Inflammatory Bowel Disease (IBD) is a chronic disorder that affects millions of peopleworldwide. Although the etiology behind the disease is yet unknown, current theoriespropose a complex interplay between genetic susceptibility, exposure to environmentalfactors and exacerbated immune responses. While important efforts have been made to linkgenetics and environmental factors to IBD pathogenesis, a major challenge remains to assignthem a causative role. Particularly since most of the IBD-risk genetic polymorphisms arefound in non-coding regions (NCRs) with unknown regulatory activity, and for the lack ofknowledge about how environmental factors can modulate the function of these elements invivo . A main problem to address this challenge in IBD research is the lack of an appropriatemodel system in vivo that allows for high-throughput experiments with combinations ofdifferent IBD-risk factors, while keeping the in vivo context. In this work, we sought toovercome this issue by using a zebrafish reporter for a specific human IBD-risk NCR, inorder to investigate the modulation of this element by two groups of common environmentalfactors: pollutants, such as PolyFluoroAlkyl Substances (PFASs); and diet, by activation ofdietary sensors. We found that the activity of the WT-NCR in zebrafish larvae was increased in the presenceof PFAS, while the activation of the dietary sensor PPAR δ decreased the activity. These datalead us to suggest that the function of PFAS can be counteracted by PPARδ activation.Therefore, we propose zebrafish as a suitable in vivo model in which we can screen forpotentially harmful or beneficial effects of environmental factors in the activity of humannon-coding regions. / Inflammatorisk tarmsjukdom (IBD) är en kronisk störning som drabbar miljontals människorvärlden över. Även om etiologin bakom sjukdomen fortfarande är okänd, föreslår nuvarandeteorier ett komplext samspel mellan genetisk mottaglighet, exponering av miljöfaktorer ochförvärrat immunförsvar. Även om stora ansträngningar har gjorts för att koppla genetik ochmiljöfaktorer till IBD-patogenes, återstår en stor utmaning att tilldela dem en orsakande roll.Särskilt eftersom de flesta av IBD-riskgenetiska polymorfismer finns i icke-kodande regioner(NCR) med okänd reglerande aktivitet samt för bristen på kunskap om hur miljöfaktorer kanmodulera funktionen hos dessa element in vivo . Ett huvudproblem för att möta dennautmaning i IBD-forskning är avsaknaden av ett lämpligt modellsystem in vivo som möjliggörexperiment med hög kapacitet och kombinationer av olika IBD-riskfaktorer in vivo . I dettaarbete försökte vi få svar på denna fråga genom att använda en zebrafiskreporter för ettspecifikt humant IBD-risk icke-kodande område. Detta möjliggjorde att vi kunde undersökamodulering av två gemensamma miljöfaktorer: föroreningar, såsom PolyFluoroAlkyl-ämnen(PFASs); och diet, genom aktivering av dietsensorer. Vi fann att aktiviteten i WT-NCR hos zebrafisklarver ökade i närvaro av PFAS, medanaktiveringen av dietsensorn PPARδ minskade aktiviteten. Denna data leder till att vi antyderatt funktionen för PFAS kan motverkas genom PPARδ-aktivering. Därför föreslår vizebrafisk som en lämplig in vivo -modell, i vilken vi kan screena för potentiellt skadliga ellergynnsamma effekter av miljöfaktorer i mänskligt icke-kodande DNA.

Introduction Inflammatory bowel disease (IBD) and its complications have been well-established. The literature shows an association between IBD and decreased bone mineral density in the adult population. However, most studies have reported an association between IBD and osteoporosis, while the risk of fractures has not been well-studied. The aim of this meta-analysis is to summarize the best available evidence regarding IBS and osteoporotic fractures. Methods A review of the literature using the MEDLINE and EMBASE databases was performed during November 2017. We included cross-sectional and cohort studies that reported the relative risks, odds ratios, and hazard ratios comparing the risk of developing osteoporotic fractures among patients with IBD patients, both ulcerative colitis (UC) and Crohn's disease (CD), versus patients without IBD as controls. The pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using the generic inverse-variance method. Results After a review of the literature, seven studies fulfilled the eligibility criteria established during the analysis. A significant association was found between IBD and osteoporosis, with a pooled OR of 1.32 (95% CI, 1.2 - 1.4). Low heterogeneity among the studies was found, I=42.3. No publication bias was found using the Egger regression test p=0.18. Sensitivity analysis showed that the inclusion of data on children by Kappelman et al. (2007) did not change the results. Conclusion A significant association between IBD and the risk of developing osteoporotic fractures was observed in this study. There is a 32% increased risk, which is consistent with different cohort studies previously done.

The herbal preparation coffee charcoal is produced by over-roasting and milling green dried Coffea arabica L. seeds, and has a long-standing tradition in the treatment of inflammatory and gastrointestinal disorders. Its therapeutic properties are commonly attributed to adsorptive and astringent effects. This insufficiently explains its mode of action, especially when used in the treatment of inflammatory diseases in lower dosages. Our investigations aimed to identify bioactive secondary plant metabolites affecting cytokine-signaling. Thus, a phytochemical analysis of coffee charcoal extract was conducted using HPLC and LC/MS. Trigonelline, neochlorogenic acid, chlorogenic acid, caffeine, cryptochlorogenic acid, feruloylquinic acid isomers, and a caffeoylquinolacton were identified in the extract. Subsequently, the effects of coffee charcoal extract, chlorogenic acid isomers, their metabolite caffeic acid, caffeine, and trigonelline on cytokine (TNF, IL-6, MCP-1) release from LPS-challenged human THP-1 macrophages were examined to evaluate anti-inflammatory activity. Coffee charcoal showed concentration-dependent mild-to-medium inhibitory effects. The chlorogenic acid isomers and caffeic acid inhibited the TNF release, with cryptochlorogenic acid exerting the most distinct effects, as well as decreasing the release of IL-6 and MCP-1. In addition, scanning electron microscopic images provided an impression of the particle constitution, indicating a larger particle size and less structured surface of coffee charcoal in comparison to activated charcoal. In conclusion, our findings underline that beyond adsorptive effects, coffee charcoal exhibits pharmacological properties, which derive from a spectrum of secondary plant metabolites and support the therapeutic use in inflammatory diseases. Chlorogenic acids, particularly cryptochlorogenic acid, appear as pivotal bioactive compounds.

<p dir="ltr">Crohn’s disease and ulcerative colitis are chronic inflammatory bowel diseases (IBD) with a rising global prevalence, influenced by clinical and demographics factors. The pathogenesis of IBD involves complex interactions between gut microbiome dysbiosis, epithelial cell barrier disruption, and immune hyperactivity, which are poorly understood. This necessitates the development of novel approaches to integrate and model multiple clinical and molecular data modalities from patients, animal models, and <i>in-vitro</i> systems to discover effective biomarkers for disease progression and drug response. As sequencing technologies advance, the amount of molecular and compositional data from paired measurements of host and microbiome systems is exploding. While it is become routine to generate such rich, deep datasets, tools for their interpretation lag behind. Here, I present a computational framework for integrative modeling of microbiome multi-omics data titled: Latent Interacting Variable Effects (LIVE) modeling. LIVE combines various types of microbiome multi-omics data using single-omic latent variables (LV) into a structured meta-model to determine the most predictive combinations of multi-omics features predicting an outcome, patient group, or phenotype. I implemented and tested LIVE using publicly available metagenomic and metabolomics data set from Crohn’s Disease (CD) and ulcerative colitis (UC) status patients in the PRISM and LLDeep cohorts. The findings show that LIVE reduced the number of features interactions from the original datasets for CD to tractable numbers and facilitated prioritization of biological associations between microbes, metabolites, enzymes, clinical variables, and a disease status outcome. LIVE modeling makes a distinct and complementary contribution to the current methods to integrate microbiome data to predict IBD status because of its flexibility to adapt to different types of microbiome multi-omics data, scalability for large and small cohort studies via reliance on latent variables and dimensionality reduction, and the intuitive interpretability of the meta-model integrating -omic data types.</p><p dir="ltr">A novel application of LIVE modeling framework was associated with sex-based differences in UC. Men are 20% more likely to develop this condition and 60% more likely to progress to colitis-associated cancer compared to women. A possible explanation for this observation is differences in estrogen signaling among men and women in which estrogen signaling may be protective against UC. Extracting causal insights into how gut microbes and metabolites regulate host estrogen receptor β (ERβ) signaling can facilitate the study of the gut microbiome’s effects on ERβ’s protective role against UC. Supervised LIVE models<b> </b>ERβ signaling using high-dimensional gut microbiome data by controlling clinical covariates such as: sex and disease status. LIVE models predicted an inhibitory effect on ER-UP and ER-DOWN signaling activities by pairs of gut microbiome features, generating a novel of catalog of metabolites, microbial species and their interactions, capable of modulating ER. Two strongly positively correlated gut microbiome features: <i>Ruminoccocus gnavus</i><i> </i>with acesulfame and <i>Eubacterium rectale</i><i> </i>with 4-Methylcatechol were prioritized as suppressors ER-UP and ER-DOWN signaling activities. An <i>in-vitro</i> experimental validation roadmap is proposed to study the synergistic relationships between metabolites and microbiota suppressors of ERβ signaling in the context of UC. Two i<i>n-vitro</i> systems, HT-29 female colon cancer cell and female epithelial gut organoids are described to evaluate the effect of gut microbiome on ERβ signaling. A detailed experimentation is described per each system including the selection of doses, treatments, metrics, potential interpretations and limitations. This experimental roadmap attempts to compare experimental conditions to study the inhibitory effects of gut microbiome on ERβ signaling and how it could elevate or reduce the risk of developing UC. The intuitive interpretability of the meta-model integrating -omic data types in conjunction with the presented experimental validation roadmap aim to transform an artificial intelligence-generated big data hypothesis into testable experimental predictions.</p>

In the present investigation peripheral blood lymphocytes from patients with inflammatory bowel disease (IBD) and different cancer states were treated with various agents and compared with lymphocytes from healthy control individuals (HCI) treated in the same way and measured in the Comet assay. For inflammatory bowel disease, patient's responses in IBD patients treated with H2O2 were higher than in HCI and Crohn's patients (CD) were found to have higher responses than Ulcerative colitis (UC) patients. The responses for all IBD and HCI were all reduced in the presence of chaga mushroom extract which behaved in an antioxidant manner. A second group of IBD patients were treated with the heterocyclic amine (food mutagen), IQ and H2O2 and responses were reduced in the presence of the flavonoids, quercetin and epicatechin and compared with HCI similarity treated. In all cells responses were reduced with flavonoids and again CD had higher responses than the UC patients and IBD patients higher than HCI. The responses with CD and UC were that confirmed in two independent studies with IBD, one with chaga mushroom extract and the other with flavonoids. Peripheral lymphocytes from malignant melanoma and suspected melanoma patients and colon cancer and polyposis patients were compared to the lymphocytes from HCI and treated with UVA. There were differential sensitivities when measured in the micronucleus and Comet assays. The cancer patients had higher responses than those in the precancerous states and they in turn were higher than responses in HCI. In all the studies, untreated baseline DNA damage values were also higher in IBD and cancer patients and pre-cancerous patients than HCIs. This would suggest that baseline frequencies of different diseases compared to controls could be an important biomarker in the diagnosis of pre-cancers and early stage cancers. Also peripheral lymphocytes are a useful surrogate for cancers and pre-cancerous disease states since, blood is present in all organs and tissues and DNA is basically the same in all cells.

Au Québec, l’abattage des poulets se fait entre 33 et 40 jours. Pour permettre cet abattage, les poulets devront être vaccinés en présence d’anticorps maternels puisque la période d’attente après la vaccination est de 21 jours. L’objectif de cette étude a été de déterminer l’efficacité d’une forte dose de vaccin et de vitamine E à contourner les anticorps maternels et à vacciner par contact les poulets non vaccinés. Des vaccins à dose normale de 104,35 TCID50/ml/oiseau et à forte dose de 105,35 TCID50/ml/oiseau ont été utilisées sur 1200 poulets repartis en 4 groupes; (1) FD100%, groupe dans lequel tous les oiseaux ont été vaccinés, (2) FD10%, groupe dans lequel 10% des oiseaux ont été vacciné à forte dose, (3) DN100%, groupe dans lequel tous les oiseaux ont été vacciné à dose normale et (4) Contrôle, groupe dans lequel aucun oiseau n’a été vacciné. Chaque groupe a été divisé en 2 sous-groupes ; un a été supplémenté en vitamine E de 50 à 100UI/kg d’aliment et l’autre de 20 à 27 UI/kg. Les résultats de la présente étude ont montré que le virus vaccinal est capable de surmonter les anticorps maternels, qui ont persisté jusqu’à 20 jours d’âge, et à provoquer une réponse immunitaire humorale. Cette étude a aussi montré que le virus est capable de se transmettre par contact direct dans un même parquet et par contact indirect d’un parquet à l’autre. Aucun retour à la virulence ni une mutation du nucléotide VP2 n’a été observé au niveau des oiseaux vaccinés par contact. Cette étude a aussi montré qu’une amélioration de l’apport de vitamine E augmente la réponse humorale après vaccination avec un vaccin vivant contre la maladie de Gumboro. / In Quebec, Canada, broilers chickens are slaughtered from 33 to 40 days of age depending on the targeted market. Considering the withdrawal period of 21 days following vaccination, chickens would have to be vaccinated in the presence of maternally derived antibodies (MDA). The purpose of this study was to determine the effectiveness of high dose of vaccine and high dietary concentration of vitamin E in circumventing the MDA. A normal dose vaccine containing 104.35 TCID50/ml/bird and a higher dose containing 105.35 TCID50/ml/bird were used on 1200 chickens, which were divided into 4 groups housed in 8 pens: a high dose of vaccine in which all chickens were given 105.35 TCID50/ml (HD100%), a high dose in which 10% of the birds were vaccinated (HD10%), a normal dose as prescribed by the manufacturer in which all birds received 104.35 TCID50/ml (ND100%), and unvaccinated control groups. Each group was divided into 2 sub-groups; one was supplemented with 50 to 100 IU/kg of vitamin E and the other was supplemented with 20 to 27 IU/kg. The result of this study showed that the vaccine virus was able to circumvent the MDA, which persisted until 20 days of age, and to initiate a high antibody response. The study also showed that the vaccine virus was able to spread by direct and indirect contact within the pen and to the next pens. No reversion to the virulence or mutation of VP2 nucleotide was detected from the contact vaccinated birds. Vitamin E at the concentration of 50 to 100 IU/kg of the diet induced significantly elevated antibody response against IBDV.

Background: Inflammatory Bowel Disease (IBD) is a group of chronic gastrointestinal diseases with a relapsing nature. The two main types are Crohn’s disease (CD) and ulcerative colitis (UC). Both CD and UC patients experience very similar and distressing symptoms: acute abdominal pain, vomiting, malnutrition, fever, fatigue, diarrhoea and rectal bleeding. These symptoms are disabling and have a severe impact on physical and psychosocial wellbeing. Around 30% of patients suffer from moderate to severe psychological distress and have difficulties coping with the illness even in remission. However, it appears that mental health is overlooked by clinicians who often focus on physical gastrointestinal symptoms only. Mindfulness-Based Cognitive Therapy (MBCT) is evidence based, group psychological intervention that has been successful in reducing depression and anxiety scores in patients with depression while improving overall quality of life. However, MBCT has never been tested in the IBD population before. PhD question: Can MBCT be used as an adjunct therapy to IBD symptom management, for improving IBD patients' general well-being and quality of life? Aims and objectives: The overall aim of the thesis was to develop and collate the evidence for a definitive randomised controlled trial (RCT) testing the effectiveness of MBCT for patients with inflammatory bowel disease (IBD). The thesis brings together six publications. The six publications were integrated into four objectives that collectively contributed in answering the overall PhD question. Results: The findings from the first three publications highlighted the disease-related concerns and psychological needs for patients with IBD. The findings from the last three publications highlighted how feasible it is to use MBCT in IBD and emphasised the IBD patients’ perspectives about MBCT. Conclusion: The thesis concluded that a definitive RCT of MBCT for IBD patients is both feasible and acceptable.

The inflammasome complex is a multiprotein complex that may play a role in the pathogenesis of inflammatory bowel disease (IBD) by secreting the inflammatory cytokines interleukin (IL)-1β and IL-18, and inducing pyroptosis, as a response to signals through several inflammasome sensors. This study looked at the expression of several inflammasome components in the ileum and colon of patients suffering from IBD. The inflammasome sensors NLRP1, NLRP3, AIM2 and pyrin were upregulated in whole intestinal tissue of IBD patients, particularly in the colon. NLRP6 expression was increased in the colon of Crohn's disease patients, but not ulcerative colitis patients relative to colon of controls, and was reduced in the ileum of Crohn's disease patients compared to control ileum. Expression of caspase-1 and IL-1β, but not IL-18, were also increased in ileum and colon tissue from Crohn's patients. To identify the cell type where inflammasome expression was altered in Crohn’s disease, transcription of inflammasome subunits in intestinal tissue enriched for epithelial cells or lamina propria (LP) cells was analysed. These analyses indicated that LP cells have greater expression of the inflammasome sensors NLRP1, NLRP3, AIM2 and pyrin relative to epithelial cells, both during disease and in control tissue. Moreover, LP cells from Crohn’s patients have higher expression level of NLRP1, AIM2 and pyrin than LP cells from controls. In contrast the inflammasome sensor NLRP6 was more highly expressed by epithelial cells relative to LP cells in general, and NLRP6 expression in LP cells from IBD patients was lower than that observed in LP cells from controls. The observed differential expression of inflammasome components in controls versus IBD intestine and in different cellular fractions of intestinal tissue highlight the importance of understanding the role of the inflammasome in IBD and hints at the possibility of targeting the inflammasome pathway as a future treatment strategy.

Au Québec, l’abattage des poulets se fait entre 33 et 40 jours. Pour permettre cet abattage, les poulets devront être vaccinés en présence d’anticorps maternels puisque la période d’attente après la vaccination est de 21 jours. L’objectif de cette étude a été de déterminer l’efficacité d’une forte dose de vaccin et de vitamine E à contourner les anticorps maternels et à vacciner par contact les poulets non vaccinés. Des vaccins à dose normale de 104,35 TCID50/ml/oiseau et à forte dose de 105,35 TCID50/ml/oiseau ont été utilisées sur 1200 poulets repartis en 4 groupes; (1) FD100%, groupe dans lequel tous les oiseaux ont été vaccinés, (2) FD10%, groupe dans lequel 10% des oiseaux ont été vacciné à forte dose, (3) DN100%, groupe dans lequel tous les oiseaux ont été vacciné à dose normale et (4) Contrôle, groupe dans lequel aucun oiseau n’a été vacciné. Chaque groupe a été divisé en 2 sous-groupes ; un a été supplémenté en vitamine E de 50 à 100UI/kg d’aliment et l’autre de 20 à 27 UI/kg. Les résultats de la présente étude ont montré que le virus vaccinal est capable de surmonter les anticorps maternels, qui ont persisté jusqu’à 20 jours d’âge, et à provoquer une réponse immunitaire humorale. Cette étude a aussi montré que le virus est capable de se transmettre par contact direct dans un même parquet et par contact indirect d’un parquet à l’autre. Aucun retour à la virulence ni une mutation du nucléotide VP2 n’a été observé au niveau des oiseaux vaccinés par contact. Cette étude a aussi montré qu’une amélioration de l’apport de vitamine E augmente la réponse humorale après vaccination avec un vaccin vivant contre la maladie de Gumboro. / In Quebec, Canada, broilers chickens are slaughtered from 33 to 40 days of age depending on the targeted market. Considering the withdrawal period of 21 days following vaccination, chickens would have to be vaccinated in the presence of maternally derived antibodies (MDA). The purpose of this study was to determine the effectiveness of high dose of vaccine and high dietary concentration of vitamin E in circumventing the MDA. A normal dose vaccine containing 104.35 TCID50/ml/bird and a higher dose containing 105.35 TCID50/ml/bird were used on 1200 chickens, which were divided into 4 groups housed in 8 pens: a high dose of vaccine in which all chickens were given 105.35 TCID50/ml (HD100%), a high dose in which 10% of the birds were vaccinated (HD10%), a normal dose as prescribed by the manufacturer in which all birds received 104.35 TCID50/ml (ND100%), and unvaccinated control groups. Each group was divided into 2 sub-groups; one was supplemented with 50 to 100 IU/kg of vitamin E and the other was supplemented with 20 to 27 IU/kg. The result of this study showed that the vaccine virus was able to circumvent the MDA, which persisted until 20 days of age, and to initiate a high antibody response. The study also showed that the vaccine virus was able to spread by direct and indirect contact within the pen and to the next pens. No reversion to the virulence or mutation of VP2 nucleotide was detected from the contact vaccinated birds. Vitamin E at the concentration of 50 to 100 IU/kg of the diet induced significantly elevated antibody response against IBDV.

No description available.