Inflammatory Bowel Disease (IBD) is an umbrella term used to describe a group of chronic, relapsing/remitting disorders of the gastrointestinal tract (GIT). While the precise aetiology of IBD is unknown, it is believed to be a result of the interaction of genetics, the immune system and the enteric microbiota. Thus, the search for potentially pathogenic microbial residents of the GIT is a current research focus. Fusobacterium nucleatum (Fn) is a member of the normal human microflora, including the GIT and has a well-characterized role in periodontitis in the oral setting. We have determined that Fn can be frequently recovered from human intestinal biopsies and furthermore, there is a positive correlation between recovery of Fn and the IBD status of the host. Fn strains from IBD patients were more invasive in vitro than strains from healthy controls and also demonstrated the ability to survive and proliferate inside host cells. Furthermore, while Fn strains from both IBD patients and healthy controls were able to induce expression of the pro-inflammatory cytokine IL-8 in vitro, in comparison to strains from controls, Fn strains from IBD patients resulted in decreased levels of IL-8 protein outside the host cells, suggesting that these strains may utilize sophisticated tactics to promote their survival. Thus, differences in virulence determinants among strains may be key to understanding a potential role for Fn in IBD. Characterization of virulence mechanisms utilized by Fn isolates from IBD patients could define a potentially important aspect of microbe/host interactions in this devastating disease, and indicate future therapeutic targets. / Canadian Institutes of Health Research, Canadian Digestive Health Foundation, Crohn's and Colitis Foundation of Canada

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Background and Aims: The opioid epidemic has become increasingly concerning, with the ever-increasing prescribing of opioid medications in recent years, especially in inflammatory bowel disease [IBD] patients with chronic pain. We aimed to isolate the effect of opioid use disorder [OUD] on 30-day readmission risk after an IBD-related hospitalization. Methods: We retrospectively extracted IBD-related adult hospitalizations and 30-day, any-cause, readmissions from the National Readmissions Database [period 2010-2014]. OUD and 30-day readmission trends were calculated. Conventional and exact-matched [EM] logistic regression and time-to-event analyses were conducted among patients who did not undergo surgery during the index hospitalization, to estimate the effect of OUD on 30-day readmission risk. Results: In total, 487 728 cases were identified: 6633 [1.4%] had documented OUD And 308 845 patients [63.3%] had Crohn's disease. Mean age was 44.8 ± 0.1 years, and 54.3% were women. Overall, 30-day readmission rate was 19.4% [n = 94,546], being higher in OUD patients [32.6% vs 19.2%; p < 0.001]. OUD cases have been increasing [1.1% to 1.7%; p-trend < 0.001], while 30-day readmission rates were stable [p-trend = 0.191]. In time-to-event EM analysis, OUD patients were 47% more likely (hazard ratio 1.47; 95% confidence interval [CI]:1.28-1.69; p < 0.001) to be readmitted, on average being readmitted 32% earlier [time ratio 0.68; 95% CI: 0.59-0.78; p < 0.001]. Conclusion: OUD prevalence has been increasing in hospitalized IBD patients from 2010 to 2014. On average, one in five patients will be readmitted within 30 days, with up to one in three among the OUD subgroup. OUD is significantly associated with increased 30-day readmission risk in IBD patients and further measures relating to closer post-discharge outpatient follow-up and pain management should be considered to minimize 30-day readmission risk.

Background & aims: The inflammatory bowel diseases (IBD), Crohn‟s disease (CD) and ulcerative colitis (UC), are common causes of chronic gastrointestinal morbidity, affecting up to 1 in 250 of the general population in Northern Europe. Up to 25% of IBD is diagnosed during childhood or adolescence. The aims for this thesis were to study the epidemiology, natural history and novel genetic determinants of childhood onset IBD in Scotland. Methods: The existing repository of childhood onset and adult onset IBD patients, established at the Western General Hospital in Edinburgh, was used and expanded. Thus, anatomical location and behaviour of disease were assessed in 416 childhood onset (276 CD, 99 UC, 41 IBDU diagnosed before 17th birthday) and 1297 adult patients (596 CD, 701 UC) using the Montreal classification. Additional phenotypic (at diagnosis and at regular follow-up intervals) and epidemiological data were gathered. In this cohort, genotyping of germline variants in putative susceptibility genes (NOD1/CARD4, IL23R, ATG16L1, IRGM, FLG) was performed to enable single variant and haplotype-tagging association studies. Genotypic data of population-matched healthy controls were obtained locally (n=342) and from the Wellcome Trust Case Control Consortium (n=2937). Results: Compared with adults, childhood-onset CD was characterized by a more extensive, “panenteric” phenotype (ileocolonic plus upper GI; p<0.0001 OR23.3; 95% CI (13.4–40.6) with less isolated ileal (p<0.0001 OR 0.06 (0.03–0.1) or colonic disease (p<0.0001, OR 0.3 (0.2–0.5)). In 39%, the anatomic extent increased within 2 years. UC was also more extensive in children at diagnosis vs adults (p<0.0001 OR 5.1 (2.7–9.4)). In population-matched and age, sex and postcode-matched case-control analysis, childhood onset IBD and CD was associated with asthma (p<0.0001 OR 1.7 (1.3-2.1) and (p=0.005 OR 2.5 (1.3-4.8), respectively). Inherited variation of NOD1/CARD4 was not a strong determinant of disease susceptibility in the Scottish population (both in single marker and haplotype-tagging studies, all p>0.05 after Bonferroni correction). We found that the allelic frequency of rs11209026*A located within the IL23R gene, differed significantly between IBD/CD cases and controls (p=0.01 OR 0.51(0.3-0.9) and p=0.04 OR 0.5 (0.3-0.98)). Using a gene-wide haplotype-tagging strategy, we demonstrated that the multiple association signals of the IL23R locus are independent of rs11209026 in childhood onset IBD and CD. In Scottish children, the effect of germline variation of ATG16L1 and IRGM on CD susceptibility was relatively small (OR< 1.4), and appeared less than in adult disease. Genotype–phenotype analysis demonstrated an association of pure ileal disease with the ATG16L1 rs2241880G-allele (p=0.02 OR 1.3 (1.03–1.7)). Using binary logistic regression analysis, we confirmed the effect of rs2241880 genotype (GG) on ileal disease versus colonic disease (p=0.03 OR 2.4 (1.05–5.6)). Null alleles of the epithelial barrier protein FLG have no important effect on IBD susceptibility (p>0.4), but contribute to the high prevalence of atopy, notably co-existent eczema and food allergy (p=0.0003 OR 3.3 (1.7–6.6) and p=0.0001 OR 4.5 (2.0–10.0), respectively). Conclusion: Childhood onset IBD is characterised by extensive intestinal involvement and progression of disease after diagnosis. Genetic association studies in childhood and adult IBD have provided evidence for a large number of new genomic loci. These loci encode genes involved in a number of homeostatic mechanisms: innate pattern recognition receptors, the differentiation of Th17-lymphocytes, autophagy, maintenance of epithelial barrier integrity and the orchestration of the secondary immune response.

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Les Maladies Inflammatoires Chroniques de l’Intestin (MICI) comprennent la maladie de Crohn (MC) et la rectocolite hémorragique (RCH). Ce sont des inflammations chroniques du tube digestif dont les causes sont inconnues. Une meilleure connaissance de leur épidémiologie pourrait orienter vers des pistes étiologiques. Jusqu’à la création du Registre EPIMAD en 1988, il n’existait en France aucune donnée d’incidence. Nous avons créé en 1988 une étude prospective d’incidence des MICI, reconnu «Registre» par l’Inserm et l’InVS en 1992. Le territoire couvert par Epimad comporte le Nord, le Pas-de-Calais, la Somme et la Seine-Maritime avec près de 6 millions d’habitants soit 9,3% de la population française. La collection des cas repose sur une collaboration multidisciplinaire incluant les gastroentérologues (GE) (libéraux, hospitaliers, adultes et pédiatres; n=262), les services d’Epidémiologie de Lille et Rouen, la plateforme d’aide méthodologique en Biostatistiques du CHRU de Lille et les Centres Hospitalo-Universitaires de Lille, Amiens et Rouen. Neuf enquêteurs se déplacent sur les lieux de consultation des GE et recueillent les informations nécessaires à la validation des diagnostics. Deux GE experts revoient chaque dossier indépendamment et posent le diagnostic final de MC ou RCH certaine, probable ou possible, de colite indéterminée, de colite aiguë ou de colite inclassée. Pour les cas atypiques et non classés, un suivi systématique est effectué pour le classement définitif (MICI ou non MICI). Un croisement des bases du Registre et des bases hospitalières est effectué une fois par an pour mesurer l’exhaustivité. 80% des cas incidents sont diagnostiqués par les GE libéraux, 13% par les GE des hôpitaux généraux et 7% par les GE universitaires. Entre 1988 et 2008, l’incidence moyenne des MICI était de 11,3/105 habitants (6,4 pour la MC, 4,4 pour la RCH et 0,5 pour IBDU). Pendant cette période, l’incidence de la MC a augmenté de 30% (100% chez l’adolescent) alors que celle de la RCH est restée stable. Le délai diagnostique médian était de 3 mois dans la MC et de 2 mois dans la RCH. Le pourcentage de patients ayant un diagnostic posé plus de 9 mois après l’apparition des symptômes a diminué avec le temps. La validité diagnostique dans les cas non classant d’emblée a été assurée par un suivi de 2 ans et a montré que seul l’âge < 40 ans était prédictif d’une évolution vers une MICI chez un patient présentant une colite aiguë. Nous avons aussi mis en évidence des présentations cliniques différentes en fonction de l’âge. Ainsi, chez l’adulte jeune, la MC est plus étendue que chez les sujets > 60 ans au diagnostic. Grâce à un nombre élevé de cas incidents, une hétérogénéité spatiale de l’incidence des MICI a été montrée dans les zones agricoles et suburbaines sans lien avec le niveau social des populations. En utilisant la méthode des statistiques de scan rajoutant la dimension temporelle à l’analyse spatiale, nous avons trouvé plusieurs clusters de sur et sous incidence constants dans le temps. Nos perspectives sont: 1) Poursuivre l’enregistrement des cas incidents et établir des données de prévalence; 2) Etudier les facteurs de risque environnementaux par des études d’épidémiologie analytique (corrélations écologiques, études cas témoins, études exposés-non exposés); 3) Etudier les facteurs de risque génétiques (fréquence des variants NOD2) dans la population du Registre; 4) Créer une étude prospective sur les paramètres prédictifs (profil génétique, profil métagénomique du microbiote intestinal, profil sérologique) de développer une MC dans une population de sujets à haut risque (sujets indemnes de MC âgés de 10 à 35 ans et appartenant à une famille multiplexe, à la descendance de formes conjugales ou à une paire de jumeaux discordants). Conclusions: EPIMAD est le plus gros Registre mondial sur les MICI en population générale, reconnu pour la qualité de ses travaux, rendu possible par la création d’un réseau-ville-hôpital unique. / Inflammatory Bowel Disease (IBD) including Crohn’s disease (CD) and ulcerative colitis (UC) are among the most serious and perplexing of digestive diseases. Their pathophysiology remains poorly understood. Geographic variations in the incidence of IBD could offer new clues about environmental risk factors. There were no data concerning the incidence of IBD in France. We created the first French prospective study on IBD incidence in 1988. This study became “Registre” recognized by Inserm and InVS in 1992. This prospective study was performed through all gastroenterologists (GE) (n=262) of the region of Nord, Pas-de-Calais, Somme and Seine-Maritime including near of 6 million of inhabitants corresponding to 9.3% of the whole French population. Collection of new cases is based on a close multidisciplinary collaboration including GE (whatever their practice), Epidemiology Unit of Hospital and University of Lille and Rouen, Biostatistics Unit of Lille Hospital and University and Academic Hospitals of Amiens, Lille and Rouen. Each GE referred patients consulting for the first time with clinical symptoms compatible with IBD. Data are collected by 9 interviewer practitioners present at the GE’s consulting room. Two independent experts GE assessed each case independently and made a final diagnosis of definite, probable, possible CD, UC or ulcerative proctitis (UP); Inflammatory Bowel Disease unclassifiable (IBDU); acute colitis or unspecified colitis. Possible cases of IBD, acute colitis and unspecified colitis are systematically followed-up and when a new event is recorded the chart is reviewed by the experts and a new final diagnosis is made. A control of the completeness collection is made each year by crossing data from Hospital Health databases. 80% of incident cases have been reported by private GE, 13% by general hospitals and 7% by academic centres. From 1988 to 2008 the mean annual incidence was 11.3/105 inhabitants for IBD including 6.4 for CD, 4.4 for UC and 0.5 for IBDU with a ratio CD/UC of 1.45. During this period CD incidence increased by 30% (100% in young adults) while that of UC remained stable. Valuable clinical information has been obtained; median time between onset of symptoms and diagnosis was 3 months in CD and 2 months in UC. The number of patients with a diagnosis delay > 9 months decreased over time. Age < 40 years at diagnosis was the only clinical predictor for subsequent IBD in patients with an initial diagnosis of acute colitis. Clinical presentation according to age at diagnosis may influence clinical course of IBD. In younger patients IBD had a more disabling course than in the elderly-onset IBD patients. Thanks to the large number of incident cases, we assessed spatial IBD incidence variation at the canton level and analyzed its association with a deprivation index. A spatial heterogeneity was found with a noteworthy predominance of CD in agricultural areas but no significant link with deprivation. We completed the spatial analysis using spatial scan statistics methods allowing revealing several time-constant (since 1988) clusters and other time-varying clusters. Perspectives: 1) To continue to record incident cases and establish prevalence data of IBD; 2) To study environmental risk factors using epidemiological analytic studies; 3) To study genetic risk factors establishing a geographic map of NOD2 variants in the EPIMAD’s area and 4) To assess the predictiveness of patient microbiota and host factors in a prospective, longitudinal study enrolling yet-healthy subjects at risk to develop CD (healthy patients aged 10-35 years and belonging to discordant twins, to offspring of IBD affected couples and to IBD multiplex families). In conclusion, since 1988, the EPIMAD registry has been recognized as a valuable tool for studies on genetic and environmental risk factors. It has also made it possible to reinforce networking between private practices, general and university hospitals at a regional level.