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English Abstract Crohn's disease together with ulcerative colitis, is a type of inflammatory bowel disease (IBD) with increasing incidence and prevalence in developed countries. IBD is an immunologically mediated multifactorial disease and it's mechanism of action is still unknown. Current well- established treatment targets the inflammation with corticosteroids and immunosuppressive drugs. Apart from the intestinal inflammation, which is the primary target of the treatment, patients are characteristically afflicted with intestinal dysbiosis. Therefore, possible interventions might be an adjuvant or biological therapy. Adjuvant therapy directly aims the microbiota with probiotics, whereas the target of biological therapy is TNF-α, a pro- inflammatory cytokine excessively secreted by macrophages. The aim of this thesis is to evaluate intestinal microbiota composition changes in IBD patients with regard to courses of adjuvant and biological therapy. Bacterial diversity was analyzed using three different DNA extraction techniques. Rapid beat beating + column (RBB+C) was chosen for analyzing patient samples, as it showed the highest DNA yield and the highest DNA purity. Primarily the bacterial diversity was analyzed using degradation gradient gel electrophoresis (DGGE) with subsequent sequencing of bands of...

Living with inflammatory bowel disease (IBD) affects physical, psychological and social dimensions, limiting the ability to engage in daily activities. Persons with IBD may need frequent and lifelong contacts with the healthcare (HC), highlighting the importance of quality care. High quality HC for persons with IBD involves a partnership between the HC professionals and the person living with the disease. Information is essential, the more a person knows about their disease, the more concordant and satisfied with their treatment they are likely to be. The overall aim of this thesis was to describe the knowledge need, life situation and perception of HC among persons living with IBD, in order to develop a questionnaire to evaluate the quality of HC. This thesis is based on three studies that are presented in four papers. Qualitative methods were used to describe aspects of life situation in relation to the disease, whereas quantitative method was used to develop a questionnaire measuring quality of care. Study I and II have an inductive qualitative design. In study I, qualitative interviews with 30 people were performed to describe the knowledge need and experience of critical incidents in daily life while living with IBD. The interviews in study I were analyzed using content analysis (results presented in Paper I) and critical incident technique (results presented in Paper II). In study II, the perceptions of HC among persons living with IBD was explored in five focus group interviews and two individual interviews, in total n=26. Study III aimed to develop and evaluate a questionnaire, measuring quality of care among persons with IBD, including 318 persons with IBD and 8 professionals. The knowledge need among persons with IBD focused on managing symptoms and course of the disease and learning to assimilate the information in order to manage everyday life. Losing bowel control was of great concern for most of the informants in the study. Many of the informants said that “the bowel ruled their life” and that it influenced them to a great extent in their daily lives. The perception of HC among persons with IBD meant being met with respect and mutual trust, receiving information at the right time, shared decision-making, competence and communication, access to care, accommodation, continuity of care and the pros and cons of specialized care. The quality of care questionnaire QoC-IBD was constructed in five dimensions, building on the results from Study I and II. The dimensions were trust and respect, decision-making, information, continuity of care and access to care consisting of 21 questions in total. QoC-IBD is a short, self-administrated questionnaire that measures experiences of healthcare among persons with IBD with promising validity and reliability. To improve quality of care, HC is recommended to consider individual care needs and take the person’s daily life and social context into account. The QoC-IBD questionnaire measures the subjective experience of quality of care. Further testing in clinical practice is necessary to evaluate if QoC-IBD can be used to evaluate the care given and areas of improvement in HC for persons living with IBD.

Background: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder (FGID) which can be defined as chronic, relapsing visceral pain with bloating associated with change in bowel habit. It affects up to 10-15% of the adult population in the UK and is more common in females. The cost of IBS in terms of health care utilisation is substantial, exceeding £45.6 million per year in the UK alone, yet its pathophysiology is incompletely understood. Visceral pain is the main and most difficult symptom to manage in IBS and many IBS female sufferers compare it to labour pain in its severity. Modulating visceral pain in healthy volunteers and IBS patients is therefore an important research area. Non-invasive magnetic stimulation may play a crucial role in this respect. Aim:The aim of this study is to ascertain whether non-invasive repetitive magnetic stimulation applied to the motor cortex and/or lumbosacrum can modulate gastrointestinal pain originating from the anorectum. Methods:Participants: 16 healthy volunteers and 10 IBS patients aged 18 and above were included in the study.Questionnaires: Healthy volunteers and IBS patients were asked to complete anxiety and depression questionnaire and IBS patients were requested to fill in an IBS severity questionnaire.Motor measurements in healthy subjects: Single-pulse lumbosacral magnetic stimulation (LSMS) was applied to the lumbosacral area for the anal sphincter where the largest motor evoked potential (MEP) amplitude response was detected. Single-pulse transcranial magnetic stimulation (TMS) was then performed at the pre-determined resting motor thresholds (RMT) for the anal sphincter and the hand.Sensory measurements in healthy subjects and IBS patients: Electrical stimulation was used to assess the changes in sensory and pain thresholds in the anorectal area. The subjects were asked to score the pain intensity using five-point categorical rating scales. In addition they were asked to describe the pain experienced using a shortened form of the McGill Pain Questionnaire. Intervention: Healthy volunteers received 6 paradigms of magnetic stimulation in a randomised order i.e. 3 repetitive LSMSs (1 Hz, 10 Hz and sham) and 3 repetitive TMSs (1 Hz, 10 Hz and sham) to investigate their modulatory effects on visceral sensitivity and to determine which of these interventions is most effective. The most effective active interventions (1 Hz rLSMS and 10 Hz rTMS) together with one sham were then trialled in a randomised fashion on IBS patients.Post intervention: Motor excitabilities were repeated at 30 min after each intervention. The assessment of sensory and pain thresholds at anal sphincter and rectum were done immediately, 30 and 60 min after each intervention. Results:Application of 1 Hz rLSMS led to alterations of anal sphincter motor excitabilities and resulted in a significant increase in the amplitude of lumbosacal-anal motor evoked potentials (MEPs) in healthy volunteers recorded at 30 min post intervention. In healthy volunteers, 1 Hz rLSMS and 10 Hz rTMS caused a significant increase in the rectal pain thresholds experienced immediately, 30 and 60 min after each intervention. 10 Hz rLSMS and 1 Hz rTMS only led to a significant rise in rectal pain thresholds immediately after their application. Furthermore, there was a significant increase in the rectal pain thresholds immediately, 30 and 60 min following 1 Hz rLSMS and 10 Hz rTMS in IBS patients. Conclusion:The application of magnetic stimulation to the cortical and lumbosacral areas to modulate visceral pain is a new concept, which reduced rectal sensitivity to painful stimuli and offers a much needed new approach in the management of abdominal pain in patients with IBS.

A l`heure où le cancer a supplanté les maladies cardiovasculaires en tant que première cause de mortalité en France, le CCR représente la deuxième cause de mortalité par cancer. Longtemps dominé par la génétique, le paradigme du cancer colorectal a récemment évolué laissant une place prépondérante aux facteurs environnementaux. Il est néanmoins difficile d’étudier l’impact de l’environnement sur la carcinogénèse colorectale de façon exhaustive compte tenu de la multiplicité de ces facteurs environnementaux. Dans la présente étude, nous avons essayé d’appréhender la contribution de la composition du microbiote intestinal, de la composition métabolomique des eaux fécales et des altérations épigénétiques de l’hôte comme témoin de ces facteurs environnementaux au cours de la carcinogénèse colorectale et d’en évaluer le bénéfice en tant que marqueur diagnostique non invasif. Nous avons ainsi pu montrer au sein d’une population de patients à risque moyen de cancer colorectal qu’il existait une signature microbiologique, métabolomique et épigénétique spécifique du cancer colorectal. Nous avons également pu montrer que ces marqueurs présentaient des performances diagnostiques supérieures au test colorimétrique au guaiac utilisé dans le dépistage organisé du cancer colorectal. / Colorectal cancer (CRC) is a significant cause of morbidity and mortality in developed countries. The majority of CRC are called sporadic, meaning they are due to environmental factors rather than constitutional genetic alterations. Indeed, the role of environment, i.e. western lifestyle, is also underlined by dramatic geographic variations in CRC incidence in both sexes. However, it is difficult to take into account the totality of human environmental exposures for a better understanding of the colorectal cancer pathogenesis. In the present work, we tried to highlight the contribution of the environment in the development of colorectal cancer by studying the role of the intestinal microbiota together with the role of the fecal metabolites and the presence of epigenetic alterations of the host. We also investigated the performance accuracy of the latter changes for colorectal cancer diagnosis as compared to the guaiac fecal occult blood test which is widely used as a non-invasive test in several screening program. We demonstrated a specific signature associated with advanced colorectal neoplasia for the intestinal microbiota and the fecal metabolite profile for colorectal cancer as well as a link between colorectal cancer and Wif-1 gene methylation in urine and/or fecal samples. Those specific signatures disclosed higher diagnostic accuracy compared to guaiac fecal occult blood test as colorectal cancer screening test.

Background: Irritable bowel syndrome (IBS) is an extremely common condition affecting approximately 10-15% of the population. Lower abdominal pain is a common feature and, if the patient also has gynaecological symptoms such as heavy periods, they may be referred to a gynaecologist especially when the bowel symptoms are relatively mild. In this setting a laparoscopy is often undertaken and endometriosis commonly identified as this condition affects up to 10% of women. Consequently pain is frequently attributed to the endometriosis even when it is relatively mild. However it is a common observation amongst gynaecologists that women with mild endometriosis often have severe symptoms which do not seem to respond well to treatment. This raises the possibility that their pain may not actually be due to endometriosis or is being amplified by the visceral hypersensitivity which is a characteristic feature of irritable bowel syndrome.Methods: 20 patients with minimal-mild endometriosis, 20 with moderate-severe endometriosis, 20 healthy volunteers (HV) who have had laparoscopy for sterilisation, 20 IBS patients and 20 patients with pain who were found to have a normal pelvis (on laparoscopy) were studied. Gastrointestinal, gynaecological, and noncolonic symptoms were recorded as well as demography, quality of life and psychological status. Visceral sensitivity was assessed in all patients and abdominal distension was studied in a sub group of 26 endometriosis patients and 20 IBS patients.Results: 20 (100%) of IBS patients, 13 (65%) of minimal-mild endometriosis patients, 11 (55%) of moderate-severe endometriosis patients, 17 (85%) of laparoscopic negative pain patients and no healthy volunteers fulfilled ROME III criteria for IBS. Patients with endometriosis and IBS had similar levels of visceral sensitivity which were significantly lower than that observed in controls (p=0·002, p<0·001).In particular, both minimal-mild and moderate-severe endometriosis patients had significantly lower (mean-95% CI) pain thresholds in mmHg 28.1(24.5, 31.6) and 28.8(24.9, 32.6) respectively compared with controls 39·5 (36·0, 43·0) p=0.001and p=0.002. However, with few exceptions, there were no distinguishing features between patients in terms of demography, symptomatology and distension.Conclusion: Clinically, it is very difficult to distinguish between endometriosis and IBS. However, visceral hypersensitivity appears to be a major component of endometriosis and may explain the problem of excessive pain especially in patients with mild disease offering a potential new target for treatment

La maladie de Crohn (MC) et la rectocolite hémorragique (RCH) sont les deux principales formes cliniques des maladies inflammatoires chroniques de l’intestin (MICI) responsables d’une atteinte inflammatoire de la paroi du tube digestif avec des ulcérations extensives. Ce sont des maladies fréquentes en Europe et en Amérique du Nord avec plus de 2.5 millions de malades. Du fait de l’augmentation importante de leur prévalence, de leur morbidité, du retentissement sur la qualité de vie des malades et du coût de leur prise en charge médicale, les MICI sont devenues un problème majeur de santé publique. Au cours de ces maladies, l’inflammation intestinale peut être contrôlée par les traitements médicamenteux ou la chirurgie sans pour autant obtenir de guérison complète et définitive. Bien que leur origine reste mal connue, l’hypothèse actuelle présente les MICI comme des maladies multifactorielles, secondaires à une réponse immunitaire muqueuse anormale dirigée contre la flore intestinale, survenant chez des individus génétiquement prédisposés et entrainant une inflammation intestinale. Le but du travail était d’explorer les mécanismes à l’origine de cette inflammation intestinale associée au développement des MICI en étudiant plus particulièrement certains facteurs environnementaux, moléculaires et microbiens. Nous avons étudiés tout d’abord l’aluminium comme facteur environnemental en démontrant qu’il pouvait participer au développement et à l’aggravation de l’inflammation intestinale sur des modèles de colite chez la souris. Nous avons ensuite étudié un facteur moléculaire important pour l’apoptose des cellules, la caspase-8. Nous avons montré que cette caspase-8 maintenait l’homéostasie intestinale des cellules épithéliales intestinales et que sont absence entraînait une inflammation intestinale ressemblant à la maladie de Crohn. Finalement nous nous sommes intéressés à un facteur microbien, Saccharomyces cerevisiae CNCM I-3856 qui est une levure. Nous avons démontré que cette levure était capable d’induire un effet anti-inflammatoire et analgésique chez l’animal en activant PPAR&#947; dans le colon. Chez l’homme nous avons montré dans une étude randomisée que Saccharomyces cerevisiae CNCM I-3856 réduisait les douleurs abdominales chez les patients atteints du syndrome de l’intestin irritable. En conclusion, l’exploration de ces trois facteurs environnementaux, moléculaires et microbiens permet de mieux comprendre le développement de l’inflammation intestinale. La perspective de ce travail est le développement dans un futur proche des nouvelles thérapeutiques ciblées permettant de lutter contre l’inflammation intestinale. / Crohn's disease (CD) and ulcerative colitis (UC) are the two main clinical forms of chronic inflammatory bowel disease (IBD) responsible for intestinal inflammation with extensive ulceration of the mucosa. These are common diseases in Europe and North America with over 2.5 million patients. Due to the significant increase in their prevalence, their morbidity, the impact on quality of life of patients and the cost of their medical care, IBD has become a major public health problem. In these diseases, intestinal inflammation may be controlled by drug treatment or surgery without obtaining a complete and final cure. Although their origin remains unclear, the current hypothesis presents IBD as multifactorial diseases secondary to an abnormal mucosal immune response directed against the intestinal flora, occurring in genetically predisposed individuals and causing intestinal inflammation. The aim of this work was to explore the mechanisms behind this intestinal inflammation associated with the development of IBD studying some particular environmental, molecular and microbial factors. We studied first the aluminum as an environmental factor and demonstrated that he could participate in the development and exacerbation of intestinal inflammation in models of colitis in mice. We then studied an important factor in molecular cell apoptosis, caspase-8. We have shown that caspase-8 was maintaining intestinal homeostasis in intestinal epithelial cells and that absence of caspase-8 leads to intestinal inflammation mimicking Crohn's disease. Finally we studied a microbial factor, Saccharomyces cerevisiae CNCM I-3856 which is yeast. We demonstrated that this yeast was capable of inducing an anti-inflammatory and analgesic effect in animals by activating PPARgamma in the colon. In humans we have shown in a randomized study that Saccharomyces cerevisiae CNCM I-3856 reduced abdominal pain in patients with irritable bowel syndrome. In conclusion, the exploration of these three environmental molecular and microbial factors helps to better understand the development of intestinal inflammation. The perspective of this work is the development in the near future of new targeted therapies directed against intestinal inflammation.

The purpose of this study was to investigate how children with Inflammatory Bowel Disease (IBD) and their families perceived their school experiences in Québec. IBD is one of many “invisible” chronic diseases. It is considered invisible because it occurs internally without significant observable external symptoms. However, children with IBD experience painful and fluctuating physical symptoms caused by intestinal inflammation, as well as the side effects from medications. As a result, they require special accommodations while they attend public or private school. The Québec Education Act (2010) stipulates that adequate services for a diverse student population must be provided. Consequently, the research sought to answer the following questions: What are the experiences of parents and children with IBD enrolled in general education classrooms? And, what are the experiences of their brother or sister? To research these questions, a case study method was used with five families. The two instruments used to collect the data were, (1) individual semi-structured interviews that followed a modified version of Seidman’s (2006) in-depth interviewing approach and (2) drawings of the family by siblings. The data were analyzed inductively. This study was the first to use a qualitative approach with multiple methods that were guided by Bronfenbrenner’s ecological systems theory (1979) and Turnbull and Turnbull’s family systems theory (2001). The findings revealed that, unlike many studies on families of children with special needs, these families with a child with IBD functioned relatively well. At the microsystem level, mothers assumed responsibility as the primary caregiver. Siblings experienced their own challenges, such as feelings of parental neglect. Nonetheless, they also maintained nurturing roles. Within the mesosystem level, the home and school relationship was impacted. Parents and children with IBD experienced school personnel who lacked awareness of IBD and provided insufficient classroom support, especially at public schools. Hence, parents-(predominantly mothers) played an integral role in advocating for necessary accommodations on their child’s behalf. In contrast to many studies on children with disabilities, children with IBD in this research had many friends in and outside of school. In the exosystem, parents struggled with feelings of guilt at having to balance employment and the high financial expense of caring for a child with IBD. They relied on assistance from government services and their IBD association. At the macrosystem level, family members believed that children with IBD were perceived negatively by society because of the lack of public awareness and the stigma that surrounds the topic of incontinence. This study makes contributions to systems theories and provides practical recommendations to school personnel and parents.

The objectives of this thesis were to synthesize existing RCT evidence and post-market observational evidence of TNF-α inhibitors in IBD. Two separate systematic reviews were performed: an overview of systematic reviews of RCTs, and a systematic review of post-market observational studies of TNF-α inhibitors in Crohn’s disease and ulcerative colitis. The overview of systematic reviews included 37 studies. RCT evidence demonstrated superiority of all agents to placebo in Crohn’s disease and ulcerative colitis, with no increased risk of malignancy or serious adverse events. Network meta-analyses have not shown superiority of any agent compared to another. The second systematic review included 255 studies. Included studies were deemed to be unamenable to pooling with substantial methodological and clinical diversity. Available evidence is insufficient to determine whether real-world effectiveness and safety is consistent with RCTs, but suggests no increased risk of malignancy and no difference in efficacy between adalimumab and infliximab.

La Broncho-Pneumopathie chronique obstructive (BPCO) est un problème majeur en santé publique puisque ce sera la 3ème cause de mortalité en 2020. Il s'agit d'une maladie inflammatoire chronique du poumon se traduisant par une obstruction progressive des bronches, partiellement ou non réversible, incluant bronchite chronique, hypersécrétion de mucus et emphysème. L'atteinte ne se limite pas au poumon et affecte d'autres organes dont le tube digestif en favorisant la maladie de Crohn. Le premier facteur de risque impliqué dans le développement de cette maladie est l’exposition à la fumée de cigarette qui induit un stress oxydatif au sein du poumon responsable d'une inflammation chronique et du développement de la BPCO. L'interleukine-17 joue un rôle essentiel dans ce processus en contrôlant l'inflammation et l'altération de la fonction respiratoire. L'objectif de cette thèse est de comprendre les facteurs contrôlant cette réponse IL-17 afin de proposer ensuite de nouvelles voies thérapeutiques. Dans la première partie, nous nous sommes focalisés sur le stress oxydatif et à son impact sur les cellules de l’immunité innée. Ensuite, nous abordons le rôle d'un facteur immunorégulateur, l'IL-10, et à son interférence avec le microbiote digestif. Cela nous a amené à nous intéresser aux lésions digestives associées au tabagisme. Un modèle murin d’exposition chronique à la fumée de cigarette a été développé afin de reproduire la physiopathologie de la BPCO. Concernant l'impact du stress oxydatif, nous avons étudié le rôle des cellules iNKT (cellules ayant un puissant potentiel dans l’immunorégulation et dans l’inflammation) qui sont activées par ce type de stress. Les cellules iNKT sont rapidement recrutées et activées au sein du poumon suite à l’exposition à la fumée de cigarette. En utilisant des souris déficientes, nous avons montré l’importance de ces cellules dans la physiopathologie de la BPCO. Cette pathogénicité est dépendante de la production de l’interleukine-17 par ces cellules et est initiée par le stress oxydatif sur les cellules épithéliales pulmonaires et les cellules dendritiques qui activent les cellules iNKT.Dans la seconde partie du projet, l’IL-10 intervient notamment dans le contrôle de l'inflammation afin d’éviter le développement de réponses immunologiques exacerbées dans certains contextes. Dans les poumons exposés à la fumée de cigarette, la production d’IL-10 est augmentée et la déficience pour cette cytokine entraîne une augmentation de la réponse Th17 et du déclin de la fonction pulmonaire. Une dysbiose (altération du microbiote) est observée avec la fumée de cigarette et la déficience à l'IL-10. De plus, une déplétion des bactéries Gram+ par antibiothérapie permet de limiter le développement de la réponse IL-17 et de l'atteinte pulmonaire soulignant l'importance du microbiote. En conclusion, nous avons identifié le stress oxydatif et l'IL-10 comme facteurs intervenant dans la réponse IL-17 associé à la BPCO. Ce travail souligne également le rôle du microbiome comme un organe à part entière et la modulation de ce dernier pourrait aboutir à l'identification de nouvelles voies thérapeutiques. / Chronic Obstructive Pulmonary Disease (COPD) is a major health problem which is going to become the third leading cause of death worldwide by 2020. COPD is characterized by a chronic inflammation of the airways causing progressive bronchial obstruction, with no completely reversible airflow limitation, including chronic bronchitis, mucus hypersecretion and emphysema. The pathology is not limited to the airways and can affect others organs including the gastro-intestinal tract promoting Crohn disease. Cigarette smoke exposure is the most important risk factor for developing COPD. Exposure to cigarette smoke induces a strong burden of reactives oxygen species and this oxidative stress is responsible for a chronic inflammation and the development of COPD. Interleukin (IL)-17 plays a critical role in controlling process of inflammation and lung function decline.The aim of this thesis is the understanding which factors are controlling the IL-17 response in order to propose new therapeutic approaches.In the first part, we focused on oxidative stress and its impact on innate immune cells. Then we addressed the role of an immunoregulatory factor, the interleukin (IL)-10, and its interference with intestinal microbiota. This part lead us to study intestinal damages linked to cigarette smoking.To mimic the physiopathology of COPD, we set up a mouse model of chronic exposure to cigarette smoke. Concerning the impact of oxidative stress, we investigated the role of iNKT cells (cells with a crucial potent role in immunoregulation and inflammation) activated by this type of stress. iNKT cells rapidly accumulate and be activated within the lungs of cigarette smoke exposed mice. Using deficient mice, we demonstrated that these cells strongly contribute to the COPD pathogenesis. This pathogenicity is iNKT cells-produced IL-17 dependant and initiated by the effect of oxidative stress on airway epithelial cells and dendritic cells activating iNKT.In the second part of the work, IL-10 interferes notably in the inflammation control in order to avoid exacerbated immunological responses development in some contexts. In cigarette smoke exposed lungs, IL-10 production is up-regulated and the deficiency for this cytokine leads to an increased Th17 response and to lung function decline. An altered microbiota (named dysbiosis) is observed with cigarette smoke exposure and IL-10 deficiency. Moreover, Gram+ bacteria depletion using antibiotics is able to limit the IL-17 response development and the lung function decline highlighting the crucial role for microbiota.To conclude, we identified two factors, oxidative stress and IL-10, implicated in IL-17 response linked to COPD. This work also underlines the role of microbioma as a whole organ and the modulation of this microbioma could result in new therapeutic ways identification in COPD.