Crohn's Disease Colitis Research Articles

Increased viability but decreased culturability of Mycobacterium avium subsp. paratuberculosis in macrophages from inflammatory bowel disease patients under Infliximab treatment.

Mycobacterium avium subsp. paratuberculosis (MAP) has long been implicated as a triggering agent in Crohn's disease (CD). In this study, we investigated the growth/persistence of both M. avium subsp. hominissuis (MAH) and MAP, in macrophages from healthy controls (HC), CD and ulcerative colitis patients. For viability assessment, both CFU counts and a pre16SrRNA RNA/DNA ratio assay (for MAP) were used. Phagolysosome fusion was evaluated by immunofluorescence, through analysis of LAMP-1 colocalization with MAP. IBD macrophages were more permissive to MAP survival than HC macrophages (a finding not evident with MAH), but did not support MAP active growth. The lower MAP CFU counts in macrophage cultures associated with Infliximab treatment were not due to increased killing, but possibly to elevation in the proportion of intracellular dormant non-culturable MAP forms, as MAP showed higher viability in those macrophages. Increased MAP viability was not related to lack of phagolysosome maturation. The predominant induction of MAP dormant forms by Infliximab treatment may explain the lack of MAP reactivation during anti-TNF therapy of CD but does not exclude the possibility of MAP recrudescence after termination of therapy.

SGK1 inhibits cellular apoptosis and promotes proliferation via the MEK/ERK/p53 pathway in colitis.

To investigate the role of serum-and-glucocorticoid-inducible-kinase-1 (SGK1) in colitis and its potential pathological mechanisms. SGK1 expression in mucosal biopsies from patients with active Crohn's disease (CD) and normal controls was detected by immunohistochemistry. We established an acute colitis model in mice induced by 2,4,6-trinitrobenzene sulfonicacid, and demonstrated the presence of colitis using the disease activity index, the histologic activity index and hematoxylin and eosin staining. The cellular events and potential mechanisms were implemented with small interference RNA and an inhibitor of signaling molecule (i.e., U0126) in intestinal epithelial cells (IECs). The interaction between SGK1 and the signaling molecule was assessed by co-immunoprecipitation. SGK1 expression was significantly increased in the inflamed epithelia of patients with active CD and TNBS-induced colitis model (0.58 ± 0.055 vs 0.85 ± 0.06, P < 0.01). At the cellular level, silencing of SGK1 by small interference RNA (siSGK1) significantly inhibited the phosphorylation of mitogen-activated protein kinase kinase 1 (MEK1) and the downstream molecule extracellular signal regulated protein kinase (ERK) 1/2, which induced the upregulation of p53 and Bcl-2-associated X protein, mediating the subsequent cellular apoptosis and proliferation in IECs. Cells treated with MEK1 inhibitor (i.e., U0126) before siSGK1 transfection showed a reversal of the siSGK1-induced cellular apoptosis. Our data suggested that SGK1 may protect IECs in colitis from tumor necrosis factor-α-induced apoptosis partly by triggering MEK/ERK activation.

Crohn Disease And The Specialty Pharmacist

Crohn disease (CD) is one of the two major types of inflammatory bowel disease (IBD); ulcerative colitis is the other. 1 IBD is characterized by chronic inflammation of all or parts of the digestive tract. 1 CD and ulcerative colitis can be differentiated by evaluating the location of the inflammation within the gastrointestinal (GI) tract, the depth of that inflammation, and whether disease activity occurs in a continuous or noncontinuous fashion. 1 2 Table 1 outlines the three major differences between CD and ulcerative colitis.

ATG16L1andNOD2polymorphisms enhance phagocytosis in monocytes of Crohn’s disease patients

To investigate if the presence of relevant genetic polymorphisms has effect on the effectual clearance of bacteria by monocytes and granulocytes in patients with Crohn's disease (CD). In this study, we assessed the differential responses in phagocytosis by measuring the phagocytic activity and the percentage of active phagocytic monocytes and granulocytes in inflammatory bowel disease patients as well as healthy controls. As both autophagy related like 1 (ATG16L1) and immunity-related guanosine triphosphatase gene are autophagy genes associated with CD and more recently nucleotide-binding ligomerization domain-containing protein 2 (NOD2) has been identified as a potent inducer of autophagy we genotyped the patients for these variants and correlated this to the phagocytic reaction. The genotyping was done with restriction fragment length polymorphisms analysis and the phagocytosis was determined with the pHrodo™ Escherichia coli Bioparticles Phagocytosis kit for flowcytometry. In this study, we demonstrate that analysis of the monocyte and granulocyte populations of patients with CD and ulcerative colitis showed a comparable phagocytic activity (ratio of mean fluorescence intensity) between the patient groups and the healthy controls. CD patients show a significantly higher phagocytic capacity (ratio mean percentage of phagocytic cells) compared to healthy controls (51.91% ± 2.85% vs 37.67% ± 7.06%, P = 0.05). The extend of disease was not of influence. However, variants of ATG16L1 (WT: 2.03 ± 0.19 vs homozygoot variant: 4.38 ± 0.37, P < 0.009) as well as NOD2 (C-ins) (heterozygous variant: 42.08 ± 2.94 vs homozygous variant: 75.58 ± 4.34 (P = 0.05) are associated with the phagocytic activity in patients with CD. Monocytes of CD patients show enhanced phagocytosis associated with the presence of ATG16L1 and NOD2 variants. This could be part of the pathophysiological mechanism resulting in the disease.

Antibiotics, probiotics and prebiotics in IBD.

The dysbiosis theory of inflammatory bowel disease (IBD) posits that there is an alteration in the gut microbiome as an important underpinning of disease etiology. It stands to reason then, that administering agents that could impact on the balance of microbes on the gut could be impactful on the course of IBD. Herein is a review of the controlled trials undertaken to assess the use of antibiotics that would kill or suppress potentially injurious microbes, probiotics that would overpopulate the gut with potentially beneficial microbes or prebiotics that provide a metabolic substrate that enhances the growth of potentially beneficial microbes. With regard to antibiotics, the best data are for the use of nitroimadoles postoperatively in Crohn's disease (CD) to prevent disease recurrence. Otherwise, the data are limited with the regard to any lasting benefit of antibiotics sustaining remission in either CD or ulcerative colitis (UC). A recent meta-analysis concluded that antibiotics are superior to placebo at inducing remission in CD or UC, although the meta-analysis grouped a variety of antibiotics with different spectra of activity. Despite the absence of robust clinical trial data, antibiotics are widely used to treat perineal fistulizing CD and acute and chronic pouchitis. Probiotics have not been shown to have a beneficial role in CD. However, Escherichia coli Nissle 1917 has comparable effects to low doses of mesalamine in maintaining remission in UC. VSL#3, a combination of 8 microbes, has been shown to have an effect in inducing remission in UC and preventing pouchitis. Prebiotics have yet to be shown to have an effect in any form of IBD, but to date controlled trials have been small. The use of antibiotics should be balanced against the risks they pose. Even probiotics may pose some risk and should not be assumed to be innocuous especially when ingested by persons with a compromised epithelial barrier. Prebiotics may not be harmful but may cause gastrointestinal side effects. Finally, the timing of ingestion of antibiotics and other dietary factors that may function as prebiotics, especially in early childhood, may be critical in shaping the gut microbiome and ultimately predisposing to or preventing IBD. Finding ways to impact on the gut microbiome to alter the course of IBD makes good sense, but should be undertaken in the setting of rigorously performed controlled trials to ensure that the interventions are truly effective and well tolerated.

High Residential Sun Exposure Is Associated With a Low Risk of Incident Crohnʼs Disease in the Prospective E3N Cohort

Vitamin D insufficiency has been suggested to be associated with high risk of Crohn's disease (CD). In France, where food fortification is limited, the major source of vitamin D is through sun exposure. The aim of this work was to analyze the relationship between residential sun exposure and the risk of incident CD or ulcerative colitis (UC). The E3N cohort consists of women living in France, aged 40 to 65 years and free of major diseases at inclusion in 1990. Among the 91,870 women included in the study, we identified 123 incident cases (45 CD, 71 UC, and 7 indeterminate colitis). To assess residential sun exposure, we used a database containing mean daily ultraviolet radiation (UVR) dose for each French county. The relationship between residential sun exposure and risk of incident inflammatory bowel diseases was explored using Cox models. Higher levels of residential sun exposure were associated with a significant decreased risk of CD (hazard ratio [HR] for the third versus the first tertile of UVR dose, 0.49; 95% confidence interval (CI), 0.23-1.01; P for trend = 0.04), but not of UC (HR, 1.21; CI, 0.61-2.11). In women with available data on dietary vitamin D intake, we observed a lower risk of CD with higher residential UVR (HR, 0.29; 95% CI, 0.11-0.80; P for trend = 0.01). Dietary vitamin D intake was neither associated with the risk of CD (HR, 0.41; 95% CI, 0.14-1.24; P for trend = 0.14) nor UC (HR, 1.61; CI, 0.61-4.23). In this prospective cohort of women, high residential sunlight exposure was associated with decreased incidence of CD, but not UC.

Mycobacterium avium subspecies paratuberculosis in the etiology of Crohn's disease, cause or epiphenomenon?

The origin of inflammatory bowel disease is unknown. Attempts have been made to isolate a microorganism that could explain the onset of inflammation, but no pathological agent has ever been identified. Johne's disease is a granulomatous chronic enteritis of cattle and sheep caused by Mycobacterium avium subspecies paratuberculosis (MAP) and shows some analogies with Crohn's disease (CD). Several studies have tried to clarify if MAP has a role in the etiology of CD. The present article provides an overview of the evidence in favor and against the "MAP-hypothesis", analyzing the methods commonly adopted to detect MAP and the role of antimycobacterial therapy in patients with inflammatory bowel disease. Studies were identified through the electronic database, MEDLINE, and were selected based on their relevance to the objective of the review. The presence of MAP was investigated using multiple diagnostic methods for MAP detection and in different tissue samples from patients affected by CD or ulcerative colitis and in healthy controls. On the basis of their studies, several authors support a close relationship between MAP and CD. Although increasing evidence of MAP detection in CD patients is unquestionable, a clear etiological link still needs to be proven.

Regulation of anergy-related ubiquitin E3 ligase, GRAIL, in murine models of colitis and patients with Crohn’s disease

Abrogating tolerance is a critical step in the pathogenesis of Crohn's disease (CD). T cell-anergy is one of the main mechanisms of tolerance and is regulated by the gene related to anergy in lymphocytes (GRAIL). This study investigated the expressions and regulation of GRAIL in CD and murine colitis models. Expressions of GRAIL mRNA and protein in CD4+ T cells were investigated in the peripheral blood and mucosal tissues of patients with CD, mice with dextran sodium salt (DSS)-induced colitis, and Il-10-deficient mice. MicroRNAs responsible for the regulation of GRAIL were examined by miRNA microarray. GRAIL-overexpressing T cells were intravenously injected in mice with DSS-induced colitis. The GRAIL expression was higher in the lamina propria (LP) CD4+ T cells of CD patients than of the control subjects, while it was lower in the peripheral blood CD4+ T cells of the CD patients than of the control subjects. The GRAIL mRNA expression was lower, but the GRAIL protein expression was higher in the LP of colitic mice than that of non-colitic mice. The miRNA microarray identified miR-290-5p as an miRNA that inhibits expression of the GRAIL protein and that is highly expressed in the LP of non-colitic mice. GRAIL-expressing T cells expressed regulatory T cell markers and showed suppressive effects in murine DSS-induced colitis. Our results show that expression of GRAIL is uniquely regulated by the specific miRNA in the intestinal mucosa, and suggest that GRAIL may associate with the pathophysiology of CD.

Oral Lesions as the Presenting Manifestation of Crohn Disease

Crohn disease (CD) is an immune-mediated disorder of the gastrointestinal tract; CD and ulcerative colitis comprise the 2 major types of inflammatory bowel disease. The underlying etiology has been attributed to defects in mucosal immunity and the intestinal epithelial barrier in a genetically susceptible host, resulting in an inappropriate inflammatory response to intestinal microbes. The lesions of CD can affect any region of the alimentary tract, as well as extraintestinal sites such as the skin, joints, and eyes.

Risk of permanent stoma in extensive Crohn's colitis: the impact of biological drugs

The overall risk of permanent stoma was determined in patients with extensive Crohn's colitis. An attempt was made to analyse whether biological drugs have modified the surgical approach in patients with anorectal involvement. In all, 233 patients with Crohn's disease colitis operated on between 1995 and 2010 were reviewed retrospectively. Fifty-one were treated before 2002 (prebiological era) and 182 after 2002 (biological era). The relationship was determined between the use of immunosuppressors, biological drugs, the presence of perianal disease and anorectal stenosis and the rate of permanent stoma formation. In the prebiological era 23 (45.1%) patients without anorectal involvement underwent colectomy and ileorectal anastomosis, 17 (33.3%) with severe anorectal disease had proctocolectomy and 11 (21.6%) with anorectal involvement had abdominal colectomy with permanent ileostomy. In the biological era 73 (40.1%) patients without anorectal involvement underwent colectomy and ileorectal anastomosis, nine (5%) with severe anorectal involvement had proctocolectomy and 100 (54.9%) with anorectal involvement had colectomy with terminal ileostomy. Of these 100, 75 have subsequently been treated with biological drugs with full regression of anorectal lesions in 81.3%. Rates of permanent stoma in the prebiological and biological era were 60.8% and 19.2% (P < 0.001). Univariate and multivariate analysis showed that only the use of biological drugs was significantly associated with an increased rate of rectal preservation (P < 0.05). The risk of a permanent stoma in patients with Crohn's colitis and anorectal involvement is significantly reduced with combined surgical and biological treatment.

Efficacy and tolerability of infliximab therapy in pediatric IBD: A retrospective single center experience

Aims: Infliximab (IFX), an anti-tumor necrosis factor-monoclonal chimeric antibody, has been shown to be an extremely potent drug for acute and maintenance treatment of both adult and pediatric patients with severe IBD, especially in those with Crohn's disease (CD). The aim of this retrospective study was to assess the efficacy and the tolerability profile in pediatric patients affected by CD and ulcerative colitis (UC).

Diagnosis and Treatment of Perianal Crohn Disease

Inflammatory bowel disease is a chronic inflammatory disorder of the gastrointestinal tract that includes both Crohn disease (CD) and ulcerative colitis. Abdominal pain, rectal bleeding, diarrhea, and weight loss characterize both CD and ulcerative colitis. The incidence of IBD in the United States is 70 to 150 cases per 100,000 individuals and, as with other autoimmune diseases, is on the rise. CD can affect any part of the gastrointestinal tract from the mouth to the anus and frequently will include perianal disease. The first description connecting regional enteritis with perianal disease was by Bissell et al in 1934, and since that time perianal disease has become a recognized entity and an important consideration in the diagnosis and treatment of CD. Perianal Crohn disease (PCD) is defined as inflammation at or near the anus, including tags, fissures, fistulae, abscesses, or stenosis. The symptoms of PCD include pain, itching, bleeding, purulent discharge, and incontinence of stool. In this report, we review and discuss the etiology, diagnosis, evaluation, and treatment of PCD.

Risk factors for depression in the elderly inflammatory bowel disease population

Background and aimsLittle is known about depression in elderly individuals with inflammatory bowel diseases (IBD). We assessed the point prevalence of depression and determined associations with disease activity, quality of life, and medication adherence in elderly patients with IBD. MethodsWe identified elderly (≥65years) individuals within Crohn's and Colitis Foundation of America Partners, an online IBD cohort. Individuals completed the short geriatric depression scale (GDS). We used bivariate statistics to determine whether demographic or disease-related factors, disease activity, quality of life or medication adherence was associated with depression. We used logistic regression to estimate independent effects of depression on medication adherence. ResultsA total of 359 elderly individuals with IBD completed the GDS. The mean age was 70.2years (SD 4.7); mean disease duration was 25.6years (SD 17.6), and 62.6% had Crohn's disease (CD). The point prevalence of depression was 22.6%. Lower education levels (p=0.001), higher corticosteroid use (<0.01) and lower exercise levels (<0.001) were associated with depression. For both CD and ulcerative colitis (UC), those with depression had increased disease activity (short Crohn's disease activity index 52.5 versus 29, p=0.005, and simple clinical colitis activity index 5 versus 2, p=0.003). Depressed patients had lower quality of life (short IBD questionnaire 4.6 versus 5.7, p<0.001). Depressed individuals had reduced medication adherence (adjusted OR 2.18; 95% CI 1.04–4.57). ConclusionsDepression is common in this geriatric IBD cohort. Depression is independently associated with reduced medication adherence. Recognition and treatment of depression in elderly patients with IBD could improve outcomes.

Associations Between Genetic Variants in the IRGM Gene and Inflammatory Bowel Diseases in the Korean Population

Recent European ancestry genome-wide association studies have identified genetic variants of IRGM as significant susceptibility loci for Crohn's disease (CD). Therefore, we investigated whether genetic variants of IRGM confer genetic susceptibility to CD or ulcerative colitis (UC) and evaluated the genotype-phenotype associations in the Korean population. This study included 510 inflammatory bowel disease (IBD) patients (253 patients with CD and 257 with UC) and 520 healthy controls in Koreans. Initially, we performed direct sequencing analysis to identify unique IRGM single nucleotide polymorphisms (SNPs). Three selected haplotype-tagging SNPs and one risk locus (rs72553867, rs10065172, rs4958847, and rs12654043) within the IRGM were then geno-typed in patients and controls. IRGM SNP rs10065172 was significantly associated with CD susceptibility in terms of allelic frequency (P = 0.004; odds ratio [OR] = 1.42) and genotype frequency (dominant model, P = 0.008; OR = 1.62). We also found a relationship between SNP rs72553867 and CD susceptibility in the analysis of allelic frequency (P = 0.0117; OR = 0.67) and genotype frequency (dominant model, P = 0.002; OR = 0.55). In addition, we observed that the association of CD with rs10065172 became stronger in patients with younger age at diagnosis (≤ 20 years) or male gender. However, there was no significant association between the four SNPs and UC susceptibility. This is the first study to identify SNP rs10065172 and rs72553867 in IRGM as principal CD susceptibility loci in an Asian population.

Adenocarcinoma in an ano-vaginal fistula in Crohn's disease

INTRODUCTIONFistulas are a relatively common occurrence in Crohn's disease (CD), and often present early in the disease process. Additionally, patients suffering from either CD or ulcerative colitis are shown to have an increased risk of colorectal malignancies compared with the general population. PRESENTATION OF CASEWe present a case of adenocarcinoma in an ano-vaginal fistula in a patient with longstanding CD. DISCUSSIONVarious pathogenic mechanisms for the development of carcinoma in fistulas have been suggested, but there is no consensus and indeed this risk may be cumulative. In this case report, we also discuss the pathogenesis of mucinous adenocarcinoma in fistulas secondary to CD. CONCLUSIONBetter detection of adenocarcinoma in patients presenting with persistent non-resolving fistulas in the presence of CD should be undertaken with regular biopsies following examinations under anaesthetic of the anorectum.

Atypical Disease Phenotypes in Pediatric Ulcerative Colitis

Definitive diagnosis of pediatric ulcerative colitis (UC) may be particularly challenging since isolated colitis with overlapping features is common in pediatric Crohn's disease (CD), while atypical phenotypes of UC are not uncommon. The Paris classification allows more accurate phenotyping of atypical inflammatory bowel disease (IBD) patients. Our aim was to identify the prevalence of atypical disease patterns in new-onset pediatric UC using the Paris classification. Information was collected from the EUROKIDS Registry, an inception cohort of untreated pediatric IBD patients undergoing evaluation at diagnosis. Patients with IBD-unclassified were excluded. Patients with isolated Crohn's colitis served as a control group. Data from 898 pediatric patients (643 UC, 255 CD colitis) were included. Extensive or pancolitis was present in 77% of UC patients and macroscopic rectal sparing in 5%. Rectal sparing was inversely associated with age (mean age with rectal sparing 9.9 years vs. 11.8 without; P = 0.02). Upper gastrointestinal (UGI) involvement occurred in 4% of patients. Erosions in the stomach were present in 3.1% of children, but frank ulcerations in 0.4%; 0.8% of children had erosions or ulcerations limited to the esophagus or duodenum. The corresponding UGI involvement in Crohn's colitis was 22%. A cecal patch occurred in 2% of patients. Extensive disease and rectal sparing are age-dependent phenotypes in pediatric UC. Rectal sparing, cecal patch, backwash ileitis, and gastric erosions are not uncommon at diagnosis, while gastric ulcerations and erosions in the duodenum or esophagus are. Recognition of atypical phenotypes in pediatric-onset UC is crucial to prevent misclassification of IBD.

Su1913 Anti-Glycan Antibodies in Relatives of Patients With Crohn's Disease

Background: Serum anti-glycan antibodies are a promising tool for differential diagnosis, disease stratification and prediction of Crohn's disease (CD). We assessed the presence of serum anti-glycan antibodies in affected and non-affected relatives of patients with CD and ulcerative colitis (UC). Methods: 393 non-inflammatory bowel disease (IBD)-affected relatives (330 CD and 63 UC relatives) of 169 IBD patients (140 CD and 29 UC patients) as well as 46 healthy controls were tested for the presence of anti-laminarin IgA (Anti-L), anti-chitin IgA (Anti-C), anti-chitobioside IgA (ACCA), anti-laminaribioside IgG (ALCA), anti-mannobioside IgG (AMCA) and anti-Saccaromyces cervisiae IgG (gASCA) carbohydrate antibodies by ELISA in a blinded fashion. Detailed clinical data of the IBD patients were available. Results:Non-affected relatives of CD patients had lower antibody levels for gASCA, ALCA, Anti-L and Anti-C and a lower quartile sum score (QSS), compared to the affected CD subjects (p<0.01). There was no difference in the levels of the antibodies when comparing first and second degree CD relatives. No similarity could be found for the pattern of positive markers in the affected CD patients compared to the non-affected relatives. In addition the ASCA status or a high versus low QSS of the affected CD patient did not influence the extent of the marker expression in the non-affected CD relative. While the QSS was similar, levels of and positivity for ACCA and AMCA were higher in the non-affected CD relatives compared to healthy controls (p<0.05). A higher proportion of healthy controls were negative for all anti-glycan antibodies compared to the non-affected IBD relatives (p<0.01). In the affected CD patients a positive family history for IBD was linked to higher levels of ACCA (p<0.03) and ALCA (p<0.04) with all other markers being unchanged. Non-affected UC relatives had lower levels of ALCA and Anti-L as well as a lower QSS compared to the affected UC patient. Conclusions: Non-affected relatives of CD patients may show a stronger immune response to glycan epitopes compared to healthy controls. The type of response appears to be distinct from the immune response of the affected CD patient. No difference between first compared to second degree relatives could be found. The presence of the antiglycan-antibodies in non-affected relatives of CD patients may represent the manifestation of a genetic susceptibility to CD. Therefore they might serve as an immunologic risk marker for CD and indicate a family member with an increased risk for developing CD in the future.

Su1914 Unique Antimicrobial and Genetic Profiles in African Americans With Crohn's Disease Suggest Underlying Mechanistic Differences

Background: Serum anti-glycan antibodies are a promising tool for differential diagnosis, disease stratification and prediction of Crohn's disease (CD). We assessed the presence of serum anti-glycan antibodies in affected and non-affected relatives of patients with CD and ulcerative colitis (UC). Methods: 393 non-inflammatory bowel disease (IBD)-affected relatives (330 CD and 63 UC relatives) of 169 IBD patients (140 CD and 29 UC patients) as well as 46 healthy controls were tested for the presence of anti-laminarin IgA (Anti-L), anti-chitin IgA (Anti-C), anti-chitobioside IgA (ACCA), anti-laminaribioside IgG (ALCA), anti-mannobioside IgG (AMCA) and anti-Saccaromyces cervisiae IgG (gASCA) carbohydrate antibodies by ELISA in a blinded fashion. Detailed clinical data of the IBD patients were available. Results:Non-affected relatives of CD patients had lower antibody levels for gASCA, ALCA, Anti-L and Anti-C and a lower quartile sum score (QSS), compared to the affected CD subjects (p<0.01). There was no difference in the levels of the antibodies when comparing first and second degree CD relatives. No similarity could be found for the pattern of positive markers in the affected CD patients compared to the non-affected relatives. In addition the ASCA status or a high versus low QSS of the affected CD patient did not influence the extent of the marker expression in the non-affected CD relative. While the QSS was similar, levels of and positivity for ACCA and AMCA were higher in the non-affected CD relatives compared to healthy controls (p<0.05). A higher proportion of healthy controls were negative for all anti-glycan antibodies compared to the non-affected IBD relatives (p<0.01). In the affected CD patients a positive family history for IBD was linked to higher levels of ACCA (p<0.03) and ALCA (p<0.04) with all other markers being unchanged. Non-affected UC relatives had lower levels of ALCA and Anti-L as well as a lower QSS compared to the affected UC patient. Conclusions: Non-affected relatives of CD patients may show a stronger immune response to glycan epitopes compared to healthy controls. The type of response appears to be distinct from the immune response of the affected CD patient. No difference between first compared to second degree relatives could be found. The presence of the antiglycan-antibodies in non-affected relatives of CD patients may represent the manifestation of a genetic susceptibility to CD. Therefore they might serve as an immunologic risk marker for CD and indicate a family member with an increased risk for developing CD in the future.

Surgical Outcome of Ileal Pouch—Anal Anastomosis When Used Intentionally for Well-Defined Crohnʼs Disease

Crohn's disease (CD) is considered a contraindication to ileal pouch--anal anastomosis (IPAA). In this study, we compare outcomes of CD and ulcerative colitis (UC) patients undergoing IPAA. Patients were considered to have CD before surgery based on a history of small bowel disease, perianal disease, noncrypt-associated granuloma, or pretreatment skip colonic lesions. Patients were prospectively assessed for pouchitis or CD. Postoperative CD (pouch inflammation into the afferent limb or pouch fistula) or pouch failure (need for permanent diversion) were assessed. Preoperative serum was assayed for IBD-associated antibodies using enzyme-linked immunosorbent assay (ELISA). Seventeen patients with preoperative CD were identified. Seven (41%) patients developed postoperative recurrent CD in the afferent limb (n = 3) or pouch fistulizing disease (n = 4). One patient (6%) required pouch excision. The incidence of postoperative CD was higher (P = 0.002) in preoperative CD patients (41%) than UC patients (11%). There was no significant difference in pouchitis or pouch failure. There was also no significant difference in any preoperative clinical feature between patients with or without postoperative CD. Afferent limb inflammation developed in three (50%) of the six patients with pANCA+/OmpC- expression compared to none of the 11 patients without this serologic profile (P = 0.03). Although the intentional use of IPAA in CD has a higher incidence of postoperative disease vs. UC patients, there was no significant difference in pouch failure. Demographics, clinical features, and serologic factors do not predict outcome of CD patients undergoing IPAA. IBD serology may identify the phenotype manifestation of postoperative recurrent CD.

Association of a Functional Variant in the Wnt Co-Receptor LRP6 with Early Onset Ileal Crohn's Disease

Ileal Crohn's Disease (CD), a chronic small intestinal inflammatory disorder, is characterized by reduced levels of the antimicrobial peptides DEFA5 (HD-5) and DEFA6 (HD-6). Both of these α-defensins are exclusively produced in Paneth cells (PCs) at small intestinal crypt bases. Different ileal CD–associated genes including NOD2, ATG16L1, and recently the β-catenin–dependant Wnt transcription factor TCF7L2 have been linked to impaired PC antimicrobial function. The Wnt pathway influences gut mucosal homeostasis and PC maturation, besides directly controlling HD-5/6 gene expression. The herein reported candidate gene study focuses on another crucial Wnt factor, the co-receptor low density lipoprotein receptor-related protein 6 (LRP6). We analysed exonic single nucleotide polymorphisms (SNPs) in a large cohort (Oxford: n = 1,893) and prospectively tested 2 additional European sample sets (Leuven: n = 688, Vienna: n = 1,628). We revealed an association of a non-synonymous SNP (rs2302685; Ile1062Val) with early onset ileal CD (OR 1.8; p = 0.00034; for homozygous carriers: OR 4.1; p = 0.00004) and additionally with penetrating ileal CD behaviour (OR 1.3; p = 0.00917). In contrast, it was not linked to adult onset ileal CD, colonic CD, or ulcerative colitis. Since the rare variant is known to impair LRP6 activity, we investigated its role in patient mucosa. Overall, LRP6 mRNA was diminished in patients independently from the genotype. Analysing the mRNA levels of PC product in biopsies from genotyped individuals (15 controls, 32 ileal, and 12 exclusively colonic CD), we found particularly low defensin levels in ileal CD patients who were carrying the variant. In addition, we confirmed a direct relationship between LRP6 activity and the transcriptional expression of HD-5 using transient transfection. Taken together, we identified LRP6 as a new candidate gene in ileal CD. Impairments in Wnt signalling and Paneth cell biology seem to represent pathophysiological hallmarks in small intestinal inflammation and should therefore be considered as interesting targets for new therapeutic approaches.