Crohns sjukdom är en kronisk inflammatorisk tarmsjukdom av okänd orsak. Det tidigaste tecknet på Crohns sjukdom är mikroskopiska sår i det s.k. follikelassocierade epitelet (FAE) som täcker ansamlingar av immunceller i tarmen. FAE är specialiserat för att fånga innehåll från tarmen och transportera det till underliggande immunvävnad. Denna funktion är viktig för att inducera skyddande immunsvar, men den utgör också en ingångsväg för sjukdomsalstrande bakterier. Crohns sjukdom är associerat med ett kraftigt ökat immunsvar mot bakterier, och sjukdomsförloppet kan ändras av stress. Det övergripande syftet med avhandlingen var att studera effekterna av stress på FAE samt att undersöka rollen av FAE vid utvecklingen av tarminflammation, särskilt vid Crohns sjukdom. Inledningsvis studerades effekterna av psykologisk stress på FAE. Stressade råttor uppvisade ökad genomsläpplighet av bakterier efter stress, och passagen var högre i FAE än i vanligt epitel. Efterföljande experiment visade att stressförändringarna i slemhinnan regleras via kortikotropinfrisättande hormon och mastceller. Vidare visade det sig att vasoaktiv intestinal peptid kunde efterlikna stressens effekter på genomsläppligheten, och att detta kunde förhindras genom att blockera mastcellerna. Studier av tunntarmsslemhinna från patienter med icke-inflammatorisk tarmsjukdom och friska kontroller visade en högre passage av bakterier i FAE än i vanligt epitel. Hos patienter med Crohns sjukdom var bakteriepassagen genom FAE betydligt ökad jämfört med kontroller. Resultaten från detta avhandlingsarbete visar att stress kan förändra upptaget av bakterier från tarmen via FAE, med mekanismer som innefattar kortikotropinfrisättande hormon och mastceller. Detta har gett nya kunskaper kring regleringen av slemhinnebarriären. Vidare presenterar denna avhandling nya insikter i sjukdomsuppkomsten vid Crohns sjukdom genom att påvisa en tidigare okänd defekt i barriärfunktionen i FAE. / The earliest observable signs of Crohn’s disease are microscopic erosions in the follicle-associated epithelium (FAE) covering the Peyer’s patches. The FAE, which contains M cells, is specialised in sampling of luminal content and delivery to underlying immune cells. This sampling is crucial for induction of protective immune responses, but it also provides a route of entry for microorganisms into the mucosa. Crohn’s disease is associated with an increased immune response to bacteria, and the disease course can be altered by stress. The overall aim of this thesis was to study the effects of stress on the FAE and elucidate the role of FAE in the development of intestinal inflammation, specifically Crohn’s disease. Initially, rats were submitted to acute and chronic water avoidance stress to study the effects of psychological stress on the FAE. Stressed rats showed enhanced antigen and bacterial passage, and the passage was higher in FAE than in regular villus epithelium (VE). Further, stress gave rise to ultrastructural changes. Subsequent experiments revealed the stress-induced increase in permeability to be regulated by corticotropin-releasing hormone and mast cells. Furthermore, vasoactive intestinal peptide (VIP) mimicked the stress effects on permeability, and the VIP effects were inhibited by a mast cell stabiliser. Human studies of ileal mucosa from patients with non-inflammatory disease and healthy controls showed a higher antigen and bacterial passage in FAE than in VE. In patients with Crohn’s disease, the bacterial passage across the FAE was significantly increased compared to non-inflammatory and inflammatory controls (ulcerative colitis). Furthermore, there was an enhanced uptake of bacteria into dendritic cells, and augmented TNF-α release in Crohn’s disease mucosa. Taken together this thesis shows that stress can modulate the uptake of luminal antigens and bacteria via the FAE, through mechanisms involving CRH and mast cells. It further shows that human ileal FAE is functionally distinct from VE, and that Crohn’s disease patients exhibit enhanced FAE permeability compared to inflammatory and non-inflammatory controls. This thesis presents novel insights into regulation of the FAE barrier, as well as into the pathophysiology of Crohn’s disease by demonstrating a previously unrecognised defect of the FAE barrier function in ileal Crohn’s disease.

Laboratory analyses, essential in screening, diagnosis, treatment, and monitoring of disease, are indispensable in health care, but appropriate utilization is intricate. The overall aim of this thesis was to study the use of laboratory tests in Sweden with the objective to evaluate and optimize test utilization. Considerable inter-county variations in test utilization in primary health care in Sweden were found; variations likely influenced by local traditions and habits of test ordering leading to over- as well as underutilization. Optimized test utilization was demonstrated to convey improved quality and substantial cost savings. It was further established that continuing medical education is a suitable means of optimizing test utilization, and consequently enhancing quality and cost-efficiency, as such education was demonstrated to achieve long-lasting improvements in the test ordering habits of primary health care physicians. Laboratory tests are closely associated with other, greater, health care costs, but their indirect effects on other areas of medicine are rarely evaluated or measured in monetary terms. In an illustrative example of the effects that optimal test utilization may have on associated health care costs it was demonstrated that F-calprotectin, a fecal marker of intestinal inflammation, has the potential to substantially reduce the number of invasive investigations necessary in, and the costs associated with, the diagnosis of Inflammatory Bowel Disease. Information on trends in test utilization is essential to optimal financial management of laboratories. A longitudinal evaluation revealed that test utilization had increased by 70% in 6 years, and even though the selection of tests more than doubled, a very small number of tests represented a stable, and disproportionally large, share of the total number of tests ordered. The study defines trends and thus has potential predictive values. In summary, appropriate utilization of laboratory analyses has both clinical and economical benefits on all levels of health care.

Understanding of chronic sequelae development after infection with foodborne pathogens is limited and an increased understanding could assist with the development of more accurate burden of disease estimates. The purpose of this thesis was to determine via systematic review and meta-analysis of the published international literature, the proportion of cases of Salmonella, Campylobacter and E. coli O157 that will develop the chronic sequelae of reactive arthritis, haemolytic uraemic syndrome, irritable bowel syndrome, inflammatory bowel disease or Guillain Barré syndrome. This information can be used to increase our understanding of the relationship between infection and the development of long term health complications while providing a key piece of information for the development of accurate burden of disease estimates. / Canadian Institutes of Health Research Institute of Population and Public Health/Public Health Agency of Canada, Applied Public Health Research Chair (awarded to Jan M. Sargeant)

Interleukin-10 (IL-10) is an important regulator of immune responses secreted by different cell types. Previous results from our group suggested that the biological effects of this cytokine critically depend on its cellular source. Recent studies reported IL-10 dependent immunosuppressive functions of a specialized subset of regulatory B cells and mast cells. These results relied on adoptive cell transfers, a technique which can potentially introduce artifacts. Therefore, we aimed to readdress these questions in independent models using IL-10 transcriptional reporter mice and various conditional IL-10 mutant mice. Findings in IL-10 reporter system suggested prominent IL-10 transcription in regulatory B cells upon LPS administration. Exposure of mice to contact allergen revealed robust reporter expression in CD8 T cells, moderate to mild reporter expression in CD4 T cells and dendritic cells (DC) respectively, and lack of reporter expression in B cells, mast cells and NK cells in allergen challenged ears. We generated cell-type specific IL-10 mutants by Cre/LoxP-mediated conditional gene inactivation. Efficiency and specificity of Cre-mediated recombination was demonstrated by Southern blot and PCR methods. Various immunogenic challenges in conditional IL-10 mutants did not reveal a role for B cell-derived IL-10 in restraining innate TLR or T cell-dependent inflammatory responses. Likewise, mice with selective inactivation of the il10 gene in mast cells exhibited normal CHS responses and unaltered immune response to CpG oligodeoxynucleotides. On the other hand, DC-specific IL-10 mutants developed excessive inflammatory responses to contact allergens, while innate responses to TLR ligands were not altered. This indicates a non-redundant role for DC-derived IL-10 in contact allergy. Thus, the conditional IL-10 ‘‘knockout’’ mice combined with the novel transcriptional IL-10 reporter system can serve as ideal tools to understand the cell-type specific contributions to IL-10-mediated immune regulation.

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...

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2017-04-07T12:49:00Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Tese Mayara final [08-09-2016].pdf: 6000027 bytes, checksum: 8aba9ff907d1176a530d19ec2bb6fad1 (MD5) / Made available in DSpace on 2017-04-07T12:49:00Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Tese Mayara final [08-09-2016].pdf: 6000027 bytes, checksum: 8aba9ff907d1176a530d19ec2bb6fad1 (MD5) Previous issue date: 2015-09-02 / CAPES / Doença inflamatória intestinal descreve um grupo heterogêneo de doenças inflamatórias crônicas do trato gastrointestinal. Os dois principais tipos de DII são retocolite ulcerativa idiopática e doença de Crohn. A patogênese dessas doenças é caracterizada pela inflamação persistente no intestino, envolvendo uma interação entre fatores genéticos, ambientais e imunológicos. Foram investigados aspectos clínico-epidemiológicos e analisados os polimorfismos dos genes da reposta imune em pacientes brasileiros com doença inflamatória intestinal em diferentes formas anátomo-clínicas. Um total de 101 pacientes foram analisados (43 - retocolite ulcerativa idiopática e 58 - doença de Crohn) para os polimorfismos dos genes do fator de necrose tumoral alfa (TNF-α -308 G/A; rs1800629), interleucina-10 (IL-10 -1082 G/A; rs1800896), domínio do recrutamento e ativação da caspase 15/receptor tipo NOD2 (CARD15/NOD2; rs2066844 e rs2066845), receptor tipo NOD contendo domínio pirina – NLRP1 (rs12150220), NLRP3 (rs35829419) e interleucina -1beta (IL-1β -511T/C; rs16944). A forma anatómica-clínica de DC predominante foi a fistulizante (29,31%), seguida por inflamatória (27,58%) e estenosante (27,58%). O grupo controle foi composto por 91 indivíduos saudáveis. Os genes do receptor tipo NOD contendo domínio pirina 1 e 3 e do domínio do recrutamento e ativação da caspase 15/receptor tipo NOD2 variantes R702W e G908R não foram associados à susceptibilidade a doença inflamatória intestinal. Em relação ao polimorfismo da interleucina 10, nenhuma diferença estatística foi encontrada entre os genótipos e alelos para a doença inflamatória intestinal comparado aos controles. Fator de necrose tumoral alfa mostrou uma associação estatisticamente significativa entre pacientes e controles de retocolite ulcerativa idiopática que sugere que a presença do alelo A predispõe o aparecimento de retocolite ulcerativa idiopática, mas não doença de Crohn. Verificou-se ainda que o genótipo AG da interleucina 1 foi associado com o desenvolvimento de retocolite ulcerativa idiopática. Os resultados sugerem que os polimorfismos de única base do fator de necrose tumoral alfa e da interleucina 1 estão envolvidos com a retocolite ulcerativa idiopática e podem contribuir para a patogênese na população brasileira estudada. / Inflammatory bowel disease describes a heterogeneous group of chronic inflammatory diseases of the gastrointestinal tract. The two main types of inflammatory bowel disease are ulcerative colitis and Crohn disease. The pathogenesis of the disease is characterized by unpredictable attacks of inflammation of the intestine, besides involving an interaction between genetic, environmental and immunological factors. Clinical and epidemiological aspects were investigated and the polymorphisms of genes of the immune response in Brazilian patients with inflammatory bowel disease in different anatomic-clinical forms were analyzed. A total of 101 patients were analyzed (43 - ulcerative colitis and 58 - Crohn disease) for the tumour necrosis factor alpha (TNF-α -308 G/A; rs1800629), interleukin-10 (IL-10 -1082 G/A; rs1800896), caspase activation and recruitment domains 15/ NOD like receptor 2 (CARD15/NOD2; rs2066844 and rs2066845), NOD like receptor pyrin domain containing – NLRP1 (rs12150220), NLRP3 (rs35829419) and interleukin-1beta (IL-1β 511T/C; rs16944) genes polymorphisms. The anatomic-clinical form of Crohn disease predominant was the fistulizing (29.31%), followed by inflammatory (27.58%) and stricturing (27.58%). A control group was composed by 91 healthy subjects group. NOD like receptor pyrin domain containing 1 and 3 and caspase activation and recruitment domains 15/ NOD like receptor 2 genes R702W and G908R variants were not associated to inflammatory bowel disease susceptibility. With respect to the polymorphism of interleukin-10, no statistical difference was found between the genotypes and alleles for inflammatory bowel disease compared to controls. Tumour necrosis factor alpha showed a statistically significant association between ulcerative colitis patients and controls which suggests that the presence of A allele predisposes the onset of ulcerative colitis but not Crohn disease. It was found yet that AG genotype of interleukin-1beta was associated with the development of ulcerative colitis. The results suggest that the tumour necrosis factor alpha and interleukin-1beta single nucleotide polymorphisms are involved with ulcerative colitis and may be contributing to pathogenesis in Brazilian population.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-10-02T18:24:18Z No. of bitstreams: 1 andrealemoscabalzar.pdf: 1656685 bytes, checksum: e9910962b3bc92892b53761e1aa94f40 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-10-09T19:56:16Z (GMT) No. of bitstreams: 1 andrealemoscabalzar.pdf: 1656685 bytes, checksum: e9910962b3bc92892b53761e1aa94f40 (MD5) / Made available in DSpace on 2017-10-09T19:56:16Z (GMT). No. of bitstreams: 1 andrealemoscabalzar.pdf: 1656685 bytes, checksum: e9910962b3bc92892b53761e1aa94f40 (MD5) Previous issue date: 2017-08-11 / Introdução: Atividade física de vida diária e capacidade de exercício nunca foram avaliadas em pacientes com Doença de Crohn (DC) em remissão induzida por infliximabe. Objetivos: Nosso objetivo foi avaliar a atividade física de vida diária, capacidade de exercício, qualidade de vida (QV) e desordens do humor em pacientes com DC moderada a grave em remissão induzida por infliximabe, e investigar variáveis associadas com atividade física de vida diária nestes pacientes. Métodos: Um estudo transversal foi conduzido, com 26 pacientes com DC foram selecionados. Controles foram indivíduos assintomáticos com dispepsia funcional. Os pacientes foram avaliados quanto à atividade física de vida diária pelo acelerômetro triaxial, à capacidade de exercício (shuttle walk test – SWT), força de preensão manual, QV e desordens de humor. As associações entre a atividade física de vida diária e a QV ou desordens do humor foram testadas. Resultados: O número de passos dado (7446 ± 3081 vs. 7898 ± 2487), o tempo ativo (80,56 ± 41,97 min vs. 89,65 ± 24,30 min), a distância percorrida no SWT (662,69 ± 252,86 m vs. 728,82 ± 346,55 m) e a força de preensão manual (34,3 ± 11,1 kgf vs. 32,9 ± 11,9 kgf) não mostraram significância estatística entre pacientes com DC e controles. O tempo gasto deitado (116,31 ± 107,38 min vs. 63,71 ± 55,79 min) e alguns domínios da QV foram superiores em pacientes com DC (p< 0,05). Nenhuma correlação foi observada entre o nível de atividade física de vida diária e QV ou desordens de humor em pacientes com DC (p>0,05). Conclusão: Nós encontramos que pacientes com DC em remissão induzida por infliximabe tem o mesmo nível de atividade física de vida diária e capacidade de exercício quando comparados com controles. / Background: Physical activity in daily life and exercise capacity have never been assessed in Crohn’s disease (CD) patients on infliximab-induced remission. Objective: We aimed to evaluate the physical activity in daily life, exercise capacity, quality of life (QoL) and mood disorders in patients with moderate-to-severe CD on infliximab-induced remission, and to investigate variables associated with physical activity in daily life in these patients. Methods: A cross-sectional study was conducted, in which 26 patients with CD were selected. Controls were currently asymptomatic individuals with functional dyspepsia. Patients underwent to evaluation of physical activity in daily life by a triaxial accelerometer, exercise capacity (shuttle walk test-SWT), handgrip strength, QoL and mood disorders. The associations between the physical activity in daily life and QoL or mood disorders were tested. Results: The number of steps taken (7446 ± 3081 vs. 7898 ± 2487), the active time (80.56 ± 41.97 min vs. 89.65 ± 24.30 min), the SWT distance (662.69 ± 252.86 m vs. 728.82 ± 346.55 m) and the handgrip (34.3 ± 11.1 kgf vs. 32.9 ± 11.9 kgf) didn’t show significant difference between CD patients and controls, respectively. The time spending lying down (116.31 ± 107.38 min vs. 63.71 ± 55.79 min) and some domains of quality of life were superior in CD patients (p< 0.05). No correlation was observed between the level of physical activity in daily life and QoL or mood disorders in CD patients (p>0.05). Conclusions: We found that patients with CD on infliximab-induced remission have the same level of physical activity in daily life and exercise capacity when compared with controls.

L’utilisation d’agents anti-TNF a grandement amélioré la prise en charge de certaines maladies inflammatoires chroniques comme la polyarthrite rhumatoïde (PR) ou les maladies inflammatoires chroniques de l’intestin (MICI). Cependant, le quart des patients environ ne vont pas répondre au traitement ou présenteront une perte de réponse secondaire. Des marqueurs prédictifs de réponse sont nécessaires afin limiter les effets secondaires et les coûts inutiles en ciblant les patients qui pourraient être améliorés par les anti-TNF. Ces travaux de recherche se sont dans un premier temps concentrés sur l’importance de l’immunogénicité de ces traitements. Des anticorps anti-médicaments (ADAs) étaient bien associés à un taux bas d’anti-TNF avec des conséquences cliniques en termes de perte de réponse clinique et d’absence de cicatrisation muqueuse dans les MICI. Des seuils cliniques d’interprétation des tests biologiques pour la détection du médicament et de ses anticorps ont pu être définis et correspondent à 4.9 μg/ml pour l’infliximab et 200 ng/ml pour les ADAs. Ces résultats obtenus par ELISA sont bien corrélés avec les tests fonctionnels réalisés en parallèle et confirment l’intérêt de cette technique dans ce dépistage. Les ADAs étaient diminués par traitement immunosuppresseur concomitant. Ensuite, la persistance d’une infection chronique mise en évidence par des anticorps anti-bactériens a été évaluée en tant que marqueur prédictif de réponse aux anti-TNF. Aucun résultat statistiquement significatif n’a pu être relevé sur ces premières données, que ça soit pour les anticorps dirigés contre la flore intestinale pour les MICI ou contre le microbiote oral dans la PR. Seul un taux élevé de MMP-3 à l’initiation de l’infliximab chez les patients PR prédisait d’une bonne réponse clinique selon les critères de l’EULAR par la suite / The use of anti-TNF agents has greatly improved the management of chronic inflammatory diseases such as rheumatoid arthritis (RA), or chronic inflammatory bowel disease (IBD). However, about a quarter of patients will not respond to treatment or will present a secondary loss of response. Predictive biomarkers of response are needed to reduce side effects and unnecessary costs by targeting patients that could be improved by anti-TNF. This research work was initially focused on the importance of immunogenicity of these treatments. Anti-drug antibodies (ADAs) were well associated with low levels of anti-TNF with clinical consequences in terms of loss of clinical response and absence of mucosal healing in IBD. Clinical thresholds for drug and ADAs have been defined and correspond to 4.9 μg/ml for infliximab and 200 ng/ml for ADAS. These results obtained by ELISA correlate well with functional tests done in parallel, and confirm the value of this technique for screening. The ADAs were decreased with concomitant immunosuppressive therapy. Then, the persistence of chronic infection as evidenced by anti-bacterial antibody was evaluated as a predictive marker for response to anti-TNF. No statistically significant results could be raised on these first data, for antibodies against the intestinal flora in IBD or against the oral microbiota in RA. Only high levels of MMP-3 at the initiation of infliximab in RA patients predicted a good clinical response according to the EULAR criteria

Background: We have recently shown that dysregulation of redox-sensitive signaling pathways and oxidative damage to biological structures are major contributors to experimental ulcerative colitis. We also demonstrated the powerful anti-oxidant and anti-inflammatory actions of dietary apple peel polyphenols (DAPP) in the intestine. Objectives: As mitochondria are major sources and target of free radicals, as well as exhibit various important cellular functions, we evaluated their roles in intestinal colitis and their responses to DAPP. Methods: Induction of intestinal inflammation in C57BL6 mice was performed by administration of 3% dextran sulfate sodium (DSS). Two different doses of DAPP (200 and 400 mg/kg/day) were administered by gavage for 10 days (before and during DSS administration) to examine the preventive and curative effects, respectively, on inflammation and oxidative stress (OxS) in the intestine, and on mitochondrial functions. Results: DSS caused a significant weight loss, shortening of the colon, increased OxS (noted by lipid peroxidation), and raised inflammation (verified by infiltration of inflammatory cells, up-regulation of MPO, and elevated TNF-α and COX2 protein expression). Furthermore, DSS induced perturbations in mitochondrial biogenesis, as reflected by alterations of the transcription factor PGC1α and mitochondrial function characterized by diminished Adenosine-5'-Triphosphate (ATP) production, lowered antioxidant defense (GPx and SOD2), amplified apoptosis (as illustrated by the high expression of Cytochrome C and AIF), and defects in DNA integrity (high 8-OHdG). However, DAPP administration improved macroscopic parameters (e.g. weight loss, colon shortening) and reduced DSS-induced clinical signs. DAPP showed an evident capability of reducing inflammation (as noted by decreased TNF-α, iNOS, COX-2 and AP-1) and OxS (as shown by reduced malondialdehyde, hydrogen peroxide levels and increased GPx) in DSS mice. Our findings also revealed that DAPP partially corrected mitochondrial dysfunction related to redox homeostasis, fatty acid β-oxidation, ATP synthesis, apoptosis and regulatory mitochondrial transcription factors (PGC1α, PPARγ and Nrf-2). Conclusion: DAPP have the ability to act on intestinal OxS, inflammation and mitochondrial dysfunction, thereby alleviating colitis progression via the modulation of cellular energy, OxS, antioxidant capacity, apoptosis and mtDNA integrity. / Contexte: L'inflammation et le stress oxydatif (OxS) participent à la pathogenèse de la colite ulcéreuse (CU). Nos résultats récents montrent que les polyphénols de la pelure de pomme (DAPP) jouent un rôle clé dans la prévention de la maladie. Objectifs: Évaluer les effets préventifs et curatifs du DAPP sur la CU et démontrer leur impact sur la dysfonction mitochondriale. Méthode: Une induction de l’inflammation intestinale a été effectuée chez des souris par administration du dextran sulfate sodium (DSS). Des doses de DAPP (200 et 400 mg/kg/j) ont été administrées par gavage pendant 10 jours afin d’évaluer les effets préventifs et curatifs, respectivement, sur l’Inflammation et le OxS au niveau intestinal ainsi que sur les fonctions mitochondriales. Résultats: Le DSS a provoqué une perte de poids, un raccourcissement du côlon, une augmentation du stress oxydant, niveaux de malondialdéhyde et une inflammation documentée par l’infiltration des cellules inflammatoires, la myéloperoxydase et les cytokines inflammatoires. D’autre part, le DSS a induit des désordres au niveau de la biogenèse (PGC1α) et des fonctions de la mitochondrie : diminution de l’ATP, altération des enzymes antioxydantes (SOD2 et GPX1), augmentation de l’apoptose (Bcl 2, Bax et Cytochrome C), et des défauts de l’intégrité de l’ADN (baisse d’OGG1). Cependant, le DAPP a amélioré significativement l’inflammation et le stress oxydant de l’intestin tout en corrigeant les aberrations mitochondriales. Conclusions: Les polyphénols ont la capacité d’agir sur le stress oxydant et le profil inflammatoire de l’intestin ainsi que sur le dysfonctionnement mitochondrial. Ils pourraient donc intervenir efficacement dans la CU.

Le diagnostic des pathologies du tube digestif pouvant favoriser la survenue du cancer colorectal(CCR) telle que les maladies inflammatoires chroniques de l'intestin (MICI) est un enjeu majeur de santé public. Un meilleur suivi du patient – impactant notamment le pronostic vital – et une meilleure compréhension de la physiopathologie de ces maladies reposent en partie sur l'émergence de nouvelles techniques diagnostiques. Dans ce contexte, ce manuscrit décrit les développements instrumentaux et méthodologiques combinant séquentiellement au sein d'un même protocole un examen par IRM endoluminale avec un examen associant l'endoscopie conventionnelle, la spectrophotométrie optique et l'endomicroscopie confocale. Les capteurs et procédures développés ont été caractérisés in vitro sur des modèles organiques puis évalués au cours de deux suivis longitudinaux sur un modèle de colite induite chimiquement chez le petit animal. Cette démarche s'inscrit dans les développements récents de techniques multimodales applicables chez des modèles animaux pour des études méthodologiques ou chez l'Homme. La première partie du manuscrit décrit un panorama de l'anatomie rectocolique ainsi que des MICI et du CCR. Les moyens diagnostics actuels utilisés de manière régulière en clinique sont également présentés. La seconde partie décrit précisément les développements instrumentaux et méthodologiques réalisés en IRM et en optique ainsi que les différentes études in vivo qui ont été menées afin d'évaluer le potentiel de la multimodalité IRM – optique. Enfin, la troisième partie de ce manuscrit présente et discute les résultats obtenus au cours de ces différentes études pour les différentes modalités. En conclusion, l'apport de nouveaux outils diagnostiques tels que présentés dans ce manuscrit permettant d'accroître la sensibilité de détection et de caractérisation des lésions tissulaires colorectales est démontré / The diagnosis of gut-inflammatory conditions such as inflammatory bowel disease (IBD), that may lead into colorectal cancer (CRC), is a major public health issue. The emergence of novel imaging-based diagnosis technics helps to improve patients’ following-up but also the growth mechanisms of such conditions. In this context, the present manuscript describes a protocol that includes sequentially endoluminal MRI examination with conventional endoscopy, optical spectroscopy and confocal endomicroscopy. The dedicated developed instrumentation has been first characterized on organic models and then evaluated in vivo on a mouse model of colitis during two longitudinal studies. This project aims to propose methodological developments offering new ways of investigating complex mechanisms on mouse models and that could be further transposed to Human. The first part of this manuscript describes an overview of the colon and rectum anatomy as well as the main characteristics of IBD and CRC. The diagnostic imaging tools that are mainly use in clinical environment for the detection, description and staging of colorectal abnormalities are then presented. The second part describes the development of endoluminal MRI with dedicated coils and the development of optical modalities. In order to assess the potential of the proposed protocol, the different in vivo studies carried out during this project are detailed. Finally, the last part of the document shows and discusses the results obtained for each and cross modalities in this context. In conclusion, bringing new ways of imaging gut diseases to increase the sensitivity of the diagnosis and enhance the morphological description of colorectal abnormalities was demonstrated