京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22329号 / 医博第4570号 / 新制||医||1041(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 坂井 義治, 教授 斎藤 通紀, 教授 岩田 想 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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...

Les maladies inflammatoires chroniques de l’intestin (MICI), qui comprennent les deux principales formes, la maladie de Crohn (MC) et la rectocolite hémorragique (RCH), sont caractérisées par une inflammation chronique et récurrente de la muqueuse intestinale, ayant un impact considérable sur la qualité de vie. À l'heure actuelle, la prise en charge thérapeutique de la MC n'est pas curative et un tiers des patients ne réagissent pas aux traitements biologiques et aux immunosuppresseurs. Par conséquent, de nouvelles stratégies pour traiter cette maladie sont fortement attendues. La dérégulation de l'interaction entre d'une part les facteurs génétiques et le système immunitaire de l'hôte, et d'autre part le microbiote intestinal et les facteurs environnementaux, est impliquée dans le développement des MICI. Cette perturbation entraîne effectivement une augmentation de la perméabilité intestinale et une inflammation persistante. Restaurer le microbiote «dysbiotique» et les fonctions intestinales altérées représentent donc une thérapeutique alternative intéressante. De ce fait, les probiotiques sont une option intéressante et ont été utilisés avec succès chez des patients souffrant de pouchite et de RCH. Cependant, leur effet protecteur est clairement souche-dépendant et plusieurs souches probiotiques bien connues n’ont pu conduire à un résultat clinique probant, en particulier chez les patients souffrant de MC. Le décryptage des mécanismes moléculaires sera donc la clé pour permettre une recommandation efficace des probiotiques dans le traitement ou la prévention des MICI. La sélection de souches basée sur des critères de sélection bien définis et en utilisant des modèles bien maitrisés est indispensable à ce processus. L'objectif principal de cette thèse était de sélectionner des lactobacilles et des bifidobactéries parmi une collection de souches françaises et libanaises, capables de présenter des propriétés protectrices contre les MICI, en se concentrant sur leurs capacités immuno-régulatrices et leurs capacités à renforcer la barrière épithéliale. Des approches in vitro ont été utilisées pour sélectionner des souches ayant une activité anti-inflammatoire et également capables d'améliorer la fonction de la barrière intestinale. Cinq souches ont été identifiées présentant des caractéristiques différentes, mais avec un potentiel thérapeutique élevé. Deux souches se sont révélées hautement protectrices dans deux modèles différents de colite aiguë et de colite de bas grade. Nos résultats ont confirmé en outre l'hypothèse selon laquelle la capacité des souches à atténuer l'inflammation est en partie due à l'amélioration de la barrière intestinale et à la restauration des protéines de jonction serrés.Un nombre croissant d’études génétiques ont prouvé que l’autophagie peut affecter plusieurs aspects de la réponse immunitaire des muqueuses, notamment via l’élimination de bactéries intracellulaires, la sécrétion de peptides antimicrobiens, la production de cytokines pro-inflammatoires et la présentation des antigènes. Par conséquent, l'autophagie peut être considérée comme un mécanisme de régulation clé impliqué dans la physiopathologie de la MC. Nous avons donc évalué la capacité des souches à activer cette voie et montré que les souches sélectionnées étaient en effet capables d’induire une activation de l’autophagie dans des cellules dendritiques murines. Nous avons démontré in vitro que le blocage de l'autophagie pouvait diminuer la capacité des souches à induire la sécrétion d'IL-10, cytokine anti-inflammatoire et, inversement, à exacerber la sécrétion d'IL-1β, cytokine pro-inflammatoire. Nous avons pu confirmer, à l'aide d'un modèle murin de colite, que la capacité protectrice d’une souche impliquait la machinerie autophagique, et nous avons pu mettre en évidence le rôle des cellules dendritiques dans ce processus [...] / Inflammatory bowel disease (IBD), including the two main types, Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic, relapsing inflammation of the gut mucosa with considerable impact on the quality of life. At present, the therapeutic management of CD is not curative and one third of patients fails to respond to current biologicals and immunosuppressive drugs. Therefore new strategies for treating this disease are imperative.The deregulation of the normal interplay between the genetics and immune system of the host on the one hand, and the gut microbiota and environmental factors on the other hand, is known to be associated with the development of IBD, as this disturbance is leading to increased intestinal permeability and persistent inflammation. Restoring the “dysbiotic” microbiota and the impaired intestinal functions represent an attractive therapeutic alternative. Probiotics represent therefore an interesting option and have been used quite successfully in patients suffering from pouchitis and UC. However, their protective effect is clearly strain-dependent and several well-known probiotic strains failed to fulfill the expected clinical outcome, especially when applied in CD. Deciphering the molecular mechanisms will be the key to the recommendation of probiotics for the treatment or prevention of IBD. Selecting strains on well-defined selection criteria and using well-studied models is indispensable to this process.The main objective of this thesis was first to select lactobacilli and bifidobacteria from a collection of French and Lebanese strains that exhibited protective properties against IBD, focusing on their immunoregulatory capacities and their capacities to strengthen the epithelial barrier.In vitro approaches were used to select strains with anti-inflammatory activity and also able to enhance intestinal barrier function. Five strains were identified with different characteristics, but entailing a high potential for the management of IBD. Two strains, e.g. were found to be highly protective in two different models of acute and low grade colitis. Our results furthermore support the hypothesis that the capacity of the strains to alleviate inflammation is in part mediated by the improvement of the intestinal barrier and the restoration of tight junction proteins.A growing number of genetic studies provided strong evidence that autophagy machinery can affect several aspects of the mucosal immune response, including intracellular bacterial killing, antimicrobial peptide secretion, pro-inflammatory cytokine production and antigen presentation. Therefore, autophagy can be considered as a key regulator mechanism most likely involved in the physio-pathogenesis of CD.We therefore evaluated the capacity of the strains to activate this pathway and showed that the selected strains were indeed able to induce autophagy activation in dendritic cells. We demonstrated in vitro that blocking the autophagy machinery can abolish the capacity to induce the secretion of the anti-inflammatory cytokine IL-10 after immune cell stimulation, while exacerbating the secretion of the pro-inflammatory cytokine IL-1β. We could confirm, using a murine model of colitis, that the protective capacity of the selected strains indeed involves autophagy mechanisms, and we could highlight the role of dendritic cells in this process. We therefore propose here that autophagy is a novel mechanism through which probiotics can exhibit their immunoregulatory capacities.

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Bakgrund: Inflammatorisk tarmsjukdom (IBD) är ett samlingsnamn för de kroniska tarmsjukdomarna Crohns sjukdom (CD) och Ulcerös kolit (UK). Det gemensamma för de två sjukdomarna är att de löper i skov med försämringsperioder och långa besvärsfria perioder samt att de drabbar relativt unga personer. Det är viktigt att sjuksköterskan kan stödja dessa individer genom evidensbaserad och personcentrerad vård för att kunna ge en så god omvårdnad som möjligt.  Syfte: Beskriva individers upplevelse av att leva med inflammatorisk tarmsjukdom Metod: En litteraturöversikt valdes som metod. Artikelsökningen genomfördes i databaserna CINAHL Complete och PubMed. De begränsningar som gjordes i databassökningarna var vetenskapliga originalartiklar, skrivna på engelska, genomgått peer-review och publicerade mellan 2009-2019. Totalt inkluderades elva artiklar i resultatet, av dessa var tio artiklar kvalitativa och en var kvantitativ. Resultat: Resultatet visade att individerna upplevde att sjukdomen påverkade deras arbetsliv, sociala liv, känslor och identitet. Deras möte med hälso- och sjukvården påverkade personernas förtroende för vården samt deras vilja att söka vård framöver. Det visades även att personer med inflammatorisk tarmsjukdom genomgick en transitionsperiod efter deras diagnos. Hur personerna upplevde att leva med IBD påverkades av om de för tillfället befann sig i ett skov eller nyligen fått diagnosen. De personer som befann sig i ett skov eller nyligen fått diagnosen hade en övervägande negativ syn.  Diskussion: Resultatet diskuterades utifrån Katie Erikssons teori om lidande och hälsa. Författarna resonerade om individernas negativa påverkan kunde kopplas till stigman av sjukdomen. De diskuterade även angående den långsiktiga påverkan av frånvaron från arbetet och sociala sammanhang. Författarna fann i resultatet att individer med IBD upplevde sjukdomen olika i sin vardag beroende på hur länge de haft sjukdomen och vilken inställning de har gentemot sin IBD. Därmed bör vården anpassas efter de individuella behoven för att säkerställa att insatserna främjar hälsan. / Background: Inflammatory bowel disease (IBD) is a chronic illness that includes Crohn´s disease (CD) and ulcerative colitis (UK). Both diseases have in common that they have relapse and periods with improvement. The diseases effects relatively young people. It is important that the nurse can support these individuals through evidence based and person-centred care in order to provide the best possible care. Aim: Describe individuals experiences of living with inflammatory bowel disease  Method: A literature review was chosen as the method. The article search was carried out in the databases CINAHL complete and PubMed. The limitations made in the database searches were scientific original articles, written in English, peer-reviewed and published over the last ten years. A total of eleven articles was included in the result, of which ten were of qualitative design and one was quantitative design. Results: The results showed that the individuals experienced that the disease affected their working life, social life, feelings and identity. Their meeting with healthcare services affected their trust in the care and their willingness to seek care in the future. It was also shown that people with inflammatory bowel disease underwent a transition period after the diagnosis. How the individuals experienced living with IBD was affected by whether they were relapsing or in remission. People currently in a relapse had a more negative view of the disease.  Discussion: The result was discussed based on Katie Eriksson´s theory of suffering and health. The authors reasoned if the negative impact of the individuals could be linked to the stigma and shame of the disease. They also discussed the long-term impact of the absence from work and social activities. The authors found in the results that individuals with IBD experienced the disease differently in their daily lives depending on how long they had the disease and what attitude they had towards their IBD. The care should be adapted to the individual needs to ensure that the efforts promotes health.

Background: Investigators are often interested in using population-level health administrative data in inflammatory bowel disease (IBD) patients to study disease outcomes, risk factors and treatment effects to enhance knowledge, shape clinical practice and influence health care policy. A major limitation of using health administrative data for these purposes is the lack of detailed clinical data to adjust for the confounding effects of differential disease severity on observed associations. Methods to account for disease severity using administrative variables would offer a major advance to population-level studies in IBD patients. Thus, in this study we aimed to use a cohort of IBD patients from The Ottawa Hospital (TOH) to validate a model that was originally developed in Manitoba for estimating clinical disease course in IBD patients through healthcare utilization measures. Objectives: The objectives of this thesis are: 1) To identify and characterize a reference cohort of IBD patients in the ambulatory clinics of four gastroenterologists from TOH on clinical disease course in the preceding year (reference cohort), based on a Manitoba definition of clinical disease course; 2) To fit a partial proportional odds (PPO) model for predicting IBD course, derived using Manitoba health administrative data, to the reference cohort of IBD patients using Ontario health administrative data; 3) To derive new PPO models of IBD disease course for the reference cohort using Ontario administrative variables and compare model performance; and 4) To apply the models to the Ontario Crohn’s and Colitis cohort (OCCC) to estimate IBD course in Ontario, and compare the distribution to that of the Manitoba IBD population.Methods: We first identified a reference cohort of IBD patients in Ontario from the outpatient clinics at TOH during fiscal year 2015. Through chart review, we classified these patients into one of four clinical disease categories (remission, mild, moderate, or severe) using the Manitoba definition. We linked these patients to Ontario health administrative datasets. Given slight differences in data structure and coding between Manitoba and Ontario, we were unable to directly test the Manitoba model and instead fit a PPO model to the Ontario cohort using analogous administrative variables to those used in the final Manitoba model (“adapted model”). We subsequently derived new PPO models using unique Ontario administrative variables under three strategies: 1) Stepwise variable selection (“stepwise model”); 2) Forced fitting of all variables (“all-variables model”); and 3) Using a two-step modelling algorithm that considered IBD-related hospitalizations separate from other administrative variables (“two-step model”). We then compared model performance from the four strategies. Finally, we applied the models to the Ontario IBD population from 2004 to 2016 and compared model estimates to those from Manitoba. Results: We identified 963 patients with IBD from TOH outpatient clinics, of which 52.3% (n=504) were males, 64.6% (n=622) had Crohn's Disease, and 89.2% (n=859) resided in an urban setting. Based on the Manitoba definition, 64.9% of patients within our reference cohort were classified as remission, while 11.4%, 14.1%, and 9.6% were classified as mild, moderate, and severe disease course, respectively. The adapted model (c-statistic 0.77, goodness-fit p-value 0.28) performed comparably to the other models: the stepwise model (c-statistic 0.77, goodness-fit p-value 0.50), the all-variables model (c-statistic 0.77, goodness-fit p-value 0.53), and the two-step model (c-statistic 0.78, goodness-fit p-value 0.75). The adapted model also resulted in overall similar estimates with regards to the disease course distribution among the Ontario IBD population. However, on closer inspection, our two-step model, in which individuals who had been hospitalized for an IBD-related indication within the past year were assumed to have severe disease, performed better with respect to accurately classifying individuals with moderate or severe disease, without sacrificing discriminative ability. Based on the two-step model, from 2004 to 2016, 89.2-91.2% of the Ontario IBD population was in remission, 0% had mild disease, 2.4-3.2% had moderate disease, and 5.9-8.4% had severe disease. Distribution of disease course among IBD patients in Ontario differed considerably than that in Manitoba. Conclusion: In the absence of clinical information within health administrative data, we present and compare four different models that can be used to partially account for the confounding effect of disease course among IBD patients in future population-based studies using Ontario health administrative data. Given that our models did not perform as originally expected, especially with regards to accurately identifying individuals with more active disease states, we advise researchers to use these models at their own discretion.

Crohn’s disease is an inflammatory bowel disease that may involve any part of the gastrointestinal tract with a variety of extraintestinal features. A flare of Crohn’s disease may present as partial small bowel obstruction or peritonitis. Dehydration, infectious agents, and cigarette smoking are some of the factors linked to a relapse of Crohn’s disease. Plesimonas Shigelloides, a bacterium that belongs to the enterobacteriaceae group may rarely lead to a flare of Crohn’s disease. We describe the case of a 31-year-old male with Crohn’s disease who developed a flare triggered by Plesimonas Shigelloides infection presenting as partial small bowel obstruction with ileal narrowing, and regional lymphadenopathy that responded to immunosuppressants.

Aim: VitaminD deficiency is a global health issue associated with increased health-care costs, and could play a role in the pathogenesis and management of inflammatory bowel disease. Prior studies show a high prevalence of vitaminD deficiency in veterans with inflammatory bowel disease. We aimed to examine the outcome differences in patients with inflammatory bowel disease, comparing treatment with ergocalciferol to cholecalciferol. Methods: A retrospective review of electronic medical records of patients with inflammatory bowel disease at a Veterans Affairs Medical Facility in the Southeastern United States was carried out. Those with at least one serum 25(OH) vitaminD level were included. Initial and follow-up vitamin D values were recorded. The type of vitaminD supplementation, whether cholecalciferol or ergocalciferol, was documented. Costs in the year after measurement of vitaminD were divided into separate inpatient and outpatient categories. Results: Veterans (n=108) with ulcerative colitis or Crohn's disease and an available 25(OH) vitaminD level were studied. There were differences in follow-up vitaminD levels; those who received weekly ergocalciferol had higher subsequent levels than those who received cholecalciferol, especially at a second follow up, although differences did not achieve statistical significance. However, those who received vitaminD3 were less likely to use laboratory, pharmacy, radiology and fee-based services, and had lower laboratory and pharmacy costs. Conclusions: Our data suggest that cholecalciferol replacement might improve outcomes to a greater extent than ergocalciferol, and might be better in limiting health-care costs and expenses in patients with inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) are known to have an increased propensity for thromboembolic events. Like any patient with a high risk of event recurrence, most of these patients can be managed successfully with long-term warfarin therapy. We present the case of a 66-year-old woman with Crohn's disease who, despite careful attention to the management of her international normalized ratio, developed a new deep vein thrombosis and required inferior vena cava filter placement in addition to ongoing warfarin therapy to prevent recurrent pulmonary emboli. This report serves as a reminder to physicians to have a low threshold for diagnosing thromboembolic events in patients with IBD, even if they are presumed to be adequately anticoagulated. Known and theoretical contributing factors to this increased clotting tendency are also reviewed.

Bakgrund: De inflammatoriska tarmsjukdomarna Morbus Crohn och Ulcerös kolit ärett växande problem i världen, ett vanligt symtom vid sjukdomarna är fatigue. Fatigueupplevs som en intensiv trötthet och är annorlunda än den trötthet som uppkommer avvardagliga aktiviteter. Syfte: Att undersöka patienters upplevelse av fatigue vidinflammatoriska tarmsjukdomar. Metod: En litteraturstudie med en induktiv ansats.Åtta artiklar har analyserats via en innehållsanalys där teman har identifierats.Resultat: Tre huvudteman skapades: fatigues påverkan på det dagliga livet, psykiskaoch fysiska påföljder av fatigue, betydelsen av stöd från omgivningen. Även femunderteman skapades: livskvalitet, upplevelsen av psykiska påföljder, upplevelsen avfysiska påföljder, oförståelse från omgivning och förståelse från omgivning. Patienterupplevde att fatiguen hade påverkat det dagliga livet negativt. Många drabbade led avångest och depression som hade tillkommit efter diagnosen. Konklusion: Hur mycketfatiguen påverkade det dagliga livet varierade från person till person. Det var vanligtatt patienterna upplevde oförståelse från allmänheten och hälso- och sjukvården. Merforskning kring varför fatigue uppkommer samt mer utbildning om sjukdomen tillallmänhet och hälso- och sjukvårdspersonal behövs. / Background: The inflammatory bowel diseases Morbus Crohn's and Ulcerativecolitis are a growing problem in the world, a common symptom of the diseases isfatigue. Fatigue is experienced as an intense tiredness and is different from the fatiguethat arises from everyday activities. Aim: To investigate patients' experience offatigue in inflammatory bowel diseases. Method: A literature study with an inductiveapproach. Eight articles have been analyzed according to content analysis wherethemes have been identified. Results: Three main themes were created: the impact offatigue on daily life, the mental and physical consequences of fatigue, the importanceof support from the environment. Five sub-themes were also created: quality of life,the experience of psychological sanctions, the experience of physical sanctions,misunderstanding from the environment and understanding from the environment.Patients felt that fatigue had affected their daily life negatively. Many patientssuffered from anxiety and depression that had developed after the diagnosis.Conclusion: How much the fatigue affected the patients daily life varied from personto person. It was common for patients to experience misunderstandings from thegeneral public and the healthcare. More research on why fatigue occurs as well asmore education about the disease to the general public and health care professionals isneeded.