Inflammatory Bowel Disease and Risk of Adverse Pregnancy Outcomes

Background and Objectives

Existing data on pregnancy complications in inflammatory bowel disease (IBD) are inconsistent. To address these inconsistencies, we investigated potential associations between IBD, IBD-related medication use during pregnancy, and pregnancy loss, pre-eclampsia, preterm delivery, Apgar score, and congenital abnormalities.

Methods

We conducted a cohort study in >85,000 Danish National Birth Cohort women who were pregnant in the period 1996-2002 and had information on IBD, IBD-related medication use (systemic or local corticosteroids, 5-aminosalicylates), pregnancy outcomes and potential confounders. We evaluated associations between IBD and adverse pregnancy/birth outcomes using Cox regression and log-linear binomial regression.

Results

IBD was strongly and significantly associated with severe pre-eclampsia, preterm premature rupture of membranes and medically indicated preterm delivery in women using systemic corticosteroids during pregnancy (hazard ratios [HRs] >7). IBD was also associated with premature preterm rupture of membranes in women using local corticosteroid medications (HR 3.30, 95% confidence interval [CI] 1.33-8.20) and with medically indicated preterm delivery (HR 1.91, 95% CI 0.99-3.68) in non-medicated women. Furthermore, IBD was associated with low 5-minute Apgar score in term infants (risk ratio [RR] 2.19, 95% CI 1.03-4.66). Finally, Crohn’s disease (but not ulcerative colitis) was associated with major congenital abnormalities in the offspring (RR 1.85, 95% CI 1.06-3.21). No child with a congenital abnormality born to a woman with IBD was exposed to systemic corticosteroids in utero.

Conclusion

Women with IBD are at increased risk of severe pre-eclampsia, medically indicated preterm delivery, preterm premature rupture of membranes, and delivering infants with low Apgar score and major congenital malformations. These associations are only partly explained by severe disease as reflected by systemic corticosteroid use.     

Pancreatitis-Associated Protein Does Not Predict Disease Relapse in Inflammatory Bowel Disease Patients

Background

The pancreatitis-associated protein (PAP) is increased in the serum of active inflammatory bowel disease (IBD) patients and its levels seem to be correlated with disease activity. Our aim was to evaluate the usefulness of serum and fecal PAP measurements to predict relapse in patients with inactive IBD.

Materials and Methods

We undertook a 12-month prospective study that included 66 Crohn''s disease (CD) and 74 ulcerative colitis (UC) patients. At inclusion, patients were in clinical remission, defined by a Harvey-Bradshaw (HB) Index≤4 (CD) or a partial Mayo Score (MS)<3 (UC), along with a normal serum C reactive protein (CRP) and fecal calprotectin. Patients were followed every 3 months. Blood and stool samples were collected and a clinical evaluation was performed at each visit. Serum PAP and CRP levels as well as fecal concentrations of PAP and calprotectin were assessed.

Results

Active CD patients had an increased mean serum PAP at the diagnosis of the flare (104.1 ng/ml) and 3 months prior to activity (22.68 ng/ml) compared with patients in remission (13.26 ng/ml), p<0.05. No significant change in serum PAP levels in UC and fecal PAP levels in CD and UC were detected during disease activity. In CD, serum PAP was a poor diagnostic predictor of disease activity, with an AUC of 0.69. In patients in remission, fecal PAP was barely detectable in UC compared with CD patients.

Conclusion

Serum PAP is increased only in active CD patients, but this marker does not predict disease activity. Inactive UC patients have marked low levels of PAP in fecal samples compared with CD patients.     

Genetic Association of Peptidoglycan Recognition Protein Variants with Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a common disease, includes Crohn''s disease (CD) and ulcerative colitis (UC), and is determined by altered gut bacterial populations and aberrant host immune response. Peptidoglycan recognition proteins (PGLYRP) are innate immunity bactericidal proteins expressed in the intestine. In mice, PGLYRPs modulate bacterial populations in the gut and sensitivity to experimentally induced UC. The role of PGLYRPs in humans with CD and/or UC has not been previously investigated. Here we tested the hypothesis that genetic variants in PGLYRP1, PGLYRP2, PGLYRP3 and PGLYRP4 genes associate with CD and/or UC and with gender and/or age of onset of disease in the patient population. We sequenced all PGLYRP exons in 372 CD patients, 77 UC patients, 265 population controls, 210 familial CD controls, and 24 familial UC controls, identified all polymorphisms in these populations, and analyzed the variants for significant association with CD and UC. We identified 16 polymorphisms in the four PGLYRP genes that significantly associated with CD, UC, and/or subgroups of patient populations. Of the 16, 5 significantly associated with both CD and UC, 6 with CD, and 5 with UC. 12 significant variants result in amino acid substitutions and based on structural modeling several of these missense variants may have structural and/or functional consequences for PGLYRP proteins. Our data demonstrate that genetic variants in PGLYRP genes associate with CD and UC and may provide a novel insight into the mechanism of pathogenesis of IBD.     

细胞因子在炎症性肠病中的作用

炎症性肠病(inflammatory bowel disease,IBD)是一组病因未明的以慢性胃肠道炎症为特征的疾病,包括克罗恩病(Crohn's disease,CD)和溃疡性结肠炎(ulcerative colitis,UC)。细胞因子在IBD肠道炎症反应和黏膜免疫反应中起重要作用,目前已成为研究IBD发病机制的热点,本文就其在IBD中的作用作一综述。     

Appendectomy and Biopsy Despite Inflammatory Disease of the Bowel

For many years surgeons have preached against the removal of the appendix when regional enteritis is present. A high rate of fistulization and abscess formation supposedly follows appendectomy in such circumstances. This was not borne out in a series of cases in which appendectomy was carried out despite regional enteritis, granulomatous colitis and ulcerative colitis. Two fistulae occurred in 23 patients. Neither fistula was from the appendiceal stump.Appendectomy is probably a reasonable procedure when enteritis is present, although judgment should be exercised if there is appendicocecal involvement.     

炎症性肠病动物模型的研究进展

克罗恩病和溃疡性结肠炎统称为炎症性肠病（IBD）,病因虽不明确,但对其发病机理已有了较多的了解。该病的发生是由于个体易感性、肠道菌群和粘膜免疫相互作用所致。炎症性肠病动物模型可通过化学性诱导、免疫学、遗传学等方法获得。三硝基苯磺酸与乙醇灌肠致炎法是目前最常用的方法,本文侧重概述介绍三硝基苯磺酸诱导的炎症性肠病的机制、模型、应用及优缺点,为疾病的研究、治疗和新药的开发提供指导。     

Effect of Alcoholic Intoxication on the Risk of Inflammatory Bowel Disease: A Nationwide Retrospective Cohort Study

PurposeThis study investigated whether alcoholic intoxication (AI) increases the risk of inflammatory bowel disease (IBD) by using a population-based database in Taiwan.MethodsThis retrospective matched-cohort study included 57 611 inpatients with new-onset AI (AI cohort) and 230 444 randomly selected controls (non-AI cohort). Each patient was monitored for 10 years to individually identify those who were subsequently diagnosed with Crohn disease (CD) and ulcerative colitis (UC) during the follow-up period. Cox proportional hazard regression analysis was conducted to determine the risk of IBD in patients with AI compared with controls without AI.ResultsThe incidence rate of IBD during the 10-year follow-up period was 2.69 per 1 000 person-years and 0.49 per 1 000 person-years in the AI and non-AI cohorts, respectively. After adjustment for age, sex, and comorbidity, the AI cohort exhibited a 3.17-fold increased risk of IBD compared with the non-AI cohort (hazard ratio [HR] = 3.17, 95% confidence interval [CI] = 2.19–4.58). Compared with the non-AI cohort, the HRs of CD and UC were 4.40 and 2.33 for the AI cohort, respectively. After stratification for the severity of AI according to the duration of hospital stay, the adjusted HRs exhibited a significant correlation with the severity; the HRs of IBD were 1.76, 6.83, and 19.9 for patients with mild, moderate, and severe AI, respectively (p for the trend < .0001).ConclusionThe risk of IBD was higher in patients with AI and increased with the length of hospital stay.     

Risk of Ischaemic Heart Disease in Patients with Inflammatory Bowel Disease: Cohort Study Using the General Practice Research Database

ObjectivePatients with inflammatory bowel disease (IBD) demonstrate an inflammatory response which bears some similarities to that seen in ischaemic heart disease (IHD). The nature of the association of IBD with IHD is uncertain. We aimed to define the extent and direction of that association.DesignThis retrospective cohort study examined records from patients aged ≥ 15 years with IBD from 1987–2009 (n = 19163) who were age and gender matched with patients without IBD (n = 75735) using the General Practice Research Database. The primary outcome was the hazard ratio for IHD.ResultsA higher proportion of IBD patients had a recorded diagnosis of IHD ever, 2220 (11.6%) compared with 6504 (8.6%) of controls. However, the majority (4494, 51.5%) developed IHD prior to IBD diagnosis (1404 (63.2%) of IBD cases and 3090 (47.5%) of controls). There was increased IHD incidence in the first year after IBD diagnosis. Mean age at IHD diagnosis was statistically similar across all IBD groups apart from for those with Ulcerative Colitis (UC) who were slightly younger at diagnosis of angina compared to controls (64.5y vs. 67.0y, p = 0.008) and coronary heart disease (65.7y vs.67.9y, p = 0.015). Of those developing IHD following IBD diagnosis, UC patients were at higher risk of IHD (unadjusted HR 1.3 (95% CI 1.1–1.5), p<0.001) or MI (unadjusted HR 1.4 (95% CI 1.1–1.6), p = 0.004).ConclusionAlthough IHD prevalence was higher in IBD patients, most IHD diagnoses predated the diagnosis of IBD. This implies a more complex relationship than previously proposed between the inflammatory responses associated with IHD and IBD, and alternative models should be considered.     

多组学分析在炎症性肠病中的应用与研究进展

炎症性肠病(IBD)是一种累及回肠、直肠和结肠的特发性慢性肠道炎症性疾病,主要包括溃疡性结肠炎和克罗恩病,在临床表现、病程和治疗反应等方面具有高度异质性。目前,关于IBD的发病机制尚未明确,治疗方法相对有限。由遗传、环境、肠道微生态以及宿主免疫失衡在内的多因素共同导致了过度活跃的炎症反应并最终引发患者的肠道粘膜屏障受损和管腔菌群紊乱。单一组学的分析无法全面揭示IBD发病过程中复杂的相互协同作用机制,更无法挖掘潜在的治疗靶点和开发有效的干预策略。因此需要运用多组学关联分析技术以帮助研究者从多个维度解析IBD的发病机制。回顾和分析了多组学技术在IBD相关研究领域中的应用,并且讨论了使用这些方法在IBD分型、早期诊断和个性化医疗等领域的潜力,以期为进一步研究IBD发病机制奠定良好基础。     

Mathematical Model of the Roles of T Cells in Inflammatory Bowel Disease

Gut mucosal homeostasis depends on complex interactions among the microbiota, the intestinal epithelium, and the gut associated immune system. A breakdown in some of these interactions may precipitate inflammation. Inflammatory bowel diseases, Crohn’s disease, and ulcerative colitis are chronic inflammatory disorders of the gastrointestinal tract. The initial stages of disease are marked by an abnormally high level of pro-inflammatory helper T cells, Th1. In later stages, Th2 helper cells may dominate while the Th1 response may dampen. The interaction among the T cells includes the regulatory T cells (Treg). The present paper develops a mathematical model by a system of differential equations with terms nonlocal in the space spanned by the concentrations of cytokines that represents the interaction among T cells through a cytokine signaling network. The model demonstrates how the abnormal levels of T cells observed in inflammatory bowel diseases can arise from abnormal regulation of Th1 and Th2 cells by Treg cells.     

SP和CGRP在炎症性肠病大鼠结肠中的表达规律

目的通过研究P物质（SP）和降钙素基因相关肽（CGRP）在炎症性肠病（IBD）大鼠结肠中的表达规律来探讨二者在IBD发生发展过程中发挥的作用。方法采用三硝基苯磺酸（TNBS）化学诱导建立IBD大鼠动物模型,应用real-time RT-PCR方法来检测SP和CGRP mRNA在模型不同时期结肠中的表达变化。结果随着炎症性肠病病理变化的加剧（第3、7天）,sP和CGRP在结肠组织中的表达水平显著升高;随着疾病的恢复（第21、28天）,其表达水平逐渐降低并趋向于正常水平。从总体来看,在IBD大鼠结肠组织中,SP和CGRP mRNA水平的变化与IBD的发生、发展呈正相关。结论神经递质SP和CGRP在IBD炎症和修复中起重要的神经免疫信号传导作用。     

Sparse Modeling Reveals miRNA Signatures for Diagnostics of Inflammatory Bowel Disease

The diagnosis of inflammatory bowel disease (IBD) still remains a clinical challenge and the most accurate diagnostic procedure is a combination of clinical tests including invasive endoscopy. In this study we evaluated whether systematic miRNA expression profiling, in conjunction with machine learning techniques, is suitable as a non-invasive test for the major IBD phenotypes (Crohn''s disease (CD) and ulcerative colitis (UC)). Based on microarray technology, expression levels of 863 miRNAs were determined for whole blood samples from 40 CD and 36 UC patients and compared to data from 38 healthy controls (HC). To further discriminate between disease-specific and general inflammation we included miRNA expression data from other inflammatory diseases (inflammation controls (IC): 24 chronic obstructive pulmonary disease (COPD), 23 multiple sclerosis, 38 pancreatitis and 45 sarcoidosis cases) as well as 70 healthy controls from previous studies. Classification problems considering 2, 3 or 4 groups were solved using different types of penalized support vector machines (SVMs). The resulting models were assessed regarding sparsity and performance and a subset was selected for further investigation. Measured by the area under the ROC curve (AUC) the corresponding median holdout-validated accuracy was estimated as ranging from 0.75 to 1.00 (including IC) and 0.89 to 0.98 (excluding IC), respectively. In combination, the corresponding models provide tools for the distinction of CD and UC as well as CD, UC and HC with expected classification error rates of 3.1 and 3.3%, respectively. These results were obtained by incorporating not more than 16 distinct miRNAs. Validated target genes of these miRNAs have been previously described as being related to IBD. For others we observed significant enrichment for IBD susceptibility loci identified in earlier GWAS. These results suggest that the proposed miRNA signature is of relevance for the etiology of IBD. Its diagnostic value, however, should be further evaluated in large, independent, clinically well characterized cohorts.     

Cytomegalovirus Infection in Inflammatory Bowel Disease Is Not Associated with Worsening of Intestinal Inflammatory Activity

Background

Cytomegalovirus is highly prevalent virus and usually occurs in immunocompromised patients. The pathophysiology and treatment of inflammatory bowel disease often induce a state of immunosuppression. Because this, there are still doubts and controversies about the relationship between inflammatory bowel disease and cytomegalovirus.

Aim

Evaluate the frequency of cytomegalovirus in patients with inflammatory bowel disease and identify correlations.

Methods

Patients with inflammatory bowel disease underwent an interview, review of records and collection of blood and fecal samples. The search for cytomegalovirus was performed by IgG and IgM blood serology, by real-time PCR in the blood and by qualitative PCR in feces. Results were correlated with red blood cell levels, C-reactive protein levels, erythrocyte sedimentation rates and fecal calprotectin levels for each patient.

Results

Among the 400 eligible patients, 249 had Crohn''s disease, and 151 had ulcerative colitis. In the group of Crohn''s disease, 67 of the patients had moderate or severe disease, but 126 patients presented with active disease, based on the evaluation of the fecal calprotectin. In patients with ulcerative colitis, only 21 patients had moderate disease, but 76 patients presented with active disease, based on the evaluation of the fecal calprotectin. A large majority of patients had positive CMV IgG. Overall, 10 patients had positive CMV IgM, and 9 patients had a positive qualitative detection of CMV DNA by PCR in the feces. All 400 patients returned negative results after the quantitative detection of CMV DNA in blood by real-time PCR. Analyzing the 19 patients with active infections, we only found that such an association occurred with the use of combined therapy (anti-TNF-alpha + azathioprine)

Conclusion

The findings show that latent cytomegalovirus infections are frequent and active cytomegalovirus infection is rare. We did not find any association between an active infection of CMV and inflammatory bowel disease activity.     

The Role of Cyclophilins in Inflammatory Bowel Disease and Colorectal Cancer

Cyclophilins (Cyps) is a kind of ubiquitous protein family in organisms, which has biological functions such as promoting intracellular protein folding and participating in the pathological processes of inflammation and tumor. Inflammatory bowel disease (IBD) and colorectal cancer (CRC) are two common intestinal diseases, but the etiology and pathogenesis of these two diseases are still unclear. IBD and CRC are closely associated, IBD has always been considered as one of the main risks of CRC. However, the role of Cyps in these two related intestinal diseases is rarely studied and reported. In this review, the expression of CypA, CypB and CypD in IBD, especially ulcerative colitis (UC), and CRC, their relationship with the development of these two intestinal diseases, as well as the possible pathogenesis, were briefly summarized, so as to provide modest reference for clinical researches and treatments in future.     

Association of IRGM Gene Mutations with Inflammatory Bowel Disease in the Indian Population

Background

Mutations in the IRGM gene have been associated with Crohn''s disease in several populations but have not been explored in Indian patients with this disease. This study examined the association of IRGM mutations with ulcerative colitis and Crohn''s disease in Indian patients with inflammatory bowel disease.

Methods

The IRGM gene was amplified in four segments and Sanger-sequenced in 101 participants (42 Crohn''s disease, 39 ulcerative colitis, and 20 healthy controls). Ten single nucleotide polymorphisms (SNP) were genotyped in 1200 participants (352 Crohn''s disease, 400 ulcerative colitis, and 448 healthy controls) using Sequenom MassARRAY iPLEX. Disease associations were evaluated for each of the ten SNPs.

Results

Thirty one mutations were identified in the IRGM gene, of which two had not hitherto been reported (150226250- ss947429272 & 150227858- ss947429273). Ten SNPs (6 from the above and 4 from the literature) were evaluated. Significant associations with Crohn''s disease were noted with the T allele of rs1000113 (OR 1.46, 95% CI 1.12–1.90), T allele of rs9637876 (OR 1.25, 95% CI 1.005–1.561) and C allele of rs 13361189 (OR 1.33, 95% CI 1.07–1.669). Two SNPs – rs11747270 and rs180802994 – did not exhibit Hardy-Weinberg equilibrium but were associated with both Crohn''s disease and ulcerative colitis in this population. The remaining SNPs did not show significant associations with either Crohn''s disease or ulcerative colitis.

Conclusions

Association of IRGM gene SNPs with Crohn''s disease is reported for the first time in Indian patients. We also report, for the first time, an association of rs 9637876 in the IRGM gene with Crohn''s disease.     

Associations between Genetic Polymorphisms in IL-33, IL1R1 and Risk for Inflammatory Bowel Disease

Background

Recent evidence suggests that the IL-33/IL1RL1 axis plays a critical role in several autoimmune and inflammatory disorders; however, its mechanistic role in inflammatory bowel disease (IBD) has not been clearly defined. We investigated the contribution of IL-33 and IL1RL1 polymorphisms to IBD risk, and possible correlations with phenotype in an Italian cohort of adult and pediatric patients.

Methods

We evaluated the association of six SNPs in IL-33 and IL1RL1 genes, in 805 Crohn’s disease (CD), 816 ulcerative colitis (UC), and 752 controls, using Taqman. IL-33 and IL1RL1 mRNA expression was also analyzed.

Results

Significant allele and genotype associations with IL-33 rs3939286 were found in CD (P = 0.004; P = 0.035) and UC patients (P = 0.002; P = 0.038). After stratifying the cohort for age at diagnosis, the differences remained significant only in the IBD adult-onset. Significant associations were also obtained in CD patients with two IL1RL1 polymorphisms (rs13015714 and rs2058660, P<0.015). By combining homo- and heterozygous carriers of the rs13015714 risk allele, differences were still significant for both CD adult- and pediatric-onset. Upon genotype-phenotype evaluation, an increased frequency of extensive colitis in adult UC (P = 0.019) and in steroid-responsive pediatric patients (P = 0.024) carrying the IL-33 rs3939286 risk genotype, was observed. mRNA expression of IL-33 and IL1RL1 in inflamed IBD biopsy samples was significantly increased.

Conclusions

Common IL-33 and IL1RL1 polymorphisms contribute to the risk of IBD in an Italian cohort of adult and pediatric patients, with some influence on sub-phenotypes.