Risk Of Ulcerative Colitis Research Articles

Food Processing and Risk of Crohn’s Disease and Ulcerative Colitis: A European Prospective Cohort Study

Industrial foods have been associated with increased risks of several chronic conditions. We investigated the relationship between the degree of food processing and risks of Crohn's disease (CD) and ulcerative colitis (UC) in the European Prospective Investigation into Cancer and Nutrition cohort. Analyses included 413,590 participants (68.6% women; mean baseline age, 51.7 y) from 8 European countries. Dietary data were collected at baseline from validated country-specific dietary questionnaires. Associations between proportions of unprocessed/minimally processed and ultraprocessed food intake and CD and UC risks were estimated using Cox models to obtain hazard ratios (HRs) and 95% CIs. Models were stratified by center, age, and sex, and adjusted for smoking status, body mass index, physical activity, energy intake, educational level, and alcohol consumption. During a mean follow-up period of 13.2 years, 179 incident cases of CD and 431 incident cases of UC were identified. The risk of CD was lower in people consuming high proportions of unprocessed/minimally processed foods (adjusted HR for the highest vs lowest quartile: 0.57; 95% CI, 0.35-0.93; P trend < .01), particularly fruits and vegetables (adjusted HRs, 0.54; 95% CI, 0.34-0.87 and 0.55; 95% CI, 0.34-0.91, respectively). There was no association between unprocessed/minimally processed food intake and the risk of UC. No association was detected between ultraprocessed food consumption and CD or UC risks. In the European Prospective Investigation into Cancer and Nutrition cohort, consumption of unprocessed/minimally processed foods was associated with a lower risk of CD. No association between UC risk and food processing was found.

Micronutrient intake and risk of ulcerative colitis: A meta-analysis of observational studies.

Ulcerative colitis (UC) poses a challenge to patients' health status and lifestyle. Micronutrient intake has been associated with the risk of UC, but the association has been inconsistent. Therefore, we performed a meta-analysis to clarify the overall association between micronutrient intake, as potentially modifiable risk factors, and the risk of UC. Based on the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) protocols, systematic searches were conducted in PubMed, Scopus, and Web of Science up to September 2021. Studies were considered eligible for inclusion if they met the following criteria: (1) observational studies that compared dietary intake of zinc, calcium, or magnesium between the UC group and the control group and (2) had means and standard deviations or medians and interquartile ranges of outcome variables. A total of 7 studies with 1197 participants were included in the meta-analysis. The random-effects meta-analysis showed that there was no significant association between the intake of calcium (WMD:-66.25mg/day, 95% CI:-276.7 to 144.21, P=0.54), magnesium (WMD:-21.47mg/day, 95% CI:-95.54 to 52.6, P=0.57), and zinc (WMD: 0.3mg/day, 95% CI:-1.5 to 2, P=0.74) and the risk of UC. However, there was high significant heterogeneity between studies in dietary intake of calcium (I2=95.1%, P<0.001), magnesium (I2=96%, P<0.001), and zinc (I2=95.8%, P=<0.001). In a location-based subgroup analysis, calcium intake in non-Asian countries was significantly lower in patients with UC compared to healthy controls. In addition, magnesium intake was negatively associated with the risk of UC in studies with a sample size of less than 190 subjects. However, for the association between zinc intake and UC risk, subgroup analysis failed to find a source of heterogeneity. No significant association was found between dietary calcium, magnesium, and zinc intake and risk of UC.

Mendelian randomization analysis reveals causal effects of food intakes on inflammatory bowel disease risk.

Traditional observational studies have indicated a link between specific food intakes and inflammatory bowel disease (IBD), but the nature of such links remains unknown. We sought to assess the potential causal relationship between food intakes and IBD risk using Mendelian randomization methods. This study used summary statistics data from large-scale genome-wide association studies (GWAS) on food intakes, Crohn’s disease (CD), and ulcerative colitis (UC). In the primary analysis, we used the inverse variance-weighted method to determine whether specific food was causal for CD and UC. In addition, we also ran four other Mendelian randomization methods, including MR Egger, weighted median, maximum likelihood, and weighted mode as a complement. The primary analysis showed that high consumption of poultry (OR, 3.696; 95% CI, 1.056–12.937; p = 0.041) and cereal (OR, 2.449; 95% CI, 1.094–5.482; p = 0.029) had a significant causal association with CD, while high oily fish intake level was found to be statistically significantly associated with the risk of UC (OR, 1.482; 95% CI, 1.002–2.194; p = 0.049). This MR study provides evidence of a potential causal link between certain food intake and CD and UC.

Are neurodegenerative diseases associated with an increased risk of inflammatory bowel disease? A two-sample Mendelian randomization study.

BackgroundSeveral studies have shown that neurodegenerative diseases (e.g., Parkinson’s disease [PD] and Alzheimer’s disease [AD]) are associated with inflammatory bowel disease (IBD), but the causality and direction of their associations remain unclear. Mendelian randomization (MR) studies have explored the causal effects of IBD on PD and AD. However, only a few studies examined this reverse association. Thus, this study aimed to explore whether there are causal associations of genetically predicted PD and AD with IBD, using a two-sample MR study.MethodsSummary statistics for IBD, ulcerative colitis (UC), and Crohn’s disease (CD) were derived from a genome-wide association study (GWAS) meta-analysis, which included the International IBD Genetics Consortium and the UK IBD Genetics Consortium (n=59,957). Genetic variants associated with the largest meta-analysis of GWAS of PD (n=1,474,097) and AD (n=455,258) were used as instrumental variables. We used multiple methods, including inverse variance weighted (IVW), weighted median (WM), MR-Egger regression, weighted mode, and Robust Adjusted Profile Score (RAPS) methods, to estimate the effects of genetically predicted PD and AD on IBD. To confirm the validity of the analysis, we also evaluated the pleiotropic effects, heterogeneity, and leave-one-out sensitivity analysis that drive causal associations.ResultsThe results of the IVW method, WM, and RAPS showed that genetically predicted PD was significantly associated with an increased risk of UC (odds ratio [OR]IVW=1.068, OR WM=1.107, OR RAPS=1.069, all P<0.05). Additionally, we found that there were significant associations of genetically predicted PD with CD (OR IVW=1.064, OR RAPS=1.065, all P<0.05) and IBD (OR IVW=1.062, OR RAPS=1.063, all P<0.05) using the IVW method and RAPS. However, there was no significant causal evidence of genetically predicted AD in IBD, UC, or CD among all MR methods. In all MR analyses, there were no horizontal pleiotropy (all P>0.05), or statistical heterogeneity. The sensitivity analysis results of the leave-one-out sensitivity analysis showed that the causal effect estimations of genetically predicted PD and AD on IBD were robust.ConclusionsOur MR study corroborated a causal association between genetically predicted PD and IBD but did not support a causal effect of genetically predicted AD on IBD. More animal experiments or population-based observational studies are required to clarify the underlying mechanisms of PD and IBD.

Polymorphisms of miR-146a and susceptibility to ulcerative colitis risk: a case-control study

Considering the role of miR-146a in the control of inflammation, we assessed the importance of two miR-146a polymorphisms (rs2910164 and rs57095329) in the development and severity of ulcerative colitis (UC) in Iran. Genomic DNA of 150 cases with UC and 200 healthy individuals were genotyped using the PCR-RFLP technique. Statistical analyses were performed using Med Calc software. The miR-146a rs2910164 C allele was significantly associated with increased risk of UC. Individuals carrying the CC (rs2910164) were more than fourfold higher risk of UC relative to wild type homozygotes. The combined GC + CC genotypes were also associated with increased UC risk. We also found that the rs2910164 CC genotype was associated with a severe form of the disease However, the distribution of variant allele and genotypes of rs57095329 did not differ between the cases and controls. In conclusion, miR-146a rs2910164 polymorphism may play a role in UC. To confirm our findings, additional well-designed studies in diverse ethnic populations are required.

Early-Life Mebendazole Exposure Increases the Risk of Adult-Onset Ulcerative Colitis: A Population-Based Cohort Study.

According to the hygiene hypothesis, exposure to parasites may protect against inflammatory bowel disease (IBD). Our aim was to examine the risk of IBD with childhood exposure to mebendazole, a broad-spectrum antihelminthic agent. We conducted a population-based cohort study using prospectively collected historical data of all individuals born in Denmark between 1995 and 2018. We identified mebendazole exposure at age younger than 18 years and during early life (younger than 5 years). We performed adjusted Cox proportional hazards regression analysis to determine the risk of IBD, ulcerative colitis (UC), and Crohn's disease with mebendazole exposure after adjusting for potential confounders. Of 1,520,290 individuals in the cohort, 615,794 had childhood or adolescence mebendazole exposure. One thousand five hundred fifty-five and 1,499 individuals were subsequently diagnosed with pediatric-onset and adult-onset IBD, respectively. On multivariable analysis, mebendazole exposure at age younger than 18 years did not affect pediatric-onset or adult-onset IBD risk (adjusted hazard ratio [aHR] 0.97, 95% confidence interval [CI] 0.87, 1.07, and 1.08, 95% CI 0.97, 1.19, respectively). On limiting mebendazole exposure to age younger than 5 years while there was no association with pediatric-onset IBD (aHR 0.98, 95% CI 0.87, 1.11), adult-onset IBD risk was increased (aHR 1.17, 95% CI 1.04, 1.31). This increase in risk was driven by UC (aHR 1.32, 95% CI 1.12, 1.55), but not Crohn's disease (1.03, 95% CI 0.87, 1.22). Early-life mebendazole exposure is associated with an increase in the risk of adult-onset UC. These findings suggest the importance of early-life exposures in shaping the risk of IBD later in life.

Habitual Fish Oil Supplementation and Risk of Incident Inflammatory Bowel Diseases: A Prospective Population-Based Study.

BackgroundInflammatory Bowel Diseases (IBDs) have been emerging in recent years with the advance of global industrialization and diet pattern transformation. Marine n-3 polyunsaturated fatty acids (n-3 PUFAs), enriched in fish oils, have well-known human health promotion. Evidence on the association of fish oil supplementation with the risk of developing IBDs was scarce. This study aimed to examine the association between the use of fish oil supplements and the risk of developing inflammatory bowel diseases (IBDs) among the general population.MethodsWe conducted a prospective cohort study of 447,890 participants aged 40–69 years from the UK Biobank. A touch screen questionnaire was used to get the data about fish oil intake at baseline. Incident diagnoses of IBDs were ascertained by the International Classification of Diseases (ICD-9 and ICD-10) or self-report. Cox proportional hazards model was applied to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of developing IBDs and their subtypes.ResultsWe documented 1,646 incident cases of IBDs, including 533 incident cases of Crohn’s disease (CD) and 1,185 incident cases of ulcerative colitis (UC) during an average of 8 years of follow-up. After multivariate adjustment, the use of fish oil was associated with a 12% lower risk of IBDs (HR: 0.88, 95% CI: 0.78–0.99, p = 0.03) compared with non-consumers. For subtypes of IBDs, fish oil supplementation was inversely associated with a 15% lower risk of UC (HR: 0.85, 95% CI: 0.75–0.99, p = 0.02) but was not correlated with the risk of CD (p = 0.22). Besides, fish oil supplementation showed a significant inverse correlation with baseline CRP levels (β = –0.021, p < 0.001) and a positive association with baseline albumin levels (β = 0.135, p < 0.001) after adjustment for multiple variates.ConclusionHabitual intake of fish oil supplements was associated with a lower risk of IBDs and UC. Fish oil users tended to have lower baseline C-reactive protein levels and higher baseline albumin levels compared with non-users. It was concluded that fish oil supplement use may be recommended for the prevention and control of IBDs.

Two-Sample Mendelian Randomization Analysis Investigates Causal Associations Between Gut Microbial Genera and Inflammatory Bowel Disease, and Specificity Causal Associations in Ulcerative Colitis or Crohn's Disease.

BackgroundIntestinal dysbiosis is associated with inflammatory bowel disease (IBD). Ulcerative colitis (UC) and Crohn’s disease (CD), two subtypes of IBD, are characterized by unique microbial signatures, respectively. However, it is unclear whether UC or CD has a specific causal relationship with gut microbiota.ObjectiveTo investigate the potential causal associations between gut microbial genera and IBD, UC, or CD, two-sample Mendelian randomization (MR) analyses were conducted.Materials and MethodsWe obtained genome-wide association study (GWAS) summary statistics of gut microbiota and IBD, UC, or CD from published GWASs. Two-sample MR analyses were performed to identify potential causal gut microbial genera for IBD, UC, and CD using the inverse-variance weighted (IVW) method. Sensitivity analyses were also conducted to validate the robustness of the primary results of the MR analyses. Finally, a reverse MR analysis was performed to evaluate the possibility of reverse causation.ResultsCombining the results from the primary and sensitivity analyses, six bacterial genera were associated with the risk of IBD, UC, or CD in the IVW method. Briefly, Eubacterium ventriosum group was associated with a lower risk of IBD (P=0.011) and UC (P=1.00×10-4), whereas Coprococcus 2 was associated with a higher risk of IBD (P=0.022) and UC (P=0.007). In addition, we found a positive association between Oxalobacter with IBD (P=0.001) and CD (P=0.002), and Ruminococcaceae UCG014 with IBD (P=0.005) and CD (P=0.007). We also noticed a negative association between Enterorhabdus (P=0.044) and IBD, and between Lachnospiraceae UCG001 (P=0.023) and CD. We did not find causal effects of IBD, UC, or CD on these bacterial genera in the reverse MR analysis.ConclusionThis study expanded gut microbial genera that were causally associated with the risk of IBD, and also revealed specificity-gut microbial genera for UC or CD.

Appendectomy and risk for inflammatory bowel disease: effect of age and time post appendectomy – a cohort study

Background and objectiveAppendectomy may modulate the risk of inflammatory bowel disease through an effect on the gut microbiota. This study investigated the associations between appendectomy and incidence of Crohn’s disease...

IL12B rs6887695 polymorphism and interaction with alcohol intake in the risk of ulcerative colitis in Japan.

The interleukin (IL)-23/Th17 pathway plays a critical role in ulcerative colitis (UC). The IL-12p40 subunit, which is shared by IL-23 and IL-12, is encoded by the IL12B gene. The current case-control study investigated the association between IL12B SNP rs6887695 and the UC risk. There were 384 cases within 4years of UC diagnosis and 661 controls who were enrolled. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, and body mass index. Subjects with the GG IL12B SNP rs6887695 genotype had a significantly increased risk of UC compared with those with the CC genotype (adjusted odds ratio [AOR], 1.60; 95% confidence interval [CI], 1.08-2.36). This positive association was also significant using the additive and recessive models (AOR, 1.25; 95% CI, 1.03-1.52; AOR, 1.50; 95% CI, 1.08-2.09, respectively). An independent inverse relationship was observed between ever alcohol consumption and the UC risk in those with the CC genotype while no significant association was found in those with at least one G allele (P for interaction=0.0008). IL12B SNP rs6887695 was significantly associated with UC. The influence of alcohol consumption might rely on rs6887695.

Environmental variables and genome-environment interactions predicting IBD diagnosis in large UK cohort

A combination of genetic susceptibility and environmental exposure is thought to cause inflammatory bowel disease (IBD), but the non-genetic component remains poorly characterized. We therefore undertook a search for environmental variables and gene-environment interactions associated with future IBD diagnosis in a large UK cohort. Using self-report and electronic health records, we identified 1946 Crohn’s disease (CD) and 3715 ulcerative colitis (UC) patients after quality control in the UK Biobank. Based on prior literature and biological plausibility, we tested 38 candidate environmental variables for association with CD, UC, and overall IBD using Cox proportional hazard regressions. We also tested whether these variables interacted with polygenic risk in predicting disease, following up significant (FDR < 0.05) results with tests for SNP-environment associations. We performed robustness analyses on all significant results. As in previous reports, appendectomy protected against UC, smoking (both current and previous) elevated risk for CD, current smoking protected against UC, and previous smoking imparted a risk for UC. Childhood antibiotic use associated with IBD, as did sun exposure during the winter. Socioeconomic deprivation was conferred a risk for IBD, CD, and UC. We uncovered negative interactions between polygenic risk and previous oral contraceptive use for IBD and UC. Polygenic risk also interacted negatively with previous smoking in predicting UC. There were no individually significant SNP-environment interactions. Thus, for a limited set of environmental variables, there was strong evidence of association with IBD diagnosis in the UK Biobank, and interaction with polygenic risk was minimal.

Fecal microbiota and bile acids in IBD patients undergoing screening for colorectal cancer

ABSTRACT Due to the potential role of the gut microbiota and bile acids in the pathogenesis of both inflammatory bowel disease (IBD) and sporadic colorectal cancer, we aimed to determine whether these factors were associated with colorectal cancer in IBD patients. 215 IBD patients and 51 non-IBD control subjects were enrolled from 10 French IBD centers between September 2011 and July 2018. Fecal samples were processed for bacterial 16S rRNA gene sequencing and bile acid profiling. Demographic, clinical, endoscopic, and histological outcomes were recorded. Characteristics of IBD patients included: median age: 41.6 (IQR 22); disease duration 13.2 (13.1); 47% female; 21.9% primary sclerosing cholangitis; 109 patients with Crohn’s disease (CD); 106 patients with ulcerative colitis (UC). The prevalence of cancer was 2.8% (6/215: 1 CD; 5 UC), high-grade dysplasia 3.7% (8/215) and low-grade dysplasia 7.9% (17/215). Lachnospira was decreased in IBD patients with cancer, while Agathobacter was decreased and Escherichia-Shigella increased in UC patients with any neoplasia. Bile acids were not associated with cancer or neoplasia. Unsupervised clustering identified three gut microbiota clusters in IBD patients associated with bile acid composition and clinical features, including a higher risk of neoplasia in UC in two clusters when compared to the third (relative risk (RR) 4.07 (95% CI 1.6–10.3, P < .01) and 3.56 (95% CI 1.4–9.2, P < .01)). In this multicentre observational study, a limited number of taxa were associated with neoplasia and exploratory microbiota clusters co-associated with clinical features, including neoplasia risk in UC. Given the very small number of cancers, the robustness of these findings will require assessment and validation in future studies.

Childhood appendicitis and future risk of inflammatory bowel disease - A nationwide cohort study in Sweden 1973-2017.

AimThe aim of this study was to investigate the association between juvenile appendicitis, treated conservatively or with appendectomy, and adult risk of inflammatory bowel disease (IBD), either ulcerative colitis (UC) or Crohn's disease (CD). We used nationwide population data from more than 100,000 individuals followed for over four decades.MethodAll Swedish patients discharged with a diagnosis of appendicitis before the age of 16 years between 1973 to 1996 were identified. Everyone diagnosed with appendicitis was matched to an individual in the general population without a history of juvenile appendicitis (unexposed) of similar age, sex and region of residence. The study population was retrospectively followed until 2017 for any development of UC or CD. Cox proportional‐hazards models compared disease‐free survival time between exposed and unexposed individuals, also analysing the impact of treatment (conservative treatment versus appendectomy).ResultsThe final cohort consisted of 52,391 individuals exposed to appendicitis (1,674,629 person years) and 51,415 unexposed individuals (1,638,888 person years). Childhood appendicitis with appendectomy was associated with a significantly lower risk of adult IBD [adjusted hazard ratio (aHR) 0.48 (0.42–0.55)], UC [aHR 0.30 (0.25–0.36)] and CD [aHR 0.82 (0.68–0.97)]. Those treated conservatively had a lower risk of adult UC [aHR 0.29 (0.12–0.69)] but not CD [aHR 1.12 (0.61–2.06)] compared with unexposed individuals.ConclusionJuvenile appendicitis treated with appendectomy was associated with a decreased risk of adult IBD, both UC and CD. Those treated conservatively instead of with surgery had a lower risk of UC only. Our findings warrant more research on the role of the appendix and gut microbiota in the pathogenesis of IBD.

Estimation of the bidirectional relationship between schizophrenia and inflammatory bowel disease using the mendelian randomization approach

It has been reported that schizophrenia (SCZ) and inflammatory bowel disease (IBD) are related. However, whether there is a bidirectional interaction between them remains unclear. The aim of this study was to conduct a bidirectional Mendelian randomization (MR) analysis to elucidate the causal relationship between SCZ and IBD and its subtypes, including Crohn’s disease (CD) and ulcerative colitis (UC). Single-nucleotide polymorphisms (SNPs) extracted from the summary data of genome-wide association studies were used as genetic instruments. MR was performed using the inverse-variance-weighted method. The MR-Egger and weighted median methods were used for sensitivity analyses. Analysis using 70 SNPs as genetic instruments showed that SCZ was associated with an increased risk of IBD (OR = 1.14, 95% CI: 1.09–1.20, P = 9.21 × 10−8), CD (OR = 1.16, 95% CI: 1.07–1.25, P = 1.42 × 10−4), and UC (OR = 1.14, 95% CI: 1.07–1.21, P = 2.72 × 10−5). The results of the sensitivity analyses were robust and no evidence of pleiotropy was observed. Bidirectional MR analyses showed no causal effects of IBD, CD, or UC on SCZ. This study suggests that SCZ has causal effects on IBD and its subtypes, whereas IBD has no effect on SCZ. Brain-gut axis interactions may help clarify the causal relationship between SCZ and IBD. However, further studies are needed to elucidate the biological mechanisms behind the brain-gut interactions.

IMPACT OF CURRENT AND FORMER SMOKING ON THE RISK OF ULCERATIVE COLITIS AMONG FAMILY HISTORY POSITIVE AND NEGATIVE INDIVIDUALS; EVIDENCE FOR GENE-SMOKING INTERACTION FROM LARGE SCALE POPULATION-BASED COHORT STUDY IN KOREA

Abstract BACKGROUND The interaction between smoking and genetic predispositions in the pathogenesis of ulcerative colitis (UC) remains to be determined. Also the effect of smoking on UC in Asian populations is not well-studied. OBJECTIVE Our aim was to evaluate the association of smoking with UC and to assess the interaction between smoking and family history in UC development. METHODS Using the National Health Insurance and National Health Screening Database which covers the entire Korean population(N=50 million) and includes data on family relationships, smoking status and other lifestyle factors, we identified 7 million individuals, comprising 3.7 million families. To examine the association of UC with current and former smoking, Cox proportional hazard regression was used and hazard ratios (HRs) were computed with a 95% confidence interval (CI). We calculated the familial risk of UC using incidence risk ratios (IRRs), and adjusted IRRs for lifestyle risk factors, including smoking and body mass index. Interactions between family history and current and former smoking were assessed on additive and multiplicative scales. RESULTS A total of 7 million people were initially included in our study and among them, we identified 1.2 million current smokers, 0.7 million former smokers and 5.1 million non-smokers. Our findings show that current smoking was associated with a decreased risk of disease (HR 0.6), while former smoking was associated with an increased risk (HR 1.2), compared to non-smokers. In the separate analysis among familial and non-familial groups, the protective effect of current smoking was less pronounced in the familial group (HR 0.5 vs 0.8) and the risk associated with former smoking also diminished in the familial group (HR 1.5 vs 1.2). In interaction analysis, the joint effect of current smoking and a positive family history of UC was lower than the product of their individual risks (p&amp;lt;0.05), suggesting a negative interaction. Also, the joint effect of former current smoking and family history was lower than the product of their individual risks with statistically significant interaction. CONCLUSION This large scale cohort study found that current smoking was associated with a decreased risk of UC and former smoking was associated with an increased risk. The impact of current and former smoking was different between family history positive and negative individuals. These results provide evidence for gene-smoking interaction in UC disease risk.

P655 Early life mebendazole exposure increases the risk of adult-onset ulcerative colitis: a population-based cohort study

Abstract Background According to the hygiene hypothesis, exposure to parasites may promote immune tolerance and protect against inflammatory bowel disease (IBD). The early life period, considered to extend from prenatal life to up to 5 years of age, is important towards immune maturation; exposures during this period are especially relevant towards IBD risk. We examined the impact of exposure to mebendazole, a broad-spectrum anthelminthic agent, during childhood and adolescence, on the risk of IBD, ulcerative colitis (UC) and Crohn’s disease (CD). Methods We used prospectively collected historical data of all individuals born in Denmark between 1995 and 2018 from national registers to conduct a population-based cohort study. Using the National Prescription Register, we identified mebendazole exposure at &amp;lt;18 years of age, as well as at &amp;lt;5 years of age. Using ICD8/10 codes in the cross-linked National Patient Register, we identified individuals who were subsequently diagnosed with UC or CD at &amp;lt;16 or ≥16 years of age. We performed adjusted Cox proportional hazards regression analyses to determine the risk of IBD, UC and CD with mebendazole exposure after adjusting for potential confounders, which included calendar period, number of siblings and half-siblings, antibiotic prescription, sex, socio-economic status, degree of urbanization and parental IBD status. Results Of 1,520,290 individuals in the cohort, 615,794 had childhood mebendazole exposure. 1,555 and 1,499 individuals were subsequently diagnosed with pediatric- and adult-onset IBD, respectively. On multivariable analysis, mebendazole exposure at &amp;lt;18 years of age did not impact pediatric- or adult-onset IBD risk (aHR 0.97, 95% CI 0.87, 1.07 and 1.08, 95% CI 0.97, 1.19, respectively) (Table). On limiting mebendazole exposure to age &amp;lt;5 years, while there was no association with pediatric-onset IBD (aHR 0.98, 95% CI 0.87, 1.11), adult-onset IBD risk was increased (aHR 1.17, 95% CI 1.04, 1.31). This increase in risk was driven by UC (aHR 1.32, 95% CI 1.12, 1.55), but not CD (1.03, 95% CI 0.87,1.22) (Figure) Table: Crude and adjusted estimates for outcome with exposure to mebendazole in early life (&amp;lt;5 years of age) Figure: Cumulative incidence curves for (a) ulcerative colitis and (b) Crohn’s disease Conclusion Early life, but not later in childhood or adolescence, mebendazole exposure is associated with increase in the risk of adult-onset UC. Mebendazole exposure does not impact pediatric-onset IBD risk or CD risk. These findings emphasize the importance of early-life exposures in shaping the risk of IBD later in life, may indicate differences between UC and CD risk factors and pathways, and may call for re-evaluation of risks and benefits of large-scale helminth eradication programs.

P628 Processed and ultra-processed food and risk of Inflammatory Bowel Disease in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC-IBD)

Abstract Background During the past decades, human diet has evolved towards higher intakes of processed and ultraprocessed food. We have investigated the association between these food groups and the risk of inflammatory bowel disease (IBD) in the European Prospective Investigation into Cancer and Nutrition. Methods 413 590 participants from 8 European countries were included. Dietary data were collected at baseline from validated food frequency questionnaires. All EPIC food items were expressed as g/day and categorized according to the NOVA classification: “group 1—unprocessed or minimally processed foods”; “group 2—processed culinary ingredients”; “group 3—processed foods”; and “group 4—ultra-processed foods (UPFs)”. Because the EPIC dietary questionnaires were conceived before the NOVA classification, the food items were retrospectively categorized into this classification. Some food items collected in the EPIC questionnaires were difficult to categorize into group 3 or 4. We therefore merged them into a single category. We tested three scenarios for the estimation of the dietary content of this merged category: lower, middle and upper contents of groups 3 + 4. The association between the proportion of each NOVA group in the diet and IBD were estimated using Cox proportional hazard models to obtain Hazards Ratios (HRs) and 95% confidence intervals. We adjusted the HR for smoking status, educational level, physical activity, BMI, alcohol consumption and energy intake and stratified by centre, age at baseline (1-y interval), and sex. Results After a mean follow-up of 16 years, 179 Crohn’s disease (CD) and 431 ulcerative colitis (UC) cases were identified. NOVA group 1 was negatively associated with CD risk (adjusted HR for the fourth vs. the first quartile = 0.58; 95% CI = 0.35–0.95; P-trend = 0.03). Within group 1, fruit intake was the only food item to be negatively associated with the risk of IBD (adjusted HR for the fourth vs. the first quartile = 0.42; 95% CI = 0.24–0.73; P-trend = 0.003). We found numerical associations between group 3 + 4 and the risk of CD with the middle or upper scenarios (adjusted HRs for the fourth vs. the first quartile = 1.50; 95% CI = 0.92–2.46; P-trend = 0.12 and 1.41; 95% CI = 0.88–2.27; P-trend = 0.09 respectively). There was no association between any category of the NOVA classification and UC risk. Conclusion In the EPIC cohort, consumption of non-processed food was associated with a lower risk of CD while consumptions of processed or ultra-processed food were numerically associated with increased risk of CD. We found no association with UC.

P563 Association between smoking status and the efficacy and safety of tofacitinib in patients with Ulcerative Colitis: Data from the tofacitinib clinical programme

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Efficacy and safety of tofacitinib were evaluated in randomised, placebo-controlled Phase (P)2 (NCT00787202) and P3 (NCT01465763; NCT01458951; NCT01458574) studies, an open-label, long-term extension (OLE) study (NCT01470612) and an ongoing P3b/4 study (NCT03281304). Ex-smokers have an increased risk of UC, but the response to therapy in these patients (pts) has not been previously evaluated. We assessed the impact of smoking status on the efficacy and safety of tofacitinib in the UC clinical programme. Methods Efficacy endpoints and adverse events (AEs) were evaluated by smoking status (ever smokers [current and ex-smokers] and never smokers) in P2 (safety only)/P3/OLE/P3b/4 studies. Efficacy endpoints were summarised by treatment allocation; pt characteristics and AEs were summarised by tofacitinib predominant dose. Results This analysis included 1156 pts (ever smokers, n=416 [36.0%; current smokers, n=59 (5.1%); ex-smokers, n=357 (30.9%)]; never smokers, n=740 [64.0%]; Table 1). Compared with never smokers, ever smokers were older and more likely to have a prior history of myocardial infarction, diabetes mellitus, or ischaemic or coronary heart disease. The proportion of pts achieving efficacy endpoints was generally similar across tofacitinib treatment groups regardless of smoking status (Table 2). AEs were reported in 88.7% of ever smokers and 83.8% of never smokers. Overall, 60.6% of ever smokers had an infection, specifically 10.8% had herpes zoster (non-serious and serious), 12.0% had a Clostridioides difficile infection and 19.5% had a lower respiratory tract infection; corresponding values for each AE among never smokers were 53.1%, 6.8%, 8.5% and 11.4% (Table 1). Major adverse cardiovascular events were reported in 1.0% of ever smokers and 0.7% of never smokers; thromboembolic events were reported in 1.0% of ever smokers and 0.9% of never smokers. Malignancies (excl. non-melanoma skin cancer [NMSC]) occurred in 2.5% of ever smokers and 1.5% of never smokers; NMSC occurred in 3.7% and 1.0%, respectively. In total, 0.6% of never smokers had colorectal cancer and there were no cases in ever smokers. Conclusion The efficacy and safety of tofacitinib were generally similar in ever smokers and never smokers. This study is limited by the combined analysis of current and ex-smokers and unknown factors such as the degree of smoking and the time between smoking cessation and UC diagnosis. These data are consistent with previous reports in the general population and pts with UC.1,2

GWAS-associated bacteria and their metabolites appear to be causally related to the development of inflammatory bowel disease.

Accumulating evidence has suggested that the imbalance of gut microbiota is commonly observed in patients with inflammatory bowel disease (IBD). However, it remains unclear whether dysbiosis is a cause or consequence of chronic intestinal inflammation. We aimed to investigate the causal relationships of gut microbiota and metabolites with IBD, including ulcerative colitis (UC) and Crohn's disease (CD). We applied two-sample Mendelian randomization using summary statistics from the gut microbiota genetic consortium (n = 1812), the Framingham Heart Study (n = 2076) and the International IBD Genetics Consortium (n = 86,640). Using the genetic approach, the increase in OTU10032 unclassified Enterobacteriaceae was associated with higher risks of IBD (OR, 1.03; 95% CI, 1.00-1.06; P = 0.033) and CD (1.04; 1.01-1.08; P = 0.015). Importantly, an Enterobacteriaceae-related metabolite taurine was positively associated with risks of IBD (1.04; 1.01-1.08; P = 0.016) and UC (1.05; 1.01-1.10; P = 0.024). Notably, we also found betaine, a downstream product of Enterobacteriaceae metabolism, was causally associated with a higher risk of CD (1.10; 1.02-1.18; P = 0.008). In addition, increased Erysipelotrichaceae family were causally related to lower risks of IBD (0.88; 0.78-0.98; P = 0.026) and UC (0.86; 0.75-0.99; P = 0.042), and Actinobacteria class (0.80; 0.65-0.98; P = 0.028) and Unclassified Erysipelotrichaceae (0.79; 0.64-0.98; P = 0.036) were associated with lower risks of UC and CD, respectively. Our finding provided new insights into the key role of gut metabolites such as taurine and betaine in host-microbiota interactions of IBD pathogenesis, indicating that host-microbe balance strongly influences inflammatory conditions.

Risk Factors for Incident Inflammatory Bowel Disease According to Disease Phenotype

We examined whether relationships between known risk factors for Crohn's disease (CD) and ulcerative colitis (UC) differ according to disease phenotype, defined by Montreal classification, at the time of diagnosis. We performed a prospective cohort study of 208,070 adults from the Nurses' Health Study (NHS), NHSII, and Health Professionals Follow-Up Study (HPFS). Dietary, lifestyle, and medical data were obtained at baseline and every 2-4 years. We confirmed cases of inflammatory bowel disease (IBD) and their phenotypes via medical record review. We tested for heterogeneity across CD subtypes using the likelihood ratio test and for linear heterogeneity across UC subtypes using the meta-regression method. We ascertained 346 cases of CD and 456 cases of UC over 5,117,021 person-years of follow-up (1986-2016 for NHS and HPFS; 1991-2017 for NHSII). Fiber intake was associated with decreased risk for ileocolonic but not ileal or colonic CD (Pheterogeneity= .04). Physical activity was associated with decreased risk of nonstricturing and nonpenetrating CD but not of penetrating CD (Pheterogeneity= .02). Higher body mass index and current smoking were associated with decreased risk of proctitis and left-sided UC but not of pan-UC (Plinear heterogeneity= .004 and .02, respectively). The associations between other risk factors examined and risk of CD and UC did not differ by disease phenotype (all Pheterogeneity > .06). In 3 large prospective cohorts, we observed that dietary and lifestyle risk factors for IBD may differ according to disease phenotype. These findings highlight the need for disease stratification in future epidemiologic studies.