. reuteri, och L. plantarum, L. rhamnosus och B. lactis mot placebo, som visade signifikant förbättring av samtliga symtom (buksmärta, uppblåsthet, gasbildning, förstoppning och negativ livskvalitet). Svårigheten att dra säkra slutsatser från de granskade studierna beror på svagheter i studierna, olika deltagarantal, låga signifikansnivåer, hög placeboeffekt och variationer i undersökta probiotikastammar. De olika utfallen i studierna ger anledning att tro att effekten av probiotika är beroende av vilken typ av probiotika som testas.  Slutsats: Probiotika hade signifikant effekt på buksmärta och avföringskonsistens, men inte på uppblåsthet, gasbildning, livskvalitet eller den sammansatta upplevelsen av IBS-symtom. Variationen i studiernas probiotikaarter och doser, tillsammans med små studiepopulationer och metodologiska svagheter, gör det svårt att avgöra vilken probiotika som är mest effektiv mot IBS-c-symtom. För att kunna dra säkra slutsatser krävs fler och större studier med standardiserade metoder.

La barrière intestinale est la plus grande surface de contact entre le milieu extérieur et le milieu intérieur. Outre ses fonctions d'absorption des nutriments, elle exerce un rôle important de défense contre les agents indésirables (toxines, bactéries) contenus dans la lumière intestinale. Une augmentation de la perméabilité intestinale a été observée chez les patients atteints du syndrome de l'intestin irritable (SII) ou des maladies inflammatoires chroniques de l'intestin (MICI). Cette hyperperméabilité intestinale est contemporaine d'une hypersensibilité viscérale à la distension de la paroi intestinale. Des travaux récents rapportent également une augmentation de l'activité protéolytique du contenu intestinal dans le cadre de ces deux pathologies. Les estrogènes, par leurs propriétés anti-inflammatoires et leur capacité à moduler la perméabilité intestinale par activation de leurs récepteurs (REs) peuvent contribuer à l'amélioration des symptômes associés à ces pathologies digestives. Une variété de traitements médicaux a été utilisée pour la prise en charge thérapeutique du SII et de MICI. Cependant, les patients questionnent les cliniciens sur des conseils diététiques susceptibles d'améliorer leur qualité de vie. Ainsi, l'objectif de ce travail était d'évaluer les effets et les mécanismes d'action impliqués, d'un traitement par du germe de soja fermenté (SG) sur l'hyperalgésie viscérale et l'hyperperméabilité intestinale dans des modèles animaux mimant le SII et les MICI afin de proposer des futures allégations santé à ce produit. Le rationnel de l'évaluation de cet ingrédient était basé sur sa composition intéressante, à savoir, sa teneur en composés à propriétés estrogéniques (isoflavones) et sa capacité à inhiber les protéases (BBI). Dans un premier temps, nous avons montré qu'un traitement oral de 15 jours par le SG diminue de façon significative l'hypersensibilité viscérale, l'hyperperméabilité intestinale ainsi que l'augmentation de l'activité protéolytique induites par un stress de contrainte chez le rat. La diminution de la perméabilité intestinale implique une surexpression de l'occludine, protéine des jonctions serrées. De même, le traitement par du SG réduit la densité des mastocytes au niveau du côlon. Tous les effets préventifs du SG sauf ceux sur l'activité protéolytique sont estrogéno-dépendants car bloqués par l'antagoniste des REs. Dans un second temps, nous avons montré qu'un traitement préventif par le SG pendant 15 jours présente des effets protecteurs vis-à-vis d'une inflammation intestinale induite par du TNBS. Le SG atténue la sévérité de l'inflammation, l'hyperperméabilité, l'hypersensibilité et l'augmentation de l'activité protéolytique induites par la colite. Les effets anti-inflammatoires du SG sont à la fois dépendants des phytoestrogènes et du contenu de l'ingrédient en BBI. En conclusion, ces données sont prometteuses pour une future utilisation du SG dans la gestion thérapeutique du SII et des MICI comme traitement adjuvant / The intestinal barrier is the largest area of contact between the external environment and internal environment. In addition to its function of nutrient absorption, the intestinal barrier plays a key role of defense against noxious agents (toxins, bacteria) contained in the intestinal lumen. An increase in intestinal permeability was observed in patients with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD). This intestinal hyperpermeability was often associated with visceral hypersensitivity to colorectal distension. Recent studies also report an increase in the proteolytic activity in patients with IBS or IBD. Estrogens, through their anti-inflammatory properties and their ability to modulate intestinal permeability by activating estrogen receptors (ERs), can play an important role in these digestive diseases. A variety of medical therapies have been used for treatment of IBS and IBD. However, patients question clinicians about dietary suggestions to improve their symptoms and quality of life. Thus, the aim of this study was to evaluate the effects and mechanisms of action involved of a treatment with fermented soy germ (SG) on visceral hyperalgesia, intestinal hyperpermeability in animal models mimicking the IBS and IBD. The evaluation of this ingredient was based on its interesting composition, i.e its content of isoflavones and a family of serine protease inhibitors known as BBI. Initially, we demonstrated that an oral treatment of 15 days by SG significantly reduces visceral hypersensitivity, intestinal hyperpermeability and increased proteolytic activity induced by acute stress in the rat. Decreased intestinal permeability is due to overexpression of occludin, a transmembrane tight junction protein. Similarly, treatment with SG reduces the density of colonic mast cells. All preventive effects of SG except those on the proteolytic activity are estrogen-dependent because blocked by the antagonist of ERs. In a second step, we demonstrated that a treatment for 15 days with SG induces protective effects against intestinal inflammation induced by TNBS. SG reduces the severity of colitis, decreases TNBS-induced hyperpermeability, hypersensitivity and increased proteolytic activity. The anti-inflammatory effects of SG are estrogen and/or BBI dependent. In conclusion, these data are promising for future use of the SG as adjuvant therapy in IBS and IBD management

<p>A diagnosis of coeliac disease (CD) in adults relies on the presence of a structurally abnormal intestinal mucosa, followed by a clear clinical remission on a gluten-free diet. There is a clear need for a rapid, simple, safe and sensitive method to determine the type and intensity of inflammation in the gut mucosa in clinical practice. The overall aims of our studies were to develop and evaluate a new technique, “the mucosal patch technique”, to characterize rectal local inflammatory process after rectal food challenge in patients with CD<b>. In study 1</b> we evaluated the potential of the new technique. The technique was well tolerated and easily applied. Pronounced neutrophil and eosinophil involvement in ulcerative colitis (UC) was demonstrated. With the high sensitivity of the technique, low-degree mucosal neutrophil activation could also be quantified in patients with collagen colitis,UC in clinical remission and in patients with irritable bowel syndrome. <b>In study 2 and 3</b> the aim was to elucidate the dynamics of the rectal inflammatory response and nitric oxide (NO) production after rectal gluten challenge. We found a pronounced neutrophil activation in coeliac patients after rectal gluten challenge. This activation was apparent 4 hours after challenge and remains for at least 48 hours. A more modest eosinophil activation started 1-2 hours later and remained at least for 48 hours. The biphasic pattern of neutrophil and eosinonphil activation after challenge suggests a biphasic inflammatory reaction. The activation of neutrophils and eosinophils precedes a pronounced enhancement of mucosal NO production. Some of our coeliac patients displayed signs of an inflammatory reaction after rectal corn gluten challenge. <b>In study 4</b> the aim was to investigate the local inflammatory reaction to gluten and cow’s milk protein in CD patients in remission. The findings indicate that not only gluten sensitivity but also cow’s milk (CM) protein sensitivity is common in CD. The data support the hypothesis that CM sensitivity may contribute to persistent symptoms in coeliac patients on gluten-free diet.</p>

A diagnosis of coeliac disease (CD) in adults relies on the presence of a structurally abnormal intestinal mucosa, followed by a clear clinical remission on a gluten-free diet. There is a clear need for a rapid, simple, safe and sensitive method to determine the type and intensity of inflammation in the gut mucosa in clinical practice. The overall aims of our studies were to develop and evaluate a new technique, “the mucosal patch technique”, to characterize rectal local inflammatory process after rectal food challenge in patients with CD<b>. In study 1</b> we evaluated the potential of the new technique. The technique was well tolerated and easily applied. Pronounced neutrophil and eosinophil involvement in ulcerative colitis (UC) was demonstrated. With the high sensitivity of the technique, low-degree mucosal neutrophil activation could also be quantified in patients with collagen colitis,UC in clinical remission and in patients with irritable bowel syndrome. <b>In study 2 and 3</b> the aim was to elucidate the dynamics of the rectal inflammatory response and nitric oxide (NO) production after rectal gluten challenge. We found a pronounced neutrophil activation in coeliac patients after rectal gluten challenge. This activation was apparent 4 hours after challenge and remains for at least 48 hours. A more modest eosinophil activation started 1-2 hours later and remained at least for 48 hours. The biphasic pattern of neutrophil and eosinonphil activation after challenge suggests a biphasic inflammatory reaction. The activation of neutrophils and eosinophils precedes a pronounced enhancement of mucosal NO production. Some of our coeliac patients displayed signs of an inflammatory reaction after rectal corn gluten challenge. <b>In study 4</b> the aim was to investigate the local inflammatory reaction to gluten and cow’s milk protein in CD patients in remission. The findings indicate that not only gluten sensitivity but also cow’s milk (CM) protein sensitivity is common in CD. The data support the hypothesis that CM sensitivity may contribute to persistent symptoms in coeliac patients on gluten-free diet.