Increased Risk Of Inflammatory Bowel Disease Research Articles

P1204 Childhood EBV infection is protective against IBD, while adulthood EBV infection is not: a population-based cohort study

Abstract Background Emerging data indicate a role of Epstein Barr Virus (EBV) infection in immune-mediated diseases risk. However, its role in inflammatory bowel disease (IBD) risk remains to be elucidated. Methods We conducted a nationwide population-based cohort study leveraging cross-linked Danish registers consisting of individuals with a record of being tested for EBV between January 1, 2008 and August 31, 2020. We determined the impact of previous EBV infection, active IBV infection, and no EBV infection on IBD risk, based on EBV serological tests, using adjusted Cox proportional hazards regression analyses after adjusting for sex, type of test, year of test, and age at test. We also determined the impact of age at infection, categorized as early or late childhood or adulthood (0-12, 13-20, and ≥21 years, respectively). Results Of 20,386 individuals included in the study who were followed from the first EBV test for a median (IQR) of 3.93 (2.18-5.95) years, 250 developed IBD. In the overall analysis, there were null associations between prior or current EBV infection and IBD risk. In analyses stratified by age, EBV infection in early and late childhood were associated with a protective effect against IBD, although not statistically significant in the former group (aHR 0.81, 95% CI 0.40, 1.66 and 0.50, 95% CI 0.26, 0.95, respectively). This association was driven by an increase in the risk of Crohn’s disease (CD), but not ulcerative colitis (aHR 0.36, 95% CI 0.15, 0.87 and aHR 0.82, 95% CI 0.32, 2.11, respectively). Among adults, while EBV infection was not associated with IBD risk (aHR 2.17, 95% CI 0.71, 6.62), the effect estimate was in the opposite direction relative to that in childhood, suggesting a potentially increased risk. Conclusion In a nationwide cohort, childhood EBV infection was protective against CD. Adulthood EBV infection was not protective, and possibly associated with increased IBD risk, although this was not statistically significant. Validation studies will help elucidate further.

Identifying novel inflammatory protein biomarkers and drug targets of inflammatory bowel disease by integrating Mendelian randomization, bioinformatics, and druggability analysis.

Inflammatory proteins have the potential to be used as therapeutic targets for inflammatory bowel disease (IBD). We conducted Mendelian randomization (MR) analysis to probe causal associations between 91 circulating inflammatory proteins and IBD in the discovery and replication cohorts. Subsequently, we conducted meta-analysis of results from two cohorts. We further conducted protein-protein interaction (PPI), enrichment analysis, and druggability evaluation to elucidate our results and prioritize potential therapeutic targets. By integrating data from two cohorts, we demonstrated that genetically predicted CD40 (odds ratio [OR] = 0.878, 95% confidence interval [CI] = 0.838-0.919) and C-X-C motif chemokine ligand (CXCL)5 (OR = 0.884, 95%CI = 0.841-0.930) decreased IBD risk. However, genetically predicted CXCL9 (OR = 1.184, 95%CI = 1.084-1.294), Interleukin (IL)-18 (OR = 1.140, 95%CI = 1.076-1.208), CD6 (OR = 1.096, 95%CI = 1.045-1.150), and 4E-binding protein 1 (4E-BP1) (OR = 1.154, 95%CI = 1.070-1.244) increased IBD risk. Moreover, genetically predicted CD40 (OR = 0.855, 95%CI = 0.801-0.912) decreased Crohn's disease (CD) risk. Genetically predicted fibroblast growth factor 21 (FGF21) (OR = 1.259, 95%CI = 1.135-1.397) and 4E-BP1 (OR = 1.202, 95%CI = 1.088-1.327) increased CD risk. We found no inflammatory protein associated with ulcerative colitis. Additionally, CD was significantly associated with elevated levels of three circulating inflammatory proteins, which are suggested to be the consequences of CD. PPI analysis demonstrated interactions between CXCL5, CXCL9, IL-18, CD40, and FGF21. Enrichment analysis indicated these identified proteins significantly enriched in inflammation-related signaling pathways, including interleukin signaling, cytokine signaling, and NF-κB pathway. Three proteins (CD40, IL-18, 4E-BP1) have been targeted for drug development on cancers and immune-related diseases, with potentials of therapeutic targets for IBD. Our results provide new biomarkers and drug targets for CD. Moreover, we further demonstrate critical roles of inflammation and immunity in the occurrence and development of IBD.

Inflammatory Bowel Disease and Endometriosis: Diagnosis and Clinical Characteristics.

Background/Objectives: Endometriosis and inflammatory bowel disease (IBD) share some epidemiological, clinical and pathogenetic features. A differential diagnosis between pelvic endometriosis and IBD may be challenging, even for expert clinicians. In the present review, we aimed to summarize the currently available data regarding the relationship between endometriosis and IBD and their possible association. Methods: The PubMed and Scopus database were considered, by searching the following terms: "Crohn's Disease", "Ulcerative Colitis", "Endometriosis", "Adenomyosis", and "Inflammatory Bowel Disease", individually or combined. Full-text papers published in English with no date restriction were considered. Results: Few studies have researched the possible association between endometriosis and IBD. Both conditions are characterized by chronic recurrent symptoms, which may be shared (abdominal pain, fatigue, infertility, menstrual irregularities, diarrhea, constipation). Deep infiltrating endometriosis (DIE) can cause bowel symptoms. In a large Danish study, a 50% increased risk of IBD was observed in women with endometriosis. A missed diagnosis of endometriosis and an increased risk of endometriosis has been reported in IBD. Current evidence does not support an association between endometriosis and IBD characteristics. However, IBD may be associated with DIE, characterized by pelvic symptoms (dyschezia, dyspareunia). Preliminary observations suggest an increased IBD risk in patients with endometriosis treated with hormonal therapy. Conclusions: Current findings suggest that a careful search is needed for concomitant endometriosis in subgroups of patients with IBD showing compatible symptoms and vice versa. A multidisciplinary approach including dedicated gastroenterologists and gynecologists is required for a proper search for IBD and endometriosis in subgroups of patients. This approach may avoid diagnostic delays or overtreatments for these conditions.

MiR-146a (rs2910164) Gene Polymorphism and Its Impact on Circulating MiR-146a Levels in Patients with Inflammatory Bowel Diseases.

MicroRNA-146a (miR-146a) has been involved in the pathophysiology of inflammatory bowel disease (IBD). However, the precise processes are still not entirely understood. Contradictory studies suggest that miR-146a expression could be influenced by the miR-146a rs2910164 C > G polymorphism. This case-control study aimed to investigate the association ofmiR-146a rs2910164 C > G gene polymorphism and its impact on circulating miR-146a expression levels in Egyptian IBD patients. We included 40 IBD patients and 30 matched healthy controls. Genotyping of miR-146a rs2910164 polymorphism and assessment of miR-146a expression level were done using quantitative real-time PCR in all participants. MiR-146a rs2910164 GG genotype and the G allele were reported in 47% and 70% of the IBD patient group, respectively. And they were associated with increased IBD risk. All the IBD patients with the CC genotype (100%) and most of those with the CG genotype (66.67%) had an inactive disease, while most IBD patients with the GG genotype (73.68%) had an active disease. The miR-146a expression level was the highest with the CC genotype and the lowest with the GG genotype. Also, miR-146a expression level decreased significantly in IBD patients than controls and with disease activity. Combined detection of fecal calprotectin with miR-146a expression level improved the diagnostic sensitivity and the negative predictive value in differentiating IBD patients with active disease from those inactive.Our study identified a strong association of miR-146a rs2910164 GG genotype and G allele with IBD-increased susceptibility and activity in the Egyptian population. The miR-146a rs2910164 polymorphism can reduce miR-146a expression levels in these patients as well. Further research on a larger sample size and different ethnic populations can be the key to progress in establishing this genetic association.

P1093 Early life exposure to agriculture and biodiversity influences Crohn’s disease risk in a population-based cohort study

Abstract Background Specific pollutants and environmental exposures are implicated in modulating inflammatory bowel disease (IBD) risk. Crohn’s disease (CD) clustering has been reported in agricultural areas. However, the role of environmental exposures, particularly in early life, towards IBD risk, has not been systematically evaluated. Methods We conducted a nationwide population-based cohort study during the study period extending from January 1, 1995, to September 1, 2020, using cross-linked Danish registers, maps, and inventories to ascertain the impact of agricultural land use, biodiversity, green space, urban space, blue space, and natural vegetation density index during pregnancy and the first two years of life on IBD, CD, and ulcerative colitis (UC) risk, using adjusted Cox proportional hazards regression analyses. We adjusted for the following covariates: sex, maternal age at delivery, calendar year of birth, municipal-level socioeconomic status, and first-degree relative with IBD. Results Of 1,438,487 individuals included in the study who were followed from age 2 years until a median (IQR) age of 14 (8-20) years, 3,768 individuals were diagnosed with IBD. Exposure to the highest and third quartiles of agriculture land use during early life, relative to the lowest quartile, were associated with increased IBD risk (aHR 1.16, 95% CI 1.02, 1.31 and 1.19, 95% CI 1.07, 1.32, respectively). Conversely, exposure to the highest and third quartiles of biodiversity in early life, compared to the lowest quartile, were associated with a lower IBD risk (aHR 0.90, 95% CI 0.82, 1.00 and 0.90, 95% CI 0.82, 0.99, respectively). These associations were driven by differences in CD risk (Figure), but there was no association with UC risk. Other environmental exposures were not associated with IBD risk. Conclusion In a nationwide cohort with long-term follow up data, early life exposure to agriculture land use was associated with an increase in CD risk, while higher biodiversity was protective.

Association between the use of lipid-lowering drugs and the risk of inflammatory bowel disease.

Observational studies have suggested an association between lipid-lowering drugs and inflammatory bowel disease (IBD) risk. This study aimed to assess the causal influence of lipid-lowering agents on IBD risk using Mendelian randomization analysis. In a population of 173,082 individuals of European ancestry, 55 single-nucleotide polymorphisms were identified as instrumental variables for 6 lipid-lowering drug targets (HMGCR, NPC1LC, PCSK9, LDLR, CETP and APOB). Summary statistics for the genome-wide association study of IBD, ulcerative colitis (UC) and Crohn's disease (CD) were obtained from the FinnGen consortium, Program in Complex Trait Genomics and UK Biobank. Inverse-variance weighted was employed as the primary MR method, and odds ratios (ORs) with 95% confidence intervals were reported as the results. Sensitivity analyses using conventional MR methods were conducted to assess result robustness. Gene-proxied inhibition of Niemann-Pick C1-like 1 (NPC1L1) was associated with an increased IBD risk (OR [95% CI]: 2.31 [1.38, 3.85]; p = .001), particularly in UC (OR [95% CI]: 2.40 [1.21, 4.74], p = .012), but not in CD. This finding was replicated in the validation cohort. Additionally, gene-proxied inhibition of low-density lipoprotein receptor was associated with reduced IBD (OR [95% CI]: .72 [.60, .87], p < .001) and UC risk (OR [95% CI]: .74 [.59, .92], p = .006), although this result was not replicated in the validation cohort. Other drug targets did not show significant associations with IBD, UC or CD risk. Inhibition of the lipid-lowering drug-target NPC1L1 leads to an increased IBD risk, mainly in the UC population.

A dose-dependent increase in the risk of inflammatory bowel disease after exposure to broad-spectrum antibiotics: A national population study in Korea.

The association between antibiotic use and risk of inflammatory bowel disease (IBD), particularly among adults, remains unclear. Furthermore, there is a scarcity of data among non-Western countries. To investigate the association and dose-response relationships between antibiotic use and subsequent IBD risk across all ages METHODS: This population-based case-control analysis used data from the Korean National Health Insurance Service database (2004-2018). We compared 68,633 patients with new-onset IBD to matched controls (n = 343,165) using multivariable conditional logistic regression analysis. We also examined the dose-response relationship using non-linear regression analysis, and separately analysed childhood-onset IBD (aged ≤14 years) risk following early-life antibiotic exposure. The mean age at diagnosis was 45.2 ± 16.8 years. Antibiotic prescriptions between 2 and 5 years before diagnosis significantly increased the odds of developing IBD (adjusted odds ratio [OR], 1.24; 95% confidence interval [CI]: 1.21-1.27). Additionally, sensitivity analysis revealed an elevated risk up to 9 years before diagnosis. Broad-spectrum antibiotics increased IBD risk, independent of gastroenteritis. A distinct dose-response relationship was observed irrespective of the IBD subtype and study population (all p < 0.001). Furthermore, antibiotic exposure within the first year of life was linked with the risk of childhood-onset IBD (OR, 1.51; 95% CI: 1.25-1.82). Broad-spectrum antibiotics dose-dependently increased the risk for IBD in the Korean population. Our findings provide a fundamental epidemiological basis for identifying antibiotic use as a significant risk factor for IBD across different environmental backgrounds.

A systematic review and meta-analysis of the relationship between advanced glycation end products ceceptor (RAGE) gene polymorphisms and the risk of inflammatory bowel disease.

In the pathogenesis of inflammatory bowel disease (IBD), the advanced glycation end product receptor (RAGE) has been involved. IBD is classified into Chron's disease (CD) and ulcerative colitis (UC). The promoter gene of the RAGE gene was discovered to have had unique polymorphisms that increased its transcriptional activity. This study, therefore, used a systematic review and meta-analysis to examine the relationship between the RAGE gene polymorphism and the risk of IBD. Databases such as PubMed, Scopus, and Cochrane library were searched to identify the relationship between RAGE gene polymorphisms and IBD susceptibility. We identified three Single Nucleotide Polymorphism (SNPs) (RAGE-429T/C, 374T/A, and G82S). The data were analyzed by RevMan 5.4. Four studies (932 cases/1366 controls) were included. The findings showed no relationship between RAGE -429T/C and -G82S polymorphisms and the risk of IBD in all genetic models significantly. TT genotype of RAGE -374T/A polymorphisms was related to increased CD risk (OR=1.37; 95%CI=1.04-1.81; P=0.02), while TA genotype was determined to be a protective factor (OR=0.75; 95%CI=0.57-0.99; P=0.04). In UC, A allele of RAGE -374T/A was related to increase risk (OR=1.26; 95%CI=1.04-1.53; P=0.02), while T allele was determined to decrease risk (OR=0.79; 95%CI= 0.65-0.96; P=0.02). Our findings demonstrated that TT genotype and A allele of RAGE -374T/A polymorphisms were related to CD and UC risks, respectively, while the TA genotype and T allele possibly had a protective effect. RAGE -429T/C and RAGE -G82S polymorphisms were not related to increased IBD risk.

Bidirectional association between inflammatory bowel disease and depression among patients and their unaffected siblings.

Background and AimApproximately 30% of inflammatory bowel disease (IBD) patients develop depression. Conversely, several studies reported increased IBD risk among patients with depression. Such bidirectional relationship has not been reported within one representative cohort, nor investigated among patients' family members. These associations may further implicate the gut–brain axis in IBD.MethodsWe conducted parallel retrospective cohort analyses to investigate depression risk among IBD patients and their unaffected siblings, and IBD risk among patients with depression and their unaffected siblings using the Taiwanese National Health Insurance Research Database. Individuals were followed up to 11 years for new‐onset depression or IBD. Controls were matched to unaffected siblings based on predefined characteristics.ResultsTo investigate depression risk among IBD ‐ 422 IBD patients, 537 unaffected siblings, and 2148 controls were enrolled. During follow‐up, 78 (18.5%) IBD patients, 26 (4.8%) unaffected siblings, and 54 (2.5%) controls developed depression. Adjusted odds ratios (ORs) for depression among IBD patients and unaffected siblings were 9.43 (95% CI 6.43–13.81; P < 0.001) and 1.82 (95% CI 1.14–2.91; P = 0.013), respectively. To investigate IBD risk among depression ‐ 25 552 patients with depression, 26 147 unaffected siblings, and 104 588 controls were enrolled. During follow‐up, 18 (0.70/1000) depression patients, 25 (0.96/1000) unaffected siblings, and 58 (0.55/1000) controls developed IBD. ORs for IBD among depression patients and unaffected siblings were 1.87 (95% CI 1.07–3.26; P = 0.028) and 1.69 (95% CI 1.05–2.69; P = 0.029), respectively.ConclusionsThis population‐based study elucidates bidirectional association between IBD and depression. Elevated risks for either disease among patients and their unaffected siblings suggest shared etiologic contributors, offering novel insight into the gut–brain axis' influence in IBD pathophysiology.

Impact of Body Mass Index on the Development of Inflammatory Bowel Disease: A Systematic Review and Dose-Response Analysis of 15.6 Million Participants.

Background: A growing trove of literature describes the effect of malnutrition and underweight on the incidence of inflammatory bowel disease (IBD). However, evidence regarding the association between underweight or obesity and IBD is limited. The study aimed to assess the association of body mass index (BMI) with a risk of IBD (Crohn’s disease (CD) and ulcerative colitis (U.C.)) incidence. Methods: We systematically searched PubMed/Medline, Cochrane, Web of Science, and Scopus for observational studies assessing the association between BMI and IBD that were published up to 30 June 2020. We estimated pooled hazard ratios (HR) with corresponding 95% confidence intervals (CI). Random effect dose-response meta-analysis was performed using the variance weighted least-squares regression (VWLS) models to identify non-linear associations. Results: A total of ten studies involving 15.6 million individuals and 23,371 cases of IBD were included. Overall, obesity was associated with an increased IBD risk (HR: 1.20, 95% CI: 1.08–1.34, I2 = 0%). Compared to normal weight, underweight (BMI < 18.5 kg/m2) and obesity (BMI ≥ 30 kg/m2) were associated with a higher risk of CD, and there was no difference in the risk of U.C. among those with BMI < 18.5 kg/m2 and BMI ≥ 30 kg/m2. There was a significant non-linear association between being underweight and obesity and the risk of development of CD (Coef1 = −0.0902, p1 < 0.001 Coef2 = 0.0713, p2 < 0.001). Conclusions: Obesity increases the risk of IBD development. Underweight and obesity are independently associated with an increased risk of CD, yet there is no evident association between BMI and the risk of U.C. Further studies are needed to clarify the underlying mechanism for these findings, particularly in CD.

Irak-4 rs4251481 gene variant: as a risk factor on inflammatory bowel disease

Background/aim Abnormal immune response occurs in individuals who have alleles associated with innate and adaptive immune mechanisms that predispose to inflammatory bowel disease (IBD). Interleukin-1 receptor-associated kinase 4 (IRAK-4) involved in the pathway produces cytokines that initiate and maintain inflammation through Toll-like receptors and interleukin-1 receptors on the membranes of innate immune cells are stimulated with antigens. It was aimed to investigate whether IRAK-4 rs3794262 and rs4251481 polymorphisms predispose to IBD and the possible effects of these polymorphisms by examining these gene polymorphisms with the clinic and prognostic parameters of IBD.Material and methodsReal-time PCR technique was used to detect IRAK-4 polymorphisms in 107 patients with IBD and 103 healthy controls. Results As a result of experimental studies, the frequency of occurrence of rs4251481 polymorphism related AG genotype (P = 0.029) and G allele (P = 0.005) was found to increase statistically in patients compared to controls. In the control group, the rs4251481 AA genotype rate of incidence increased compared with the patient group (P = 0.005).Conclusion Consequently, this is the first study in terms of both polymorphisms on IBD. These results suggest that rs4251481 AG genotype and G allele are associated with increased IBD risk in patients.

Stress resilience and the risk of inflammatory bowel disease: a cohort study of men living in Sweden

ObjectiveTo determine if low psychosocial stress resilience in adolescence (increasing chronic stress arousal throughout life) is associated with an increased inflammatory bowel disease (IBD) risk in adulthood. Subclinical Crohn's disease...

Combinatorial effects of diet and genetics on inflammatory bowel disease pathogenesis.

Inflammatory bowel disease (IBD) encompasses a group of disorders affecting the gastrointestinal tract characterized by acute and chronic inflammation. These are complex and multifactorial disorders that arise in part from a genetic predisposition. However, the increasing incidence of IBD in developing countries suggests that environmental factors, such as diet, are also critical components of disease susceptibility. Evidence suggests that consumption of a Western diet, enriched with saturated fat, refined carbohydrates, and food additives, is associated with increased IBD risk. Dietary components, such as omega-6 fatty acids, long-chain fatty acids, protein, and digestible carbohydrates, may contribute to IBD pathogenesis through altering intestinal microbiota, increasing intestinal permeability, and promoting inflammation; whereas omega-3 fatty acids, medium chain triglycerides, and nondigestible carbohydrates improve these parameters and intestinal health. However, the limited amount of prospective studies, small sample sizes, and the heterogeneity of disease subtype result in inconsistencies between studies and difficulty in conclusively determining the specific effects of diet on intestinal homeostasis. There are no standard clinical dietary recommendations for patients with IBD. However, exclusionary diet interventions have shown some efficacy in relieving symptoms or inducing remission, suggesting more research is needed to fully understand how diet influences disease behavior or combines with other IBD risk factors to promote disease. This review focuses on the associations of various dietary components and IBD risk in clinical studies and genetically susceptible IBD models.

Risk of inflammatory bowel disease following a diagnosis of irritable bowel syndrome

BackgroundIrritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) symptoms often overlap. In some IBS cases there are subtle inflammatory changes similar to the immune-mediated pathophysiology of IBD, and the risk of both increases after infectious gastroenteritis (IGE).MethodsTo evaluate the effect of IBS and IGE on IBD risk utilizing US Department of Defense medical encounter data, active duty personnel with IBS were matched to subjects without IBS. Medical encounter history was analyzed to assess for incident IBD. IGE was identified from documented medical encounters and by self-report. Relative risks were calculated using Poisson regression models.ResultsWe identified 9,341 incident IBS cases and 18,678 matched non-IBS subjects and found an 8.6-fold higher incidence (p < 0.0001) of IBD among those with IBS (238.1 per 100,000 person-years) compared to our referent population (27.8 per 100,000 person-years). In a subset (n = 2,205) of well-defined IBS cases, IBD risk was 15 times that of subjects without IBS. The median time between IBS and IBD diagnoses was 2.1 years. IGE also increased IBD risk approximately 2-fold ( p < 0.05) after controlling for IBS.ConclusionsThese data reflect a complex interaction between illness presentation and diagnosis of IBS and IBD and suggest intercurrent IGE may increase IBD risk in IBS patients. Additional studies are needed to determine whether IBS lies on the causal pathway for IBD or whether the two are on a pathophysiological spectrum of the same clinical illness. These data suggest consideration of risk reduction interventions for IGE among IBS patients at high disease risk.

Increased Risk of IBD Among Military Personnel with IBS

Purpose: Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) often share overlapping symptoms, and it is often noted that individuals with newly diagnosed IBD have had IBS symptoms for several years preceding their IBD diagnosis. Furthermore, recent data have emerged suggesting that in some cases of IBS there are subtle inflammatory and immune markers which share common features with the immune-mediated pathophysiology associated with IBD, and both have been identified to occur at higher rates after an episode of infectious gastroenteritis (IGE). To evaluate the risk of IBS on IBD and evaluate the effect of intercurrent IGE, we designed a retrospective cohort study utilizing data from the US Department of Defense medical encounter data repository. Methods: Active duty military members with IBS were identified and matched with 2 subjects (one each with an unrelated acute or chronic disease). The medical encounter history was analyzed for the duration of service time (or disease onset) to assess for incident IBD. Episodes of IGE were assessed from documented medical encounters and by self-report using a post-deployment health assessment tool completed by each service member following deployment. Relative risks were calculated using Poisson regression models to determine the relationship between IBS and IBD and to control for important covariates. Results: In our dataset of 28,173 subjects, we found that IBS increased IBD risk by 8-fold with an IBD incidence of 238.1 per 100,000 person-years (95% Confidence Interval (CI: 184.2, 291.9) compared to 27.6 per 100,000 person-years (95% CI: 15.2, 40.0) in our referent population (p<0.0001). In a subset (N=2205) of subjects that only included IBS confirmed by negative endoscopy, the risk of IBD was 15 times that of those subjects with no antecedent IBS. The mean time to IBD onset following initial IBS diagnosis was 2.9 years (standard deviation: 1.8). We also found an approximate 2-fold increase in IBD risk following an episode IGE (p<0.05), although our study was underpowered to observe that effect after controlling for IBS. Conclusion: These data reflect a complex interaction in the pathophysiology of IBS and IBD and suggest that intercurrent IGE may increase one's subsequent IBD risk. Additional studies are needed to determine whether IBS lies on the causal pathway for IBD or whether the two lie on the same pathophysiological spectrum of the same clinical illness.