Maladies inflammatoires chroniques de l'intestin, facteurs d'environnement et expositions médicamenteuses : étude épidémiologique

Inflammatory bowel diseases refer to two conditions: Crohn's disease and ulcerative colitis. These diseases display an important geographic heterogeneity worldwide and an increase in incidence during the last fifty years. Their physiopathology is complex, involving anormal composition of gut microbiota (dysbiosis), dysfonction of epithelial barrier and dysregulation of innate and adaptative immune response. More than 163 predisposing genes have been identified, but most of them carry modest association with IBD (Odds ratios varrying from 1.02 to 1.3) (1–3). Environmental factors seem to play an important role in IBD onset. Smoking has a positive effect on UC and harmfull effect on CD. Sun exposure, vitamin D, diet, infections have been inconsistently associated with IBD. This epidemiology thesis is devoted to IBD and specifically, to environemental risk factors, and also to the risk of cancer associated to IBD drugs. It is based on French and European databases. Our first work, explored the association between isotretinoin and UC reported in a US study. Our study was performed in a case-control study in the whole French territory thanks to a medico-administrative database (SNIIRAM). In this work, only a few patients with IBD were exposed to isotetinoin in the year before disease onset. Exposure to isotretinoin was not associated with UC but negatively associated with CD.In a second study, we explored the global impact of diet on UC and CD in a European prospective study (European Prospective Investigation Into Cancer (EPIC)). A dietary pattern with “high sugars and soft drinks” was associated with UC risk when restricted to cases diagnosed at least two years after dietary assessment. No dietary pattern was associated with CD. Mediterranean diet had no effect on UC nor CD risks.In the third part of this work, we investigated the risk of cancer associated with IBD drugs: immunosuppresive agents and anti-TNF. These medications are more and more prescribed nowadays. Howevere, they are associated with an increased risk of cancer in observationnal studies: lymphoma and non melanoma skin cancer with thiopurines and anti-TNF agents respectively. Therefore, we aimed to investigate the cancer risks associated with thiopurine and/or anti-TNF exposure in the whole French territory in the real life , using a medico-adminstrative database (SNIRAM). Currently, we are still analyzing the results.Our work shows that studying large databases can answer an important issue in clinical practice related to a potential link between isotretinoin and IBD. Also, it has generated hypotheses about the link between dietary pattern and IBD. Limitations of our work (detailed in the manuscript) should be considered.. Otr studies using larger databases and other statistical methods should address these limitations.Les maladies inflammatoires chroniques de l'intestin (MICI) désignent deux affections, la maladie de Crohn (MC) et la rectocolite hémorragique (RCH). Ces maladies sont caractérisées par une grande disparité de répartition dans le monde et une forte augmentation de leur incidence depuis 50 ans. Leur physiopathologie fait intervenir une composition anormale du microbiote intestinal (appelée dysbiose), une dysfonction de la barrière épithéliale, un déficit de l'immunité innée et une dérégulation de l'immunité adaptative. Plus de 163 gènes de prédisposition ont été identifiés, mais la plupart d'entre eux ne sont associés qu'à une augmentation modeste du risque de MICI (Odds Ratios compris entre 1,02 et 1,2). Les facteurs d'environnement semblent jouer un rôle important dans la survenue de ces maladies. Le tabagisme a un effet démontré, favorable dans la RCH, néfaste dans la MC. L'exposition solaire, la vitamine D, l'alimentation, les agents infectieux et les médicaments ont été associés aux MICI mais leur effet est moins bien démontré. Cette thèse d'épidémiologie est consacrée aux MICI; plus précisément, à l'étude de leurs facteurs d'environnement, et au risque de cancer associé aux médicaments des MICI. Elle est fondée sur l'étude de bases de données françaises et européennes. Un premier travail a exploré l'association entre l'exposition à l'isotrétinoïne (médicament prescrit pour traiter l'acné) et la survenue de RCH, rapportée par une étude américaine. Cette étude cas témoin a été menée à l'échelle de la France entière à partir des données du système national d'information inter-régimes de l'assurance maladie (SNIIRAM). Dans ce travail très peu de patients atteints de MICI ont reçu de l'isotrétinoïne durant l'année précédant le diagnostic de la maladie. La prise d'isotrétinoïne n'est pas associée au risque de RCH mais inversement associée au risque de MC.Dans un deuxième travail, nous avons étudié l'impact gobal de l'alimentation en modélisant les profils alimentaires associés à la survenue de RCH et de MC dans la cohorte prospective européenne EPIC (European Prospective Investigation Into Cancer). Un profil alimentaire riche “en produits sucrés et sodas” est associé à l'incidence de RCH dans le sous-groupe diagnostiqué au delà de 2 ans. Aucun profil alimentaire n'est associé au risque de MC. Le régime méditerranéen n'est ni associé à la RCH ni à la MCDans un troisième travail, nous nous sommes intéressés aux risques de cancer associés à l'exposition aux médicaments des MICI : immunosuppresseurs et anti-TNF. Leur prescription a beaucoup augmenté ces dernières années. Cependant ils ont été associés à un risque de lymphome, de cancer de la peau non mélanocytaire et de mélanome pour les thiopurines et les anti-TNF, respectivement. Nous avons évalué prospectivement le risque de cancer associé à ces médicaments, à l'échelle de la France entière dans des conditions de prescription courante, grâce aux données du SNIIRAM. Les résultats sont en en cours d'analyse.Notre thèse montre que l'étude des bases de données peut apporter une réponse à une question importante en pratique clinique , portant sur le lien entre isotrétinoïne et MICI. Notre travail a également permis de générer des hypothèses sur le lien entre les profils alimentaires et la survenue de MICI. Les limites de l'exercice (détaillées dans le manuscrit) ne doivent pas être sous estimées. Nos résultats suscitent des questions et appellent d'autres travaux, menés à une échelle encore plus vaste et avec d'autres méthodes statistiques

The Tumor Coagulome as a Transcriptional Target and a Potential Effector of Glucocorticoids in Human Cancers

Background: The coagulome, defined as the repertoire of genes that locally regulate coagulation and fibrinolysis, is a key determinant of vascular thromboembolic complications of cancer. In addition to vascular complications, the coagulome may also regulate the tumor microenvironment (TME). Glucocorticoids are key hormones that mediate cellular responses to various stresses and exert anti-inflammatory effects. We addressed the effects of glucocorticoids on the coagulome of human tumors by investigating interactions with Oral Squamous Cell Carcinoma, Lung Adenocarcinoma, and Pancreatic Adenocarcinoma tumor types. Methods: We analyzed the regulation of three essential coagulome components, i.e., the tissue factor (TF), urokinase-type plasminogen activator (uPA), and plasminogen activator inhibitor-1 (PAI-1) in cancer cell lines exposed to specific agonists of the glucocorticoid receptor (GR) (dexamethasone and hydrocortisone). We used QPCR, immunoblots, small-interfering RNA, Chromatin immunoprecipitation sequencing (ChIPseq) and genomic data from whole tumor and single-cell analyses. Results: Glucocorticoids modulate the coagulome of cancer cells through a combination of indirect and direct transcriptional effects. Dexamethasone directly increased PAI-1 expression in a GR-dependent manner. We confirmed the relevance of these findings in human tumors, where high GR activity/high SERPINE1 expression corresponded to a TME enriched in active fibroblasts and with a high TGF-β response. Conclusion: The transcriptional regulation of the coagulome by glucocorticoids that we report may have vascular consequences and account for some of the effects of glucocorticoids on the TME.</p

Distribution of living benthic foraminifera in the northern Chukchi Sea

This is a post-peer-review, pre-copyedit version of an article published in Arktos. The final authenticated version is available online at: https://doi.org/10.1007/s41063-018-0062-y.Living (Rose Bengal stained) benthic foraminifera were studied in the topmost sediments of five multi- and box cores collected on the continental shelf, upper and lower slopes, of the Chukchi Sea to provide background information on modern benthic foraminiferal distribution, useful for future studies. Sediment cores were collected during August–September 2015, when the area is seasonally ice-free. Benthic foraminiferal contents in the 63–125 µm and > 125 µm size fractions are discussed in terms of water masses distribution, and sedimentological (grain size) and organic geochemical (total organic carbon, total nitrogen, C/N ratio and δ13Corg) characteristics of the surface sediments. Marine organic carbon-rich clay sediments characterize the faunal microhabitats. Despite relatively high organic carbon contents, standing stocks of living benthic foraminifera are generally low, especially for the 63–125 µm size fraction. This low living stock seems to reflect post-bloom conditions in August and September in the area. The reduced supply of fresh organic carbon also affects faunal microhabitats in the sediment with a concentration of living fauna in the upper 2 cm of the sediment. Over the Chukchi Sea shelf, a relatively mixed upper sediment layer likely due to bioturbation or bio-structures induces a disturbed vertical distribution in the sediment. Corrosive Pacific-derived bottom water over the shelf likely explains the relative importance of agglutinated vs. calcareous fauna in this shallow setting. Our results suggest that, in a post-bloom context, the main environmental control on benthic foraminiferal assemblages in the Chukchi Sea is the nature of the bottom water masses

Carbohydrate Intake in the Etiology of Crohn's Disease and Ulcerative Colitis

Background: Diet may have a role in the etiology of inflammatory bowel disease. In previous studies, the associations between increased intakes of carbohydrates, sugar, starch, and inflammatory bowel disease are inconsistent. However, few prospective studies have investigated the associations between these macronutrients and incident Crohn's disease (CD) or ulcerative colitis (UC). Methods: A total of 401,326 men and women were recruited between 1991 and 1998. At recruitment, dietary intakes of carbohydrate, sugar, and starch were measured using validated food frequency questionnaires. The cohort was monitored identifying participants who developed incident CD or UC. Cases were matched with 4 controls, and odds ratios were calculated for quintiles of total carbohydrate, sugar, and starch intakes adjusted for total energy intake, body mass index, and smoking. Results: One hundred ten participants developed CD, and 244 participants developed UC during follow-up. The adjusted odds ratio for the highest versus the lowest quintiles of total carbohydrate intake for CD was 0.87, 95% CI = 0.24 to 3.12 and for UC 1.46, 95% CI = 0.62 to 3.46, with no significant trends across quintiles for either (CD, Ptrend = 0.70; UC, Ptrend = 0.41). Similarly, no associations were observed with intakes of total sugar (CD, Ptrend = 0.50; UC, Ptrend = 0.71) or starch (CD, Ptrend = 0.69; UC, Ptrend = 0.17). Conclusions: The lack of associations with these nutrients is in agreement with many case–control studies that have not identified associations with CD or UC. As there is biological plausibility for how specific carbohydrates could have an etiological role in inflammatory bowel disease, future epidemiological work should assess individual carbohydrates, although there does not seem to be a macronutrient effect

Dietary Polyphenols in the Aetiology of Crohn's Disease and Ulcerative Colitis—A Multicenter European Prospective Cohort Study (EPIC)

Background: Oxidative stress may be involved in the aetiology of inflammatory bowel disease and whether dietary polyphenols, which possess antioxidants properties, prevent its development is unknown. Methods: A total of 401,326 men and women aged 20 to 80 years from 8 countries were recruited between 1991 and 1998 and at baseline completed validated food frequency questionnaires. Dietary polyphenol intake was measured using Phenol-Explorer, a database with information on the content of 502 polyphenols. Incident cases of Crohn's diseases (CD) and ulcerative colitis (UC) were identified during the follow-up period of up to December 2010. A nested case–control study using conditional logistic regression estimated the odds ratios (ORs), and 95% confidence intervals, for polyphenol intake (categories based on quartiles) and developing CD or UC. Results: In total, 110 CD (73% women) and 244 UC (57% women) cases were identified and matched to 440 and 976 controls, respectively. Total polyphenol intake was not associated with CD (P trend = 0.17) or UC (P trend = 0.16). For flavones and CD, there were reduced odds for all quartiles, which were statistically significant for the third (OR3rd versus 1st quartile = 0.33; 95% confidence interval, 0.15–0.69) and there was an inverse trend across quartiles (P = 0.03). Similarly, for resveratrol, there was an inverse association with CD (OR4th versus 1st quartile = 0.40; 95% confidence interval, 0.20–0.82) with an inverse trend across quartiles (P = 0.02). No significant associations between subtypes of polyphenols and UC were found. Effect modification by smoking in CD was documented with borderline statistical significance. Conclusions: The data supports a potential role of flavones and resveratrol in the risk of developing CD; future aetiological studies should investigate these dietary components and further examine the potential for residual confounding.Multiple funders including MRC and CRUK listed on paper

Prediagnostic Serum Vitamin D Levels and the Risk of Crohn’s Disease and Ulcerative Colitis in European Populations: A Nested Case-Control Study

Background: A low vitamin D status has been put forward as a potential risk factor for the development of inflammatory bowel disease (IBD). This study investigated the association between prediagnostic circulating vitamin D concentrations and dietary intakes of vitamin D, and the risk of Crohn’s disease (CD) and ulcerative colitis (UC). Methods: Among 359,728 participants of the European Prospective Investigation into Cancer and Nutrition cohort, individuals who developed CD or UC after enrollment were identified. Each case was matched with2 controls by center, gender, age, date of recruitment, and follow-up time. At cohort entry, blood samples were collected and dietary vitamin D intakes were obtained from validated food frequency questionnaires. Serum 25-hydroxyvitamin D levels were measured using liquid chromatography-tandem mass spectrometry. Conditional logistic regression was performed to determine the odds of CD and UC. Results: Seventy-two participants developed CD and 169 participants developed UC after a median follow-up of 4.7 and 4.1 years, respectively. Compared with the lowest quartile, no associations with the 3 higher quartiles of vitamin D concentrations were observed for CD (p trend = 0.34) or UC (p trend = 0.66). Similarly, no associations were detected when serum vitamin D levels were analyzed as a continuous variable. Dietary vitamin D intakes were not associated with CD (p trend = 0.39) or UC (p trend = 0.83). Conclusions: Vitamin D status was not associated with the development of CD or UC. This does not suggest a major role for vitamin D deficiency in the etiology of IBD, although larger studies are needed to confirm these findings

Comparison of abdominal adiposity and overall obesity in relation to risk of small intestinal cancer in a European Prospective Cohort

Published version. Source at http://dx.doi.org/10.1007/s10552-016-0772-z Background: The etiology of small intestinal cancer (SIC) is largely unknown, and there are very few epidemiological studies published to date. No studies have investigated abdominal adiposity in relation to SIC. Methods: We investigated overall obesity and abdominal adiposity in relation to SIC in the European Prospective Investigation into Cancer and Nutrition (EPIC), a large prospective cohort of approximately half a million men and women from ten European countries. Overall obesity and abdominal obesity were assessed by body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR). Multivariate Cox proportional hazards regression modeling was performed to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). Stratified analyses were conducted by sex, BMI, and smoking status. Results: During an average of 13.9 years of follow-up, 131 incident cases of SIC (including 41 adenocarcinomas, 44 malignant carcinoid tumors, 15 sarcomas and 10 lymphomas, and 21 unknown histology) were identified. WC was positively associated with SIC in a crude model that also included BMI (HR per 5-cm increase = 1.20, 95 % CI 1.04, 1.39), but this association attenuated in the multivariable model (HR 1.18, 95 % CI 0.98, 1.42). However, the association between WC and SIC was strengthened when the analysis was restricted to adenocarcinoma of the small intestine (multivariable HR adjusted for BMI = 1.56, 95 % CI 1.11, 2.17). There were no other significant associations. Conclusion: WC, rather than BMI, may be positively associated with adenocarcinomas but not carcinoid tumors of the small intestine. Impact: Abdominal obesity is a potential risk factor for adenocarcinoma in the small intestine

Fibre intake and the development of inflammatory bowel disease – a European prospective multi-centre cohort study (EPIC-IBD)

Background and Aims: Population-based prospective cohort studies investigating fibre intake and development of inflammatory bowel disease (IBD) are lacking. Our aim was to investigate the association between fibre intake and the development of Crohn’s disease (CD) and ulcerative colitis (UC) in a large European population. Methods: 401 326 participants, aged 20–80 years, were recruited in 8 countries in Europe between 1991 and 1998. At baseline, fibre intake (total fibres, fibres from fruit, vegetables and cereals) was recorded using food frequency questionnaires. The cohort was monitored for the development of IBD. Each case was matched with four controls and odds ratios (ORs) for the exposures were calculated using conditional logistic regression. Sensitivity analyses according to smoking status were computed. Results: In total, 104 and 221 participants developed incident CD and UC, respectively. For both CD and UC, there were no statistically significant associations with either quartiles, or trends across quartiles, for total fibre, or any of the individual sources. The associations were not affected by adjusting for smoking and energy intake. Stratification according to smoking status showed null findings apart from an inverse association with cereal fibre and CD in non-smokers (Quartile 4 vs 1 OR=0.12, 95% CI=0.02–0.75, P=0.023, OR trend across quartiles=0.50, 95% CI=0.29–0.86, P=0.017). Conclusion: The results do not support the hypothesis that dietary fibre is involved in the aetiology of UC, although future work should investigate whether there may be a protective effect of specific types of fibre according to smoking status in CD

The association of coffee intake with liver cancer risk is mediated by biomarkers of inflammation and hepatocellular injury: data from the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Higher coffee intake has been purportedly related to a lower risk of liver cancer. However, it remains unclear whether this association may be accounted for by specific biological mechanisms. OBJECTIVE: We aimed to evaluate the potential mediating roles of inflammatory, metabolic, liver injury, and iron metabolism biomarkers on the association between coffee intake and the primary form of liver cancer-hepatocellular carcinoma (HCC). DESIGN: We conducted a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition among 125 incident HCC cases matched to 250 controls using an incidence-density sampling procedure. The association of coffee intake with HCC risk was evaluated by using multivariable-adjusted conditional logistic regression that accounted for smoking, alcohol consumption, hepatitis infection, and other established liver cancer risk factors. The mediating effects of 21 biomarkers were evaluated on the basis of percentage changes and associated 95% CIs in the estimated regression coefficients of models with and without adjustment for biomarkers individually and in combination. RESULTS: The multivariable-adjusted RR of having ≥4 cups (600 mL) coffee/d compared with <2 cups (300 mL)/d was 0.25 (95% CI: 0.11, 0.62; P-trend = 0.006). A statistically significant attenuation of the association between coffee intake and HCC risk and thereby suspected mediation was confirmed for the inflammatory biomarker IL-6 and for the biomarkers of hepatocellular injury glutamate dehydrogenase, alanine aminotransferase, aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), and total bilirubin, which-in combination-attenuated the regression coefficients by 72% (95% CI: 7%, 239%). Of the investigated biomarkers, IL-6, AST, and GGT produced the highest change in the regression coefficients: 40%, 56%, and 60%, respectively. CONCLUSION: These data suggest that the inverse association of coffee intake with HCC risk was partly accounted for by biomarkers of inflammation and hepatocellular injury.This is the final version of the article. It was first available from American Society for Nutrition via http://dx.doi.org/10.3945/​ajcn.115.11609

Plasma antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort study

Objective: Examine the relationship between antibodies to 25 oral bacteria and pancreatic cancer risk in a prospective cohort study. Design: We measured antibodies to oral bacteria in prediagnosis blood samples from 405 pancreatic cancer cases and 416 matched controls, nested within the European Prospective Investigation into Cancer and Nutrition study. Analyses were conducted using conditional logistic regression and additionally adjusted for smoking status and body mass index. Results: Individuals with high levels of antibodies against Porphyromonas gingivalis ATTC 53978, a pathogenic periodontal bacteria, had a twofold higher risk of pancreatic cancer than individuals with lower levels of these antibodies (OR 2.14; 95% CI 1.05 to 4.36; >200ng/ml vs 200ng/ml). To explore the association with commensal (non-pathogenic) oral bacteria, we performed a cluster analysis and identified two groups of individuals, based on their antibody profiles. A cluster with overall higher levels of antibodies had a 45% lower risk of pancreatic cancer than a cluster with overall lower levels of antibodies (OR 0.55; 95% CI 0.36 to 0.83). Conclusion: Periodontal disease might increase the risk for pancreatic cancer. Moreover, increased levels of antibodies against specific commensal oral bacteria, which can inhibit growth of pathogenic bacteria, might reduce the risk of pancreatic cancer. Studies are needed to determine whether oral bacteria have direct effects on pancreatic cancer pathogenesis or serve as markers of the immune response