IBD5 is a general risk factor for inflammatory bowel disease: replication of association with Crohn disease and identification of a novel association with ulcerative colitis

Inflammatory bowel disease (IBD) refers to complex chronic relapsing autoimmune disorders of the gastrointestinal tract that have been traditionally classified into Crohn disease (CD) and ulcerative colitis (UC). We have previously reported that genetic variation within a 250-kb haplotype (IBD5) in the 5q31 cytokine gene cluster confers susceptibility to CD in a Canadian population. In the current study, we first replicated this association by examining 368 German trios with CD and demonstrating, by transmission/disequilibrium testing (TDT), that the same haplotype is associated with CD (chi2=5.97; P=.007). Our original association study focused on the role of IBD5 in CD; we next explored the potential contribution of this locus to UC susceptibility in 187 German trios. Given the TDT results in the present cohort with UC, IBD5 may also act as a susceptibility locus for UC (chi2=8.10; P=.002). We then examined locus-locus interactions between IBD5 and CARD15, a locus reported elsewhere to confer risk exclusively to CD. Our current results indicate that the two loci act independently to confer risk to CD but that these two loci may behave in an epistatic fashion to promote the development of UC. Moreover, IBD5 was not associated with particular clinical manifestations upon phenotypic stratification in the current cohort with CD. Taken together, our results suggest that IBD5 may act as a general risk factor for IBD, with loci such as CARD15 modifying the clinical characteristics of disease.     

MDR1 C3435T polymorphism and inflammatory bowel disease risk: a meta-analysis

The C3435T polymorphism of the multidrug resistance gene (MDR1) has been implicated in inflammatory bowel disease (IBD) risk, but the reported results are inconsistent. Here we performed a meta-analysis to evaluate the association between C3435T polymorphism and the risk of IBD using all case–control studies published before February 2013 according to PubMed and Web of Science. A total of 13 case–control studies, including 6,757 cases and 4,295 controls, were included. Pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated using fixed- or random-effects model. Overall, no evidence has indicated that the C3435T polymorphism was associated with the susceptibility to IBD (dominant model: OR = 1.05, 95 % CI: 0.96–1.16; CT vs. CC: OR = 1.06, 95 % CI: 0.95–1.17; TT vs. CC: OR = 1.04, 95 % CI: 0.92–1.17; recessive model: OR = 0.99, 95 % CI: 0.90–1.09). Besides, stratified analysis by clinical type also indicated that no significant association between MDR1 C3435T and the risk of Crohn’s disease and ulcerative colitis was observed. This meta-analysis indicated that the C3435T polymorphism of MDR1 may not confer susceptibility to IBD.     

Multiple outcome meta-analysis of gene-expression data in inflammatory bowel disease

We performed a multivariate meta-analysis of microarray data in Crohn's disease (CD) and Ulcerative colitis (UC), which are the main forms of inflammatory bowel disease (IBD). They share similar symptoms but differ in the location and extent of inflammation and in complications. We identified 249 differentially expressed genes (DEGs) in CD and 38 in UC at a false discovery rate of 1%. 20 of the DEGs were common to both diseases. A multivariate test identified 260 DEGs associated with IBD, 53 of which were not found in any of the disorders. We identified important molecular pathways implicated in the pathogenesis of IBD, such as the JAK/STAT and interferon-gamma signaling pathways, genes involved in cell adhesion, apoptosis and carcinogenesis. Among others, BCAT1 and GZMB are interesting novel DEGs that deserve further investigation in experimental models. The method could also be useful to other cases of meta-analysis of gene expression data.     

The peroxisome-proliferator-activated gamma receptor and chronic inflammatory bowel disease (PPARgamma and IBD)

PPARgamma has been recently described as being a gene of susceptibility for Intestinal Bowel Diseases (IBD) as NOD2/CARD15 gene. IBD are pathologies due to an abnormal immune response, in genetically predisposed patients, to the bacteria of the intestinal flora. PPARgamma, known for its significant role in adipogenesis, is strongly expressed by the epithelial cells of the colon mucosa. PPARgamma is implicated in the regulation of inflammation. Indeed, agonists of this nuclear receptor decrease strongly the intensity of inflammation during experimental colitis induced by chemical agents. A deficit of PPARgamma in patients with ulcerative colitis has been highlighted, that could in part explain the acute inflammation. In addition, bacteria, including those of the commensal flora, are able to regulate PPARgamma. Toll Like Receptor-4 (TLR-4), responsible for the recognition of bacterial motif as lipopolysaccharide (LPS), is implicated in PPARgamma regulation and its anti-inflammatory properties. All these arguments make of PPARgamma a very interesting therapeutic target for the treatment of IBD.     

Linkage and association between inflammatory bowel disease and a locus on chromosome 12.

Genetic epidemiological studies have shown that genetic factors are important in the pathogenesis of the idiopathic inflammatory bowel diseases (IBD), Crohn disease (CD), and ulcerative colitis (UC). A genome screen in the United Kingdom found linkage of IBD to a 41-cM region of chromosome 12, surrounding D12S83. We aimed to replicate this linkage and to narrow the region of interest. Nonparametric linkage analyses at microsatellites surrounding D12S83 were performed in 122 North American Caucasian families containing 208 genotyped IBD-affected relative pairs. Transmission/disequilibrium tests (TDTs) were also performed. We confirmed that IBD is linked to chromosome 12 (peak GENEHUNTER-PLUS LOD* score 2.76 [P = .00016] between D12S1724 and D12S90). The evidence for linkage is contributed by both the group of CD-affected relative pairs (peak GENEHUNTER-PLUS LOD* score 1.79 [P = .0021] between D12S1724 and D12S90) and the group of UC-affected relative pairs (peak GENEHUNTER-PLUS LOD* score 1.82 [P = .0019] at D12S335). The TDT is positive at the D12S83 locus (global chi2 = 16.41, 6 df, P = .012). In conclusion, we have independently confirmed linkage of IBD to the chromosome 12 region that we investigated. A positive TDT at D12S83 suggests that we have greatly narrowed the chromosome 12 region that contains an IBD locus.     

TLR5 risk-associated haplotype for canine inflammatory bowel disease confers hyper-responsiveness to flagellin

Single nucleotide polymorphisms (SNP) in the TLR5 gene have been associated with human inflammatory bowel disease (IBD) and animal models of this disease. We recently demonstrated a significant association between three non-synonymous SNPs in the canine TLR5 gene and IBD in German shepherd dogs (GSDs). However, so far, no direct link between these SNPs and a disturbance in TLR5 function was shown. In the present study, we determined the functional significance of the canine TLR5 SNPs by transfecting the identified risk-protective and risk-associated haplotype into human embryonic kidney cells (HEK) and assessed nuclear factor-kappa B (NF-κB) activation and CXCL8 production after stimulation. In addition, a whole blood assay for TLR5 activation was developed using blood derived from carrier dogs of either haplotype. There was a significant increase in NF-kB activity when cells transfected with the risk-associated TLR5 haplotype were stimulated with flagellin compared to the cells expressing the risk-protective TLR5 haplotype. This difference in NFkB activation correlated with CXCL8 expression in the supernatant measured by ELISA. Furthermore, whole blood taken from carrier dogs of the risk-associated TLR5 haplotype produced significantly more TNF after stimulation with flagellin compared to that taken from carriers of the risk-protective haplotype. Thus, we show for the first time a direct functional impact of the canine IBD risk-associated TLR5 haplotype, which results in hyper-responsiveness to flagellin compared to the IBD risk-protective TLR5 haplotype. Our data potentially suggest that similarly to human IBD and experimental models, TLR5 may also play a role in canine IBD. Blocking the hyper-responsive receptor found in susceptible dogs with IBD may alleviate the inappropriate inflammation seen in this disease.     

Association between the Pro12Ala polymorphism of peroxisome proliferator-activated receptor gamma 2 and inflammatory bowel disease: a meta-analysis

Background

Peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor, has been implicated playing a role in the development of inflammatory bowel disease (IBD). However, previous studies evaluating the association between the PPARγ2 Pro12Ala polymorphism and IBD are inconsistent. We performed a meta-analysis to determine whether the PPARγ2 Pro12Ala mutation was associated with the presence of IBD.

Methods and Findings

Electronic databases were searched for case-control studies evaluating the association between the Pro12Ala mutation and the presence of IBD. Effects were summarized with the methods recommended by the Cochrane Collaboration. A total of 7 studies including 1002 ulcerative colitis (UC) cases, 1090 Crohǹs disease (CD) cases and 1983 controls were involved in this meta-analysis. In the overall analysis, no significant association of this polymorphism with UC or CD was found. In the subgroup analyses in different populations, AlaAla genotype seemed to protect the European Caucasian population against the development of CD (Pro vs Ala: OR = 1.135, 95%CI = 0.951–1.354, P = 0.162, Bon = 1.000; ProPro vs ProAla: OR = 1.042, 95%CI = 0.852–1.273, P = 0.690, Bon = 1.000; ProPro vs AlaAla: OR = 2.379, 95%CI = 1.110–5.100, P = 0.026, Bon = 0.156; ProAla vs AlaAla: OR = 2.315, 95%CI = 1.064–5.037, P = 0.034, Bon = 0.204; Pro homozygotes vs Ala positives: OR = 1.094, 95%CI = 0.899–1.330, P = 0.371, Bon = 1.000; Pro positives vs Ala homozygotes: OR = 2.360, 95%CI = 1.103–5.053, P = 0.027, Bon = 0.162; heterozygotes vs all homozygotes: OR = 0.976, 95%CI = 0.799–1.192, P = 0.809, Bon = 1.000). There was no significant association of this polymorphism with UC or CD in the East Asian population and the Turkish population.

Conclusion

AlaAla genotype may be a protective factor in the European Caucasian population against the development of CD in a recessive way.     

Cytokines in inflammatory bowel disease

Over the past decade, much has been learned regarding the role of various cytokines in the pathogenesis of inflammatory bowel disease. Several cytokine 'knockout' models in mice have been shown to develop colitis, while alterations in the production of various cytokines has been documented in human Crohn's disease and ulcerative colitis. In recent years, attempts have been made to treat these diseases through modulation of cytokine production or action. This review focuses on the cytokines that have been implicated in the pathogenesis of inflammatory bowel disease. The evidence for and against a role for particular cytokines in intestinal inflammation is reviewed, as is the experimental and clinical data suggesting that cytokines are rational targets for the development of new therapies.     

Somatostatin in inflammatory bowel disease

Intestinal inflammation is controlled by various immunomodulating cells, interacting by molecular mediators. Neuropeptides, released by enteric nerve cells and neuroendocrine mucosa cells, are able to affect several aspects of the general and intestinal immune system, with both pro- as well as anti-inflammatory activities. In inflammatory bowel disease (IBD) there is both morphological as well as experimental evidence for involvement of neuropeptides in the pathogenesis. Somatostatin is the main inhibitory peptide in inflammatory processes, and its possible role in IBD is discussed.     

Hypoxia and inflammatory bowel disease

Inflammatory bowel disease (IBD) is a general term to describe inflammatory diseases of the gastrointestinal tract such as Crohn's disease and ulcerative colitis. IBD affects approximately 1 in 200 individuals and exerts a significant health and quality of life burden on patients. Surgical intervention can be curative in ulcerative colitis but there is currently no cure for Crohn's disease. Since this is the case, and the fact that patients are often diagnosed at a young age, IBD exerts a significant financial burden on the health care system, and society as a whole.The underlying pathology of IBD is complex and involves a combination of genetic, environmental and microbial factors. Regardless of the underlying causes of the condition, this disease is universally characterized by disruption to the protective epithelial barrier separating the intestinal lumen above from the mucosal immune system below. Once this barrier becomes compromised a sequence of events ensues, that can occur in repetitive cycles to ensure long-term and serious damage to the gut.The role of hypoxia and hypoxia-dependent signalling pathways are increasingly appreciated to play a role in the physiology and pathophysiology of the intestine. The intestinal epithelium normally exists in a state of physiological hypoxia, with additional tissue hypoxia a feature of active inflammatory disease. Furthermore, recent pre-clinical animal studies have clearly supported the rationale for pharmacologically manipulating the oxygen-sensitive hypoxia-inducible factor (HIF) pathway in models of IBD. Thus, this review will discuss the contribution of hypoxia sensitive pathways in the pathology of IBD. Finally we will discuss the emerging evidence for manipulation of hypoxia-sensitive pathways in the treatment of IBD.     

Contribution of allergic inflammatory response to the pathogenesis of malaria disease

Plasmodium falciparum, the aetiological agent of human lethal malaria, is responsible for over 2 million deaths per year and malaria episodes may vary considerably in their severity and clinical manifestations. Dysregulated balance of the inflammatory response and a defect in the anti-Plasmodium parasite immune response represent the hallmarks of malaria disease. Among the many possible mechanisms, it is now widely recognized that the production of pro-inflammatory mediators and cytokines and upregulation of endothelial cell adhesion molecules play important roles in malaria pathogenesis. We and others provided evidence that some components of allergic inflammatory response to malaria parasites or elicited by by-products of parasite infection may contribute to malaria pathogenesis. This review provides some clue regarding these mechanisms where mast cells and histamine, an inflammatory mediator generated following IgE-independent or IgE-mediated immune response, were found to play a major role in parasite transmission and malaria pathogenesis, respectively. This article is part of a Special Issue entitled: Mast cells in inflammation.     

Nematode modulation of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic disease arising due to a culmination of genetic, environmental, and lifestyle-associated factors and resulting in an excessive pro-inflammatory response to bacterial populations in the gastrointestinal tract. The prevalence of IBD in developing nations is relatively low, and it has been proposed that this is directly correlated with a high incidence of helminth infections in these areas. Gastrointestinal nematodes are the most prevalent parasitic worms, and they efficiently modulate the immune system of their hosts in order to establish chronic infections. Thus, they may be capable of suppressing unrelated inflammation in disorders such as IBD. This review describes how nematodes, or their products, suppress innate and adaptive pro-inflammatory immune responses and how the mechanisms involved in the induction of anti-nematode responses regulate colitis in experimental models and clinical trials with IBD patients. We also discuss how refinement of nematode-derived therapies should ultimately result in the development of potent new therapeutics of clinical inflammatory disorders.     

Bacteria in the pathogenesis of inflammatory bowel disease

Twin studies have demonstrated the importance of environmental factors in the pathogenesis of inflammatory bowel disease, but progress has been relatively slow in identifying these, with the exception of smoking, which is positively associated with Crohn's disease and negatively associated with ulcerative colitis. Genetic studies have identified risk alleles which are involved in host-bacterial interactions and the mucosal barrier, and evidence is building for a likely pathogenic role for changes in the gut microbiome, with respect to both faecal and mucosa-associated microbiota. Some of these changes may be secondary to inflammation, nevertheless promising new therapeutic targets are beginning to emerge.     

A potent human C5a receptor antagonist protects against disease pathology in a rat model of inflammatory bowel disease

The complement system is implicated in the pathogenesis of human inflammatory bowel disease, but the specific role of C5a has never been examined. We have compared the efficacy of an orally active human C5a receptor antagonist (AcPhe[Orn-Pro-D-cyclohexylalanine-Trp-Arg]), prednisolone, and infliximab against trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. The drugs were administered either 2 days before or 24 h after TNBS instillation, and rats were then examined after 8 days. Drug-free colitis control rats showed severe disease pathology with significant mortality (39%). Rats pre or posttreated with the C5a antagonist (10 mg/kg/day peroral, 0.3 mg/kg/day s.c.) had reduced mortality and significantly improved macroscopic scores, colon edema, colon myeloperoxidase levels, reduced concentrations of TNF-alpha levels in the colon and serum, and had greater food intake resulting in greater weight gains than colitis-only rats. Rats pretreated with prednisolone (1 mg/kg/day s.c.) displayed significant improvement in parameters measured, but posttreatment was ineffective. Single dose pretreatment with the TNF-alpha inhibitor infliximab (3 mg/kg i.v.) also had significant improvements in the parameters measured. Rats pretreated with a combination of the C5a antagonist and prednisolone showed no greater improvements than either drug alone. These findings suggest a central role for complement, particularly C5a, in the pathology of TNBS-induced colitis in rats, indicating a possible therapeutic role for C5a antagonists in inflammatory bowel disease.