No description available.

No description available.

No description available.

No description available.

No description available.

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

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)

Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) are two of the most commonly diagnosed chronic digestive disorders in Western countries with increasing prevalence among Canadians. However, the etiology of IBS and IBD remain poorly understood due to a complex interplay of genetic, psychosocial and environmental factors, which hampers efforts at early detection/screening, accurate diagnosis and effective treatments notably in children. This thesis aims to reveal new biochemical insights into the pathophysiology underlying IBS and IBD when using an untargeted metabolite profiling (i.e., metabolomics) approach on urine and stool specimens based on multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS). Chapter I reviews brief history and current challenges in diagnosis and treatment, as well as current metabolomics literature of IBS and IBD. Chapter II first develops a robust method for high throughput profiling of anionic metabolites in human urine samples when using MSI-CE-MS. For the first time, we demonstrate that incidental capillary fractures are caused by irreversible aminolysis of the outer polyimide coating due to the frequent use of volatile ammonia based buffers under alkaline conditions (pH > 9) in electrospray ionization-MS. Chapter III subsequently applies this validated method to investigate differentially excreted urinary metabolites between adult IBS patients and healthy controls, which indicated significantly accelerated rates of collagen degradation and cell turn-over in IBS patients. Chapter IV later develops a novel stool extraction protocol for characterization of the fecal metabolome together with meta-genomic data for elucidating complex host-gut microflora interactions from a cohort of pediatric IBD patients, including Crohn’s disease and ulcerative colitis. In this pilot study, a panel of discriminating metabolites in urine is shown to allow for differential diagnosis of major pediatric IBD sub-types as an alternative to colonoscopy and histopathology that are invasive, expensive and prone to ambiguous test results. Finally, Chapter V involves a longitudinal metabolomics study that aims to identify metabolic trajectories that predict treatment responses of a cohort of pediatric Crohn’s disease patients following initiation of exclusive enteral nutrition (EEN) therapy. In the end, Chapter VI highlights major outcomes of thesis and future direction of metabolomics in IBS and IBD with a specific focus on improved stool specimen collection and validation of biomarker specificity relative to other related gastrointestinal disorders. In summary, this thesis has demonstrated metabolic processes that are associated with exacerbation of symptoms or remission in subset of IBS and pediatric IBD patients. With follow up studies with larger cohort of patients, potential biomarkers identified in this thesis will contribute the development of more accurate and non-invasive decision making process for diagnosis and treatment, resulting in long-lasting remission and improved quality of life of patients suffering from chronic digestive disorders. / Thesis / Doctor of Science (PhD)

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.