Genetic evidence supporting the association of protease and protease inhibitor genes with inflammatory bowel disease: a systematic review

As part of the European research consortium IBDase, we addressed the role of proteases and protease inhibitors (P/PIs) in inflammatory bowel disease (IBD), characterized by chronic mucosal inflammation of the gastrointestinal tract, which affects 2.2 million people in Europe and 1.4 million people in North America. We systematically reviewed all published genetic studies on populations of European ancestry (67 studies on Crohn's disease [CD] and 37 studies on ulcerative colitis [UC]) to identify critical genomic regions associated with IBD. We developed a computer algorithm to map the 807 P/PI genes with exact genomic locations listed in the MEROPS database of peptidases onto these critical regions and to rank P/PI genes according to the accumulated evidence for their association with CD and UC. 82 P/PI genes (75 coding for proteases and 7 coding for protease inhibitors) were retained for CD based on the accumulated evidence. The cylindromatosis/turban tumor syndrome gene (CYLD) on chromosome 16 ranked highest, followed by acylaminoacyl-peptidase (APEH), dystroglycan (DAG1), macrophage-stimulating protein (MST1) and ubiquitin-specific peptidase 4 (USP4), all located on chromosome 3. For UC, 18 P/PI genes were retained (14 proteases and 4 protease inhibitors), with a considerably lower amount of accumulated evidence. The ranking of P/PI genes as established in this systematic review is currently used to guide validation studies of candidate P/PI genes, and their functional characterization in interdisciplinary mechanistic studies in vitro and in vivo as part of IBDase. The approach used here overcomes some of the problems encountered when subjectively selecting genes for further evaluation and could be applied to any complex disease and gene family.

Association of a common vitamin D-binding protein polymorphism with inflammatory bowel disease

Inflammatory bowel diseases (IBDs), Crohn's disease, and ulcerative colitis (UC), are multifactorial disorders, characterized by chronic inflammation of the intestine. A number of genetic components have been proposed to contribute to IBD pathogenesis. In this case-control study, we investigated the association between two common vitamin D-binding protein (DBP) genetic variants and IBD susceptibility. These two single nucleotide polymorphisms (SNPs) in exon 11 of the DBP gene, at codons 416 (GAT>GAG; Asp>Glu) and 420 (ACG>AAG; Thr>Lys), have been previously suggested to play roles in the etiology of other autoimmune diseases.

Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease

More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10(-16), odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.

Therapy of steroid-resistant inflammatory bowel disease

Although systemic corticosteroids are successfully administered for the induction of clinical response and remission in the majority of patients with inflammatory bowel disease (IBD) presenting with a flare, a proportion of these patients demonstrate a primary nonresponse to steroids or in the case of an initial response, they develop a resistance or a steroid dependence. Long-term therapy with corticosteroids for treatment of IBD should be avoided, given the high frequency of adverse treatment effects. Knowledge about treatment strategies in case of steroid nonresponse is therefore highly relevant.

First-line therapies in inflammatory bowel disease

Medical therapy of inflammatory bowel disease (IBD) is becoming more complex, given the increasing choice of drugs to treat Crohn's disease (CD) and ulcerative colitis (UC). We aimed to summarize the current guidelines for first-line treatments in IBD.

Rifaximin treatment for the irritable bowel syndrome with a positive lactulose hydrogen breath test improves symptoms for at least 3 months

While rifaximin was able to improve symptoms in patients with irritable bowel syndrome (IBS) in phase III trials, these results are yet to be repeated in phase IV studies.

Expression of Toll-like receptor 2 in duodenal biopsies from dogs with inflammatory bowel disease is associated with severity of disease

There is growing evidence that aberrant innate immune responses towards the bacterial flora of the gut play a role in the pathogenesis of canine inflammatory bowel disease (IBD). Toll-like receptors (TLR) play an important role as primary sensors of invading pathogens and have gained significant attention in human IBD as differential expression and polymorphisms of certain TLR have been shown to occur in ulcerative colitis (UC) and Crohn's disease (CD). The aim of the current study was to evaluate the expression of two TLR important for recognition of commensals in the gut. TLR2 and TLR4 mRNA expression in duodenal biopsies from dogs with IBD was measured and correlated with clinical and histological disease severity. Endoscopic duodenal biopsies from 20 clinical cases and 7 healthy control dogs were used to extract mRNA. TLR2 and TLR4 mRNA expression was assessed using quantitative real-time PCR. TLR2 mRNA expression was significantly increased in the IBD dogs compared to controls, whereas TLR4 mRNA expression was similar in IBD and control cases. In addition, TLR2 mRNA expression was mildly correlated with clinical severity of disease, however, there was no correlation between TLR2 expression and histological severity of disease.

Small-bowel MRI in children and young adults with Crohn disease: retrospective head-to-head comparison of contrast-enhanced and diffusion-weighted MRI

Small-bowel MRI based on contrast-enhanced T1-weighted sequences has been challenged by diffusion-weighted imaging (DWI) for detection of inflammatory bowel lesions and complications in patients with Crohn disease.

Myoelectric activity of the ileum, cecum, proximal loop of the ascending colon, and spiral colon in cows with naturally occurring cecal dilatation-dislocation

OBJECTIVE: To analyze myoelectric activity of the ileum, cecum, proximal loop of the ascending colon (PLAC), and spiral colon in cows with naturally occurring cecal dilatation-dislocation (CDD) and compare findings with those in healthy cows. ANIMALS: 8 CDD-affected and 6 healthy control cows. PROCEDURES: Immediately after diagnosis, CDD-affected cows underwent surgery; control cows underwent a similar surgical procedure. Before completion of surgery, 8 bipolar silver electrodes were implanted in the ileum (n = 2), cecum (1), PLAC (1), and spiral colon (4) of each cow. Beginning the day after surgery, intestinal myoelectric activity was recorded daily (8-hour period) for 4 days; data were analyzed by use of specialized software programs. Quantitative variables of myoelectric activity were compared between groups. RESULTS: Cows of both groups recovered without complications after surgery. In control cows, physiologic myoelectric activity was recorded in all intestinal segments on all days after surgery. Apparently normal myoelectric activity was evident in the ileum of CDD-affected cows on the first day after surgery, but myoelectric activity patterns in the cecum, PLAC, and spiral colon were variable with no organized cyclic myoelectric patterns, incomplete or normally organized migrating myoelectric complexes, and slow normalization over time. CONCLUSIONS AND CLINICAL RELEVANCE: After surgery for CDD, normal myoelectric patterns were disrupted in the large intestine of cows, especially in the spiral colon. Clinical recovery with effective transit of ingesta occurred before normalization of myoelectric activity in the large intestine. Therapeutic protocols for restoration or normalization of spiral colon motility should be developed for treatment of CDD-affected cattle.

Drugs that inhibit gastric acid secretion may alter the course of inflammatory bowel disease

Recent data suggest that acid suppressive medications may alter factors central to the pathophysiology of inflammatory bowel diseases (IBD), whether through shifts in the intestinal microbiome due to acid suppression or effects on immune function.

Pregnancy and breastfeeding in inflammatory bowel disease

Inflammatory bowel disease (IBD) is frequent in women during their peak reproductive years. Accordingly, a significant number of questions and uncertainties arise from this population regarding the risk of transmission of IBD to the offspring, the impact of the disease and therapies on the fertility, the role of the disease on the course of the pregnancy and the mode of delivery, the impact of the therapy on the pregnancy and fetal development as well as breastfeeding. The safety of medical therapy during pregnancy and lactation is a major concern for both pregnant women and their partners as well as for physicians. As a general rule, it can be stated that the benefit of continuing medical therapy in IBD during pregnancy outweighs the potential risks in the vast majority of instances. This article will review recent developments on this topic consistent with the European Crohn's and Colitis Organization guidelines.