Differential effects of NOD2 polymorphisms on colorectal cancer risk: a meta-analysis

Introduction

Since Kurzawski et al. described an association between the 3020insC NOD2 single nucleotide polymorphism and the risk of colorectal cancer(CRC) in 2004, reports published in the past several years have controversial results regarding the relationship between the development of CRC and NOD2 gene polymorphisms. To clarify the potential role of NOD2 P286S, R702W, G908R, and 3020insC polymorphisms in CRC patients, we have undertaken a systematic review and meta-analysis of published articles.

Materials and methods

Studies reporting on NOD2 polymorphisms and CRC were searched in the PubMed, EMBASE, and the Science Citation Index from the inception of each database to May, 2009. The search strategy included the keywords “CRC”, “colon cancer”, “rectal cancer”, “polymorphism”, and “NOD2/CARD15”.

Result

Eight eligible case-control studies about Caucasians from four countries contributed data on 5,888 subjects (cases: 3,524; controls: 2,364). Compared to the wild genotype, the R702W, G908R, and 3020insC polymorphisms were associated with an increased risk of CRC (odds ratio (OR): 1.59, 1.98, 1.44; 95% confidence interval (CI): 1.09–2.32, 1.14–3.44, 1.13–1.84; P?=?0.02, 0.01, 0.003). However, P268S polymorphism did not influence CRC risk (OR: 1.27; CI: 0.32–5.00; P?=?0.73).

Conclusions

These findings indicate that NOD2 R702W, G908R, and 3020insC polymorphisms contribute to CRC susceptibility in Caucasians. Meta-analysis of these polymorphisms in NOD2 gene will help determine their role in CRC carcinogenesis.     

NOD2 Mutations Affect Muramyl Dipeptide Stimulation of Human B Lymphocytes and Interact with Other IBD-Associated Genes

Background

Genetic and functional studies have associated variants in the NOD2/CARD15 gene with Crohn’s disease.

Aims

This study aims to replicate the association of three common NOD2 mutations with Crohn’s disease, study its effect on NOD2 expression in B cells and its interaction with other IBD-associated genes.

Methods

A total of 294 IBD patients (179 familial IBD, 115 sporadic IBD) and 298 unrelated healthy controls were from central Pennsylvania. NOD2 mutations were analyzed by primer-specific amplification, PCR based-RFLP, and validated with the ABI SNPlex^M genotyping system. Gene–gene interaction was studied using a statistical model for epistasis analysis.

Results

Three common NOD2 mutations are associated with Crohn’s disease (p = 5.08 × 10^?7, 1.67 × 10^?6, and 1.87 × 10^?2 for 1007fs, R720W, and G908R, respectively), but not with ulcerative colitis (p = 0.1046, 0.1269, and 0.8929, respectively). For IBD overall, 1007finsC (p = 4.4 × 10^?5) and R720W (p = 9.24 × 10^?5) were associated with IBD, but not G908R (p = 0.1198). We revealed significant interactions of NOD2 with other IBD susceptibility genes IL23R, DLG5, and OCTN1. We discovered that NOD2 was expressed in both normal human peripheral blood B cells and in EBV-transformed B cell lines. Moreover, we further demonstrated that muramyl dipeptide (MDP) stimulation of B lymphocytes up-regulated expression of NF-κB-p50 mRNA.

Conclusion

NOD2 is expressed in peripheral B cells, and the up-regulation of NOD2 expression by MDP was significantly impaired by NOD2 mutations. The finding suggests a possible role of NOD2 in the immunological response in IBD pathogenesis.     

Granulomas of Intestinal Tuberculosis and Crohn's Disease Can Be Differentiated by CD73 Cell Surface Marker Expression: A Pilot Study

Background

Intestinal tuberculosis (ITB) and Crohn's disease are similar granulomatous disorders. Granulomas are present in both and difficult to differentiate on histopathology alone. A recent study demonstrated recruitment of mesenchymal cells (MSCs) at the periphery of granulomas in lymph node tuberculosis which suppressed T cell responses. We hypothesized that granulomas of ITB would also recruit MSCs to evade host immune response.

Aim

The purpose of this study was to demonstrate MSC markers in granulomas of ITB and evaluate whether distribution of MSC markers could differentiate between granulomas of Crohn's and ITB.

Methods

We initially retrospectively enrolled 17 patients with confirmed ITB (8) or Crohn's (9) with granulomas on histopathology. Tissues were evaluated by immunofluorescence for MSC markers CD29, CD90, CD73 and absence of haematopoietic markers CD31, CD34, CD45 and CD14. Double-staining was done to confirm presence of MSCs. Subsequently, 23 postoperative specimens of Crohn's (18) and ITB (5) were analyzed for validation.

Results

Overall, 27 Crohn's and 13 ITB cases were assessed. CD29 and CD90 positive cells were noted around both ITB and Crohn's granulomas. MSC marker CD73 was expressed around the granulomas of ITB alone and was completely absent in the Crohn's. The subsequent assessment of granulomas in postoperative specimens of Crohn's and ITB also showed similar results.

Conclusion

Granulomas of ITB and Crohn's disease can be differentiated by CD73 MSC surface marker expression. The differential CD73 expression around ITB granuloma indicates that Mycobacterium tuberculosis evades host immunity by recruiting MSCs with CD73 expression. MSCs with increased CD73 expression could be the future for therapeutic intervention in Crohn's.     

Genetic variants of membrane metallopeptidase genes in inflammatory bowel diseases

Background

The substance P pathway modulates neuroimmune interactions during intestinal inflammation.

Aims

To analyse mucosal expression and genetic variants of the genes coding for substance P, neurokinin-1 receptor and neutral endopeptidase in patients with inflammatory bowel disease.

Methods

qRT-PCR was used to analyse mRNA levels in matched, paired samples of inflamed colonic mucosa and adjacent non-inflamed endoscopic tissue from 26 Crohn's disease and 25 ulcerative colitis patients. Allele and genotype frequencies of tag-SNPs were determined in 908 Crohn's disease, 929 ulcerative colitis, and 853 controls. Expression levels and genotype distributions were examined within patients’ clinical sub-phenotypes.

Results

All 3 evaluated genes were overexpressed in inflamed tissues from Crohn's disease (P = 0.033, P = 4 × 10⁻⁵, P = 0.001), while in ulcerative colitis only higher levels of the gene coding for neutral endopeptidase were statistically significant (P = 2.5 × 10⁻⁵). Smoking habit and perianal disease were significantly associated with substance P (P = 0.002) and neurokinin-1 receptor levels (P = 0.02) in Crohn's disease. Neutral endopeptidase rs701109 variant was associated with inflammatory bowel disease (Crohn's disease: P = 0.022; ulcerative colitis: P = 0.045), and with the need for colectomy in ulcerative colitis (P = 0.008, OR = 2.46, 95% CI = 1.27–4.76).

Conclusions

Genetic variants of the gene coding for neutral endopeptidase might affect the neuroimmune interaction during intestinal inflammation and influence clinical sub-phenotypes in patients with inflammatory bowel disease.     

A non-interventional study of the genetic polymorphisms of NOD2 associated with increased mortality in non-alcoholic liver transplant patients

Background

Infections after liver transplantation are the main cause of death in the first year. Recent reports indicate that NOD2 gene mutations increase the risk for inflammatory bowl disease and the severity of graft-versus-host disease in bone marrow transplant patients. Data on polymorphisms in liver transplant patients are sparse. We analyzed 13 single-nucleotide polymorphisms (SNPs) of 13 different gene variants including the SNPs of NOD2 genes from liver recipients. The aim of the study was to evaluate the impact of the SNPs on dialysis-dependent kidney failure, the incidence of infections and patient survival.

Methods

During a period of 20-months, 231 patients were recruited in this non-interventional, prospective study. Thirteen different SNPs and their impact on the patients’ survival, infection rate, and use of dialysis were assessed.

Results

NOD 2 wildtype genes were protective with respect to the survival of non-alcoholic, cirrhotic transplant patients (3 year survival: 66.8% wildtype vs. 42.6% gene mutation, p?=?0.026). This effect was not observed in alcoholic transplant recipients. The incidence of dialysis-dependent kidney failure and infection in the liver transplant patients was not influenced by NOD 2 gene polymorphisms. No effect was noted in the remaining 12 SNPs. Patients with early allograft dysfunction experienced significantly more infections, required dialysis and had significantly worse survival. In contrast, the donor-risk-index had no impact on the infection rate, use of dialysis or survival.

Conclusion

NOD2 gene variants seem to play a key role in non-alcoholic, liver transplant recipients. However these data should be validated in a larger cohort.     

PTGER4 modulating variants in Crohn’s disease

Purpose

Variants modulating expression of the prostaglandin receptor 4 (PTGER4) have been reported to be associated with Cohn’s disease (CD), but the clinical impact remains to be elucidated. We analyzed these variants in a large German inflammatory bowel disease (IBD) cohort and searched for a potential phenotype association.

Methods

The variants rs4495224 and rs7720838 were studied in adult German IBD patients (CD, n?=?475; ulcerative colitis (UC), n?=?293) and healthy controls (HC, n?=?467). Data were correlated to results from NOD2 genotyping and to clinical characteristics.

Results

We found a significant association for the rs7720838 variant with overrepresentation of the T allele to CD (p?=?0.0058; OR 0.7703, 95 % CI 0.641–0.926) but not to UC. Furthermore, logistic regression analysis revealed that the presence of the T allele was associated with stricturing disease behavior in CD patients (p?=?0.03; OR 1.84, 95 % CI 1.07–3.16). Interestingly, the chance for developing stricturing disease behavior was enhanced if mutant alleles in both rs7720838 and NOD2 were present (OR 2.87, 95 % CI 1.42–5.81; p?=?0.003). No overall association to CD or UC was found for the rs4495224 variant.

Conclusions

The PTGER4 modulating variant rs7720838 increases susceptibility for CD and might resemble a risk factor for stricturing disease behavior.     

Evaluation of Early Atherosclerosis in Patients with Inflammatory Bowel Disease

Background

Data regarding early atherosclerosis and inflammatory bowel disease are limited and conflicting results are present.

Aims

The purpose of this study was to evaluate serological and sonographical evidence of subclinical vascular involvement in patients with inflammatory bowel disease.

Methods

Thirty-nine patients with inflammatory bowel disease (20 Crohn's disease, and 19 ulcerative colitis patients) and 31 healthy controls were consecutively enrolled in the study. Flow mediated dilatation of the brachial artery and intima media thickness assessments of the common carotid artery were measured sonographically. Soluble CD40 ligand levels were evaluated. Crohn's disease activity index and modified Truelove-Witt’s criteria were also noted.

Results

Age, sex distribution, serum lipids, smoking status, and intima media thickness of the common carotid artery were similar between the inflammatory bowel disease patients and controls (p > 0.05). However, both endothelium dependent and independent flow mediated dilatation values were significantly impaired in the inflammatory bowel disease group compared with healthy controls (p < 0.05). Erythrocyte sedimentation rate, C-reactive protein and soluble CD40 ligand values were significantly increased in inflammatory bowel disease patients compared with controls (p < 0.05), and soluble CD40 ligand was negatively correlated with flow mediated dilatation (r = ?0.3, p < 0.05). Flow mediated dilatation was significantly predicted from the concentrations of C-reactive protein and soluble CD40 ligand.

Conclusion

Functional atherosclerosis is present in inflammatory bowel disease before early structural changes occur in vasculature. Higher sCD40L may indicate worse vascular outcome for IBD.     

NOD2/CARD15基因R702W、G908R及L1007fs多态性与广西壮族人群炎症性肠病的相关性

目的:探讨我国广西壮族人群NOD2/CARD15基因R702W、G908R及L1007fs的遗传多态性与炎症性肠病的相关性.方法:分别收集2007-02/2010-10在广西地区无亲缘关系的壮族(n=70)和汉族(n=76)IBD患者及壮族(n=80)和汉族(n=84)正常对照者的肠黏膜组织.采用酚氯仿法提取各组织样本DNA,采用聚合酶链反应-限制性片段长度多态性分析(PCR-RFLP)方法对NOD2/CARD15基因R702W、G908R及L1007fs进行检测,统计基因型及等位基因频率,分析上述3个多态性位点与广西壮族人群炎症性肠病的相关性.结果:广西壮族和汉族IBD患者与正常对照者均未发现NOD2/CARD15基因R702W、G908R及L1007fs突变型基因型,所有多态性位点上的基因型全部为野生型纯合子,其基因型频率和等位基因频率分布在IBD患者和正常对照者中差异无统计学意义(P>0.05).结论:NOD2/CARD15基因R702W、G908R及L1007fs多态性与广西壮族人群炎症性肠病无明显相关性.     

Presence of intestinal Mycobacterium avium subspecies paratuberculosis (MAP) DNA is not associated with altered MMP expression in ulcerative colitis

Background

Mycobacterium avium subspecies paratuberculosis (MAP) is suspected to be a causative agent in human Crohn's disease (CD). Recent evidence suggests that pathogenic mycobacteria and MAP can induce the expression of Matrix Metalloproteinases (MMP), which are the main proteases in the pathogenesis of mucosal ulcerations in inflammatory bowel disease (IBD). Within this study we assessed the prevalence of intestinal MAP specific DNA in patients with Crohn's disease, ulcerative colitis (UC), and healthy controls. We further analysed regulation patterns of MMPs in mucosal tissues of UC patients with and without intestinal MAP DNA detection.

Methods

Colonic biopsy samples were obtained from 63 Norwegian and German IBD patients and 21 healthy controls. RNA was quantified by quantitative real-time polymerase chain reaction (PCR) to study MMP gene expression in both pathological and healthy mucosal specimens. The presence of MAP DNA in colonic mucosa was examined using MAP specific PCR.

Results

MAP DNA was detected in 20% of UC patients and 33% of healthy controls but only in 7% of patients with CD. UC patients treated with corticosteroids exhibited a significantly increased frequency of intestinal MAP DNA compared to those not receiving corticosteroids. Expression of MMP-1, -2, -7, -9, -13, -19, -28 and TNF-α did not differ between UC patients with presence of intestinal MAP DNA compared to those without. MMP-2, MMP-9 and MMP-13 were significantly decreased in UC patients receiving corticosteroids.

Conclusions

The presence of intestinal MAP specific DNA is not associated with altered MMP expression in UC in vivo. Corticosteroids are associated with increased detection of intestinal MAP DNA and decreased expression of certain MMPs. Frequent detection of MAP DNA in healthy controls might be attributable to the wide environmental distribution of MAP and its presence in the food-chain.     

Intradermal α1-antitrypsin therapy avoids fatal anaphylaxis, prevents type 1 diabetes and reverses hyperglycaemia in the NOD mouse model of the disease

Aims/hypothesis

Human α1-antitrypsin (hAAT) gene therapy prevents type 1 diabetes in a NOD mouse model of diabetes. However, repeated i.p. injections of hAAT into NOD mice leads to fatal anaphylaxis. The aim of the study was to determine if an alternative route of administration avoids anaphylaxis and allows evaluation of hAAT’s potential for diabetes prevention and reversal. We also sought to determine if the addition of granulocyte colony-stimulating factor (G-CSF), augments hAAT’s capacity to prevent or reverse disease in the NOD mice.

Methods

To evaluate hAAT pharmacokinetics, serum hAAT levels were monitored in NOD mice receiving a single dose (2 mg) of hAAT by i.p., s.c. or i.d. injection. For studies of type 1 diabetes prevention and reversal, mice received i.d. hAAT (2 mg/mouse/3 days) for 8 or 10 weeks or hAAT and G-CSF (i.p., 6 μg/day) for 6 weeks. Blood glucose determinations, glucose tolerance testing and insulin tolerance tests were performed.

Results

Both i.p. and s.c. injections resulted in fatal anaphylaxis. The i.d. injection avoided anaphylaxis and i.d. injection of hAAT into 11-week-old NOD mice prevented disease (p?=?0.005, AAT vs PBS at 40 weeks of age). Treatment of diabetic NOD mice with hAAT or hAAT plus G-CSF provided long-term (at least 100 days) reversal of diabetes in 50% of treated animals. G-CSF did not enhance the reversal rates of hAAT. Glucose tolerance and insulin levels were normalised in mice with hAAT prevention and reversal.

Conclusions/interpretation

Intradermal hAAT prevents and reverses disease in a NOD mouse model of type 1 diabetes without inducing anaphylaxis.     

A Systematic Analysis of Treatment and Outcomes of NOD2-Associated Autoinflammatory Disease

Objectives

Yao syndrome, formerly named NOD2-associated autoinflammatory disease, is a periodic disease characterized by fever, dermatitis, polyarthritis/leg swelling, and gastrointestinal and sicca-like symptoms associated with specific NOD2 sequence variants. Our aim was to evaluate the treatment and outcomes of the disease.

Interaction between CTLA4 gene and IBD5 locus in Hungarian Crohn��s disease patients

Backgrounds and aims

The IGR2198a_1 and IGR2096a_1 variants of the IBD5 region were found to be associated with Crohn??s disease (CD) in the Hungarian population, while IGR2230a_1 does not seem to confer risk for the disease. In the present study, our aim was to investigate the statistical interaction of these three IBD5 polymorphisms with the +49 A/G substitution within the cytotoxic T lymphocyte antigen-4 (CTLA4) gene, detected previously as neutral gene variant in Hungarian IBD patients.

Methods

A total of 305 unrelated subjects with CD and 310 healthy controls were genotyped with PCR-RFLP methods.

Results

In contrast with single gene effects, after genotype stratification, the IGR2198a_1 C and IGR2096a_1 T variants were found to confer susceptibility only in subjects with CTLA4 +49 AA genotype (P?=?0.008; OR?=?1.86 and P?=?0.016; OR?=?1.74, respectively), for IGR2230a_1 no such effect on disease risk could be demonstrated.

Conclusion

Analysis of specific genotype combinations unfolded a possible association between the CTLA4 +49 A/G substitution and two of the observed IBD5 variants with respect to disease risk.     

Video-assisted anal fistula treatment (VAAFT) combined with advancement flap repair in Crohn’s disease

Background

It was the aim of this prospective study to analyze both the feasibility and preliminary results of video-assisted anal fistula treatment (VAAFT) combined with advancement flap repair for complex fistulas in Crohn's disease.

Methods

All patients with perianal Crohn's disease suffering from complex fistulas who underwent definitive surgery using VAAFT combined with advancement flap repair were prospectively enrolled in the study. Only complex fistulas with concurrent stable disease and without any evidence of severe inflammatory activity or perianal sepsis were treated using the VAAFT technique. Patients with Crohn's proctitis or prior proctectomy were not candidates for the procedure. VAAFT was performed by using the VAAFT equipment (Karl Storz, Tuttlingen, Germany). Key steps included visualization of the fistula tract and/or side tracts using the fistuloscope and correct localization of the internal fistula opening under direct vision with irrigation. Diagnostic fistuloscopy was followed by advancement flap repair. In addition to feasibility, primary end points included detection of side tracts, success and continence status (assessed by the Cleveland Clinic Incontinence Score). Success was defined as closure of both internal and external openings, absence of drainage without further intervention and absence of abscess formation. Follow-up information was derived from clinical examination 3, 6 and 9 months postoperatively.

Results

Within a 3-month observation period (September to November 2011), VAAFT was attempted in 13 patients with Crohn's associated complex fistulas. The completion rate was 85 % (11/13). In these 11 patients (median age 34 years, 64 % females), complex fistulas were transsphincteric (8), suprasphincteric (2) and recto-vaginal (1). Forty-six percent (5/11) had concomitant therapy with biologic drugs. In 36 % (4/11), VAAFT was performed with fecal diversion. Median duration of surgery was 22 (range 18–42) minutes. Using VAAFT, additional side tracts not detected preoperatively could be identified in 64 % (7/11). No morbidity occurred. After a mean follow-up of 9 months, the success rate was 82 % (9/11). No deterioration of continence was documented (Cleveland Clinic Incontinence Score 2.4 vs. 1.6, p > 0.05).

Conclusion

Preliminary results of the addition of the VAAFT technique to advancement flap repair in Crohn's fistulas demonstrate that this leads to a high identification rate of occult side tracts with encouraging short-term healing rates. Moreover, a completion rate of 85 % seems promising.     

Bactericidal Permeability Increasing Protein Gene Polymorphism is Associated with Inflammatory Bowel Diseases in the Turkish Population

Background/Aims:

Inflammatory bowel disease, a chronic inflammatory disease with unknown etiology, affects the small and large bowel at different levels. It is increasingly considered that innate immune system may have a central position in the pathogenesis of the disease. As a part of the innate immune system, bactericidal permeability increasing protein has an important role in the recognition and neutralization of gram-negative bacteria. The aim of our study was to investigate the involvement of bactericidal permeability increasing protein gene polymorphism (bactericidal permeability increasing protein Lys216Glu) in inflammatory bowel disease in a large group of Turkish patients.

Patients and Methods:

The present study included 528 inflammatory bowel disease patients, 224 with Crohn''s disease and 304 with ulcerative colitis, and 339 healthy controls.

Results:

Bactericidal permeability increasing protein Lys216Glu polymorphism was found to be associated with both Crohn''s disease and ulcerative colitis (P = 0.0001). The frequency of the Glu/Glu genotype was significantly lower in patients using steroids and in those with steroid dependence (P = 0.012, OR, 0.80; 95% confidence interval [CI]: 0.68-0.94; P = 0.0286, OR, 0.75; 95% CI: 0.66-0.86, respectively). There was no other association between bactericidal permeability increasing protein gene polymorphism and phenotypes of inflammatory bowel disease.

Conclusions:

Bactericidal permeability increasing protein Lys216Glu polymorphism is associated with both Crohn''s disease and ulcerative colitis. This is the first study reporting the association of bactericidal permeability increasing protein gene polymorphism with steroid use and dependence in Crohn''s disease.     

Investigation of innate immunity genes CARD4, CARD8 and CARD15 as germline susceptibility factors for colorectal cancer

Background

Variation in genes involved in the innate immune response may play a role in the predisposition to colorectal cancer (CRC). Several polymorphisms of the CARD15 gene (caspase activating recruitment domain, member 15) have been reported to be associated with an increased susceptibility to Crohn disease. Since the CARD15 gene product and other CARD proteins function in innate immunity, we investigated the impact of germline variation at the CARD4, CARD8 and CARD15 loci on the risk for sporadic CRC, using a large patient sample from Northern Germany.

Methods

A total of 1044 patients who had been operated with sporadic colorectal carcinoma (median age at diagnosis: 59 years) were recruited and compared to 724 sex-matched, population-based control individuals (median age: 68 years). Genetic investigation was carried out following both a coding SNP and haplotype tagging approach. Subgroup analyses for N = 143 patients with early manifestation of CRC (≤50 age at diagnosis) were performed for all CARD loci and subgroup analyses for diverse age strata were carried out for CARD15 mutations R702W, G908R and L1007fs. In addition, all SNPs were tested for association with disease presentation and family history of CRC.

Results

No significant differences were observed between the patient and control allelic or haplotypic spectra of the three genes under study for the total cohort (N = 1044 patients). None of the analysed SNPs was significantly associated with either tumour location or yielded significant association in the familial or non-familial CRC patient subgroups. However, in a patient subgroup (≤45 age at diagnosis) with early disease manifestation the mutant allele of CARD15 R702W was found to be significantly associated with disease susceptibility (9.7% in cases vs 4.6% in controls; P_allelic = 0.008, P_genotypic = 0.0008, OR_allelic = 2.22 (1.21-4.05) OR_ressessive = 21.9 (1.96-245.4).

Conclusion

Variation in the innate immunity genes CARD4, CARD8 and CARD15 is unlikely to play a major role in the susceptibility to CRC in the German population. But, we report a significant disease contribution of CARD15 for CRC patients with very early disease manifestation, mainly driven by variant R702W.     

SDF-1alpha G801A polymorphism in Southern Iranian patients with colorectal and gastric cancers

Background

A single nucleotide polymorphism (SNP) in the stromal cell-derived factor-1 (SDF-1) gene at position 801 (G>A) is associated with susceptibility to certain tumors. This study aimed to investigate an association between this SNP and colorectal and gastric cancers in an Iranian population.

Method

Genotype and allele frequencies of SDF-1 801 G>A were assessed using polymerase chain reaction-restriction fragment length polymorphism in 109 patients with colorectal cancer, 124 with gastric cancer, and 262 normal control volunteers.

Results

No statistically significant difference was observed in the frequencies of genotypes and alleles between patients and controls (p?>?0.05).

Conclusion

SDF-1 gene polymorphism at position 801 (G>A) was not associated with colorectal and gastric cancers in Southern Iranian patients.     

Opioid Use is Associated with Decreased Quality of Life in Patients with Crohn's Disease

Background/Aims:

Quality of life is an important consideration in the management of patients with Crohn''s disease. Previous studies suggest that Crohn''s disease patients using opioids may have decreased quality of life and increased risk of mortality. Our aim was to determine the association between health-related quality of life (HRQoL) and opioid use in patients with Crohn''s disease while controlling for disease severity.

Patients and Methods:

We conducted a cross-sectional study recruiting Crohn''s disease patients at our center. Disease activity was measured using the Harvey-Bradshaw Index (HBI), and HRQoL was measured using the Inflammatory Bowel Disease Questionnaire (IBDQ).

Results:

We enrolled 38 Crohn''s disease patients using opioids and 62 patients not using opioids. Patients using opioids had an increased duration of disease (median 18.5 vs. 9 years, P = 0.005), increased surgeries related to Crohn''s disease (median 3 vs. 0, P < 0.001), and increased prednisone use (29% vs. 11.3%, P = 0.03). Patients using opioids had increased disease activity (median HBI score 9.0 vs. 3.0, P < 0.001). Quality of life was lower in patients using opioids (mean IBDQ score 109.3 vs. 162.9, P < 0.001). This finding was significant when controlling for HBI scores, number of previous surgeries, and prednisone use (P = 0.003).

Conclusions:

Opioid use in Crohn''s disease patients appears to be associated with disease activity and severity. HRQoL is markedly decreased in patients using opioids and this association is significant even when controlling for variables reflecting disease severity. Our findings suggest that Crohn''s disease patients using opioids are likely to be significantly impacted by their disease.     

Pseudomonas fluorescens alters epithelial permeability and translocates across Caco-2/TC7 intestinal cells

Background

Pseudomonas fluorescens has long been considered as a psychrotrophic microorganism. Recently, we have shown that clinical strains of P. fluorescens (biovar 1) are able to adapt at a growth temperature of 37°C or above and induce a specific inflammatory response. Interestingly, a highly specific antigen of P. fluorescens, I2, is detected in the serum of patients with Crohn's disease but the possible role of this bacterium in the disease has not yet been explored. In the present study, we examined the ability of a psychrotrophic and a clinical strain of P. fluorescens to modulate the permeability of a Caco-2/TC7 intestinal epithelial model, reorganize the actin cytoskeleton, invade the target cells and translocate across the epithelium. The behaviour of these two strains was compared to that of the well known opportunistic pathogen P. aeruginosa PAO1.

Results

Both strains of P. fluorescens were found to decrease the transepithelial resistance (TER) of Caco-2/TC7 differentiated monolayers. This was associated with an increase in paracellular permeability and F-actin microfilaments rearrangements. Moreover, the invasion and translocation tests demonstrated that the two strains used in this study can invade and translocate across the differentiated Caco-2/TC7 cell monolayers.

Conclusions

The present work shows for the first time, that P. fluorescens is able to alter the intestinal epithelial barrier function by disorganizing the F-actin microfilament network. Moreover, we reveal that independently of their origins, the two P. fluorescens strains can translocate across differentiated Caco-2/TC7 cell monolayers by using the transcellular pathway. These findings could, at least in part, explain the presence of the P. fluorescens specific I2 antigen in the serum of patients with Crohn's disease.     

A national survey on the patterns of treatment of inflammatory bowel disease in Canada

Background

There is a general lack of information on the care of inflammatory bowel disease (IBD) in a broad, geographically diverse, non-clinic population. The purposes of this study were (1) to compare a sample drawn from the membership of a national Crohn's and Colitis Foundation to published clinic-based and population-based IBD samples, (2) to describe current patterns of health care use, and (3) to determine if unexpected variations exist in how and by whom IBD is treated.

Methods

Mailed survey of 4453 members of the Crohn's and Colitis Foundation of Canada. The questionnaire, in members stated language of preference, included items on demographic and disease characteristics, general health behaviors and current and past IBD treatment. Each member received an initial and one reminder mailing.

Results

Questionnaires were returned by 1787, 913, and 128 people with Crohn's disease, ulcerative colitis and indeterminate colitis, respectively. At least one operation had been performed on 1159 Crohn's disease patients, with risk increasing with duration of disease. Regional variation in surgical rates in ulcerative colitis patients was identified. 6-Mercaptopurine/Azathioprine was used by 24% of patients with Crohn's disease and 12% of patients with ulcerative colitis (95% CI for the difference: 8.9% – 15%). In patients with Crohn's disease, use was not associated with gender, income or region of residence but was associated with age and markers of disease activity. Infliximab was used by 112 respondents (4%), the majority of whom had Crohn's disease. Variations in infliximab use based on region of residence and income were not seen. Sixty-eight percent of respondents indicated that they depended most on a gastroenterologist for their IBD care. There was significant regional variation in this. However, satisfaction with primary physician did not depend on physician type (for example, gastroenterologist versus general practitioner).

Conclusion

This study achieved the goal of obtaining a large, geographically diverse sample that is more representative of the general IBD population than a clinic sample would have been. We could find no evidence of significant regional variation in medical treatments due to gender, region of residence or income level. Differences were noted between different age groups, which deserves further attention.