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Bilirubin influence on the progression of inflammatory bowel disease.
Patková, Anna ; Nachtigal, Petr (advisor) ; Hronek, Miloslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Bilirubin influence on the progression of inflammatory bowel disease Diploma thesis Anna Patková Supervisor: doc. PharmDr. Petr Nachtigal, Ph.D. Background: Inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gut caused by an interaction of genetic and environmental factors. It is thought that tissue damage is also partly caused by an oxidative stress. Heme oxygenase-1 and bilirubin are strong antioxidants and both of them provide an anti-inflammatory effect in various tissues. The aim of this diploma thesis was to detect changes of expression of HO-I in the large intestine of normobilirubinemic and hyperbilirubinemic rats after the induction of acute or chronic experimental colitis. Methods: We used Gunn rats with hereditary defect of UDP-glucuronyltransferase, which causes hyperbilirubinemia. The control group of animals was made up of heterozygous littermates of the Gunn rats, which have normal serum bilirubin levels. All animals were treated by dextran sulfate sodium in order to induce an experimental colitis. Rats were divided into two groups. Each of them contained hyperbilirubinemic and normobilirubinemic...
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Role of bacteria and mucosal immune system and their interaction in the pathogenesis of inflammatory bowel disease
Du, Zhengyu ; Hudcovic, Tomáš (advisor) ; Prokešová, Ludmila (referee) ; Kamanová, Jana (referee)
Although the etiology and pathogenesis of inflammatory bowel disease (IBD) is not fully understood, it is generally accepted that the inflammation results from aberrant immune responses to antigens of gut microbiota in genetically susceptible individuals (Sartor et al., 2006). Alteration in intestinal microbiota has been found in IBD patients with increased abundance of certain bacteria and decreased abundance of others. Due to the complexity of the disease, multifaceted interactions between genetic factors, host immune response, gut microbiota and environment factors need to be taken into account. In this thesis, the pathogenesis of IBD was first reviewed in respect with the four factors mentioned above. Then we concentrated on the interaction between IBD-associated bacteria and mucosal immune system. We investigated the ability of mucosal-associated bacteria (MAB) from IBD patients to induce spontaneous colitis in germ-free (GF) mice and the impact of those bacteria on the development of dextran sulfate sodium (DSS)-colitis. Together with the analysis of the composition of gut microbiota of MAB colonized mice, we demonstrated the potential deleterious microbes were able to increase the susceptibility to DSS-colitis once they found a suitable niche. We revealed the mechanism of an E.coli strain...
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Risk factors of manifestation and course of treatment of inflammatory bowel disease in children
Lerchová, Tereza ; Hradský, Ondřej (advisor) ; Ďuricová, Dana (referee) ; Havličeková, Zuzana (referee)
Risk factors of manifestation and course of treatment of inflammatory bowel disease in children Typical Crohn's disease (CD), Crohn's colitis, typical and atypical ulcerative colitis (UC) are currently perceived as different forms of inflammatory bowel disease (IBD). The incidence of IBD is increasing worldwide in both the adult and paediatric populations. Although the role of genetic background and environmental factors in the development of these diseases is known to some extent, the exact cause of IBD has still not been determined. Comprehensive care requires a precise and data-driven approach to minimize the risk of complicated disease course and the development of disease-related and/or treatment-associated complications. The main goal of this work is to identify new predictive factors affecting individual areas of care of paediatric patients with IBD. The range of clinical situations addressed in this work includes the possibility of predicting the diagnosis, the generally complicated disease course, the response to a particular therapeutic regimen, the development of side effects associated with the therapeutic procedure and the patient's adherence to the treatment. Part of the original works was done in a retrospective design, part as prospective observational studies and two of the original works...
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Metabolomics in the study of microbiome
Nazmutdinova, Anastasiia ; Kuzma, Marek (advisor) ; Cahová, Monika (referee)
Inflammatory bowel disease is a serious condition with an incomplete etiology and pathogenesis. In this thesis, a mouse model of sodium dextran sulfate-induced inflammation was used to study different changes in the metabolism of germ-free and conventionally raised mice due to the development of the inflammatory process. NMR metabolomics of fecal, urine and serum samples, combined with uni- and multivariate statistical analysis, were used to characterize the changes. It was shown that the metabolic signature differs between germ-free and conventional mice. In germ-free mice, significant amounts of carbohydrates were found in feces. Their levels decreased during inflammation as they were excreted in urine. In contrast to conventional mice, germ-free mice also excreted large amounts of amino acids in feces during the developing inflammation. Disorders of sugar and protein metabolism found in germ-free mice indicate severe malnutrition caused by inflammation. The results show that the presence of a microbiome represents a protective mechanism against significant disruption in the body. A stability study of fecal extracts of healthy conventionally colonized mice confirmed that none of the identified and quantified metabolites showed significant systemic changes in several consecutively collected...
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Bacterial components in experimental intestinal inflammation prevention and therapy
Kverka, Miloslav ; Tlaskalová - Hogenová, Helena (advisor) ; Šedivá, Anna (referee) ; Stříž, Ilja (referee)
Although strong protective immune response is essential for preventing invasion by pathogens, equivalent responses against antigens originating from commensal bacteria can lead to chronic inflammatory diseases, such as inflammatory bowel disease (IBD). Manipulating the mucosal immune responses with microbial antigens might be an excellent tool to IBD therapy or prevention. Our aim was to gain some insight into the regulation of the intestinal inflammation and to isolate bacterial immunomodulatory components that could be used in intestinal inflammation therapy and prevention. One particular mechanism of how healthy colon tissue regulates the inflammation during acute experimental colitis is through modulation of bioavailability of glucocorticoids (GCs) in gut mucosa. Here, we show that intestinal inflammation changes the local GC metabolism, which ultimately leads to decrease in inflammatory readiness of cells in the gut mucosa and in mesenteric lymph nodes. This pre-receptor regulation of GC function could represent an important homeostatic function of the gut mucosa. The actual triggers of intestinal inflammation in IBD seem to be either microbial dysbiosis or microbes with special "pathogenic" abilities, which both could be rectified by feeding with probiotics. Here, we report that oral feeding with live...
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Clinical and genetic predictors of drug dependency in inflammatory bowel disease
Ďuricová, Dana ; Lukáš, Milan (advisor) ; Keil, Radan (referee) ; Špičák, Julius (referee)
IN ENGLISH Drug dependency in inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), is a specific disease phenotype which determines disease prognosis and hence may be used as a prognostic marker for treatment management. Drug dependency in IBD has been well described in corticosteroid treatment and recently also in infliximab (IFX) therapy. The aims of this thesis were: 1) to assess the occurrence of IFX dependency in paediatric and adult patients with CD; further to search for clinical and genetic predictors of IFX outcome and to evaluate the impact of IFX dependency on surgical rate; 2) to assess in CD patients the outcome of the first course of 5-ASA monotherapy with emphasis on 5-ASA dependency and to define clinical predictors of 5-ASA treatment outcome. We found that 66% of children and 29% of adults with CD became IFX dependent. The high frequency in paediatrics is in agreement with previously published studies, while the finding in adult patients indicates a lower rate of IFX dependency in the only study to date. Perianal disease and no bowel surgery prior to IFX start were predicative of IFX dependency in paediatric patients. In adult cohort, 2 genetic variants LTA c.207 A>G and CASP9 c.93 C>T were associated with IFX outcome, whereas no relevant clinical...
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Mechanisms of immune dysregulation leading to inflammatory bowel disease
Horáčková, Klára ; Froňková, Eva (advisor) ; Filipp, Dominik (referee)
Bc. Klára Horáčková DIPLOMA THESIS Mechanisms of immune dysregulation leading to inflammatory bowel disease Abstract Inflammatory bowel disease (IBD) is a complex disorder characterized by chronic inflammation of the gastrointestinal tract. Classical IBD is a multifactorial disease with adulthood or later-childhood onset. However, children with very early onset IBD (VEO-IBD, before 6 years of age) are a specific cohort, whose pathology can be caused by severe genetic defects in genes connected to immune homeostasis in the gut. We aimed to identify the causal genetic variants in 20 pediatric patients diagnosed with IBD (age of onset from 3 to 154 months) using whole exome sequencing (WES). We evaluated several bioinformatical approaches for WES data analysis. This included a comparison of two methods of variant identification using VarScan2 or GATK4-based tools. Furthermore, we compared 4 gene lists ("virtual panels") for variant filtering, one of which was compiled purposefully for this thesis. We identified and validated via segregation analysis 5 causal variants in 4 genes (DUOX2 compound heterozygote, FOXP3, NLRP3 and NOD2) accounting for 20 % of the cohort. NOD2 (p.A755V) variant has already been reported in IBD cases, while DUOX2 (p.R1216W + p.A1131T), FOXP3 (p.H400L) and NLRP3 (p.V200M) were newly...
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The effect of serum 25-hydroxycholekalciferol levels on musculoskeletal system in children with inflammatory bowel disease
Maratová, Klára ; Šumník, Zdeněk (advisor) ; Zapletalová, Jiřina (referee) ; Kutílek, Štěpán (referee)
The effect of serum 25-hydroxycholekalciferol levels on musculoskeletal system in children with inflammatory bowel disease Background: Low bone mineral density and osteoporosis represent severe secondary complications that can be a result of childhood chronic disease. According to Frost's mechanostat theory impaired muscle functions may contribute to the changes observed on the skeleton. Aims: The aim of this study was to: 1) evaluate parameters of bone mineral density, bone geometry and dynamic muscle functions in children and adolescent with chronic disease - inflammatory bowel disease (IBD) and type 1 diabetes (T1D); 2) evaluate a possible effect of vitamin D deficiency and vitamin D supplementation or duration of the disease on the musculoskeletal unit; 3) determine clinical or laboratory predictors of muscle and bone parameters. Methods: The study was divided into two substudies according to the diagnosis. Seventy patients with IBD (median age 13.8 years) were included in one study, fifty-five of which completed all of the planned procedures. During the study, IBD patients were supplemented with 2000 IU/d of vitamin D. In the second study 95 patients with T1D were included (median age 16.4 years). BMD and bone geometry of non-dominant tibia was evaluated using peripheral quantitative computed...
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Inflammatory Bowel Diseases in pregnancy
Kovářová, Tereza ; Krátká, Zuzana (advisor) ; Hadlová, Petra (referee)
(EN) Inflammatory bowel disease is a chronic autoimmune disease of the intestinal tract including Crohn's disease, ulcerative colitis, and other unspecified colitis. Depending on the type of disease, inflammation affects the small or large intestine or rectum. It is a multifactorial disease in which the intestinal microflora, the immune system status, and genetic predisposition are crucial. IBD is most often diagnosed in late adolescence or early adulthood. Due to the availability of quality treatment, the health status of IBD patients also improves, allowing them to consider starting a family after the disease has calmed down. Patients have fewer children than the general population, but there was no significantly higher risk of infertility. A prerequisite for successful pregnancy and childbirth is a stable condition of the disease and the use of treatment during pregnancy to prevent relapse. A specific problem of patients is voluntary childlessness because of worries about the worsening of IBD during or after pregnancy, about negative effects of treatment on a foetus, but also an occurrence of disease in offspring This work aims to summarize the issue of pregnancy in patients with IBD and to provide information on the current situation in patients with IBD in the Czech Republic. Keywords:...
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