Genetic association and functional role of Crohn disease risk alleles involved in microbial sensing, autophagy, and endoplasmic reticulum (ER) stress.
; ; et al
in Autophagy (2013), 9(12), 2046-55
Genome-wide association studies have identified several genes implicated in autophagy (ATG16L1, IRGM, ULK1, LRRK2, and MTMR3), intracellular bacterial sensing (NOD2), and endoplasmic reticulum (ER) stress ... [more ▼]
Genome-wide association studies have identified several genes implicated in autophagy (ATG16L1, IRGM, ULK1, LRRK2, and MTMR3), intracellular bacterial sensing (NOD2), and endoplasmic reticulum (ER) stress (XBP1 and ORMDL3) to be associated with Crohn disease (CD). We studied the known CD-associated variants in these genes in a large cohort of 3451 individuals (1744 CD patients, 793 ulcerative colitis (UC) patients and 914 healthy controls). We also investigated the functional phenotype linked to these genetic variants. Association with CD was confirmed for NOD2, ATG16L1, IRGM, MTMR3, and ORMDL3. The risk for developing CD increased with an increasing number of risk alleles for these genes (P<0.001, OR 1.26 [1.20 to 1.32]). Three times as many (34.8%) CD patients carried a risk allele in all three pathways, in contrast to 13.3% of the controls (P<0.0001, OR = 3.46 [2.77 to 4.32]). For UC, no significant association for one single nucleotide polymorphism (SNP) was found, but the risk for development of UC increased with an increasing total number of risk alleles (P = 0.001, OR = 1.10 [1.04 to 1.17]). We found a genetic interaction between reference SNP (rs)2241880 (ATG16L1) and rs10065172 (IRGM) in CD. Functional experiments hinted toward an association between an increased genetic risk and an augmented inflammatory status, highlighting the relevance of the genetic findings. [less ▲]Detailed reference viewed: 20 (1 ULg)
Unique gene expression and MR T2 relaxometry patterns define chronic murine dextran sodium sulphate colitis as a model for connective tissue changes in human Crohn's disease.
; ; et al
in PloS one (2013), 8(7), 68876
INTRODUCTION: Chronically relapsing inflammation, tissue remodeling and fibrosis are hallmarks of inflammatory bowel diseases. The aim of this study was to investigate changes in connective tissue in a ... [more ▼]
INTRODUCTION: Chronically relapsing inflammation, tissue remodeling and fibrosis are hallmarks of inflammatory bowel diseases. The aim of this study was to investigate changes in connective tissue in a chronic murine model resulting from repeated cycles of dextran sodium sulphate (DSS) ingestion, to mimic the relapsing nature of the human disease. MATERIALS AND METHODS: C57BL/6 mice were exposed to DSS in drinking water for 1 week, followed by a recovery phase of 2 weeks. This cycle of exposure was repeated for up to 3 times (9 weeks in total). Colonic inflammation, fibrosis, extracellular matrix proteins and colonic gene expression were studied. In vivo MRI T 2 relaxometry was studied as a potential non-invasive imaging tool to evaluate bowel wall inflammation and fibrosis. RESULTS: Repeated cycles of DSS resulted in a relapsing and remitting disease course, which induced a chronic segmental, transmural colitis after 2 and 3 cycles of DSS with clear induction of fibrosis and remodeling of the muscular layer. Tenascin expression mirrored its expression in Crohn's colitis. Microarray data identified a gene expression profile different in chronic colitis from that in acute colitis. Additional recovery was associated with upregulation of unique genes, in particular keratins, pointing to activation of molecular pathways for healing and repair. In vivo MRI T2 relaxometry of the colon showed a clear shift towards higher T2 values in the acute stage and a gradual regression of T2 values with increasing cycles of DSS. CONCLUSIONS: Repeated cycles of DSS exposure induce fibrosis and connective tissue changes with typical features, as occurring in Crohn's disease. Colonic gene expression analysis revealed unique expression profiles in chronic colitis compared to acute colitis and after additional recovery, pointing to potential new targets to intervene with the induction of fibrosis. In vivo T2 relaxometry is a promising non-invasive assessment of inflammation and fibrosis. [less ▲]Detailed reference viewed: 8 (1 ULg)
Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease.
; ; et al
in Gut (2013)
OBJECTIVE: Altered microbiota composition, changes in immune responses and impaired intestinal barrier functions are observed in IBD. Most of these features are controlled by proteases and their ... [more ▼]
OBJECTIVE: Altered microbiota composition, changes in immune responses and impaired intestinal barrier functions are observed in IBD. Most of these features are controlled by proteases and their inhibitors to maintain gut homeostasis. Unrestrained or excessive proteolysis can lead to pathological gastrointestinal conditions. The aim was to validate the identified protease IBD candidates from a previously performed systematic review through a genetic association study and functional follow-up. DESIGN: We performed a genetic association study in a large multicentre cohort of patients with Crohn's disease (CD) and UC from five European IBD referral centres in a total of 2320 CD patients, 2112 UC patients and 1796 healthy controls. Subsequently, we did an extensive functional assessment of the candidate genes to explore their causality in IBD pathogenesis. RESULTS: Ten single nucleotide polymorphisms (SNPs) in four genes were significantly associated with CD: CYLD, USP40, APEH and USP3. CYLD was the most significant gene with the intronically located rs12324931 the strongest associated SNP (pFDR=1.74e-17, OR=2.24 (1.83 to 2.74)). Five SNPs in four genes were significantly associated with UC: USP40, APEH, DAG1 and USP3. CYLD, as well as some of the other associated genes, is part of the ubiquitin proteasome system (UPS). We therefore determined if the IBD-associated adherent-invasive Escherichia coli (AIEC) can modulate the UPS functioning. Infection of intestinal epithelial cells with the AIEC LF82 reference strain modulated the UPS turnover by reducing poly-ubiquitin conjugate accumulation, increasing 26S proteasome activities and decreasing protein levels of the NF-kappaB regulator CYLD. This resulted in IkappaB-alpha degradation and NF-kappaB activation. This activity was very important for the pathogenicity of AIEC since decreased CYLD resulted in increased ability of AIEC LF82 to replicate intracellularly. CONCLUSIONS: Our results reveal the UPS, and CYLD specifically, as an important contributor to IBD pathogenesis, which is favoured by both genetic and microbial factors. [less ▲]Detailed reference viewed: 14 (1 ULg)
Serum adalimumab concentration and clinical remission in patients with Crohn's disease.
; ; et al
in Inflammatory bowel diseases (2013), 19(6), 1112-22
BACKGROUND: Drug concentration monitoring may be useful to guide therapeutic adjustments for anti-tumor necrosis factor agents in Crohn's disease. The relationship between serum adalimumab concentrations ... [more ▼]
BACKGROUND: Drug concentration monitoring may be useful to guide therapeutic adjustments for anti-tumor necrosis factor agents in Crohn's disease. The relationship between serum adalimumab concentrations and clinical outcomes was assessed using data from CLinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn's Disease (CLASSIC) I/II. METHODS: Serum adalimumab concentrations at week 4 of CLASSIC I and weeks 4, 24, and 56 of CLASSIC II were compared by clinical remission status (yes/no). Logistic regression and Classification and Regression Tree analyses explored factors associated with remission at weeks 4, 24, and 56. Threshold analyses and receiver operating characteristic curves evaluated the relationship between serum concentrations and clinical remission/response. RESULTS: Serum adalimumab concentrations for 275 patients were available. Median adalimumab concentrations were significantly higher in patients who achieved clinical remission than those who did not at week 4 of CLASSIC I (8.10 versus 5.05 microg/mL, P < 0.05). At all time points, adalimumab concentrations demonstrated considerable variability and overlap between patients with and without remission. With Classification and Regression Tree analyses, baseline Crohn's Disease Activity Index, baseline C-reactive protein, and adalimumab concentrations were associated with early remission at week 4 of CLASSIC I and week 4 of CLASSIC II, but not at weeks 24 and 56. Receiver operating characteristic curves demonstrated low utility of cutoff thresholds to discriminate by clinical response/remission status. CONCLUSIONS: A positive association between serum adalimumab concentration and remission was identified at several time points. A threshold concentration reliably associated with remission was not identified. Further prospective evaluations are needed before recommendations for adalimumab concentration monitoring can be made. [less ▲]Detailed reference viewed: 9 (1 ULg)
Effects of infliximab therapy on transmural lesions as assessed by magnetic resonance enteroclysis in patients with ileal Crohn's disease.
; ; Louis, Edouard et al
in Journal of Crohn's & colitis (2013), 7(12), 950-7
BACKGROUND AND AIMS: Anti TNF therapy induces mucosal healing in patients with Crohn's disease, but the effects on transmural inflammation in the ileum are not well understood. Magnetic resonance ... [more ▼]
BACKGROUND AND AIMS: Anti TNF therapy induces mucosal healing in patients with Crohn's disease, but the effects on transmural inflammation in the ileum are not well understood. Magnetic resonance-enteroclysis (MRE) offers excellent imaging of transmural and peri-enteric lesions in Crohn's ileitis and we aimed to study its responsiveness to anti TNF therapy. METHODS: In this multi-center prospective trial, anti TNF naive patients with ileal Crohn's disease and with increased CRP and contrast enhanced wall thickening received infliximab 5 mg/kg at weeks 0, 2 and 6, and q8 weeks maintenance MRE was performed at baseline, 2 weeks and 6 months and assessed based on a predefined MRE score of severity in ileal Crohn's Disease. RESULTS: Twenty patients were included; of those, 18 patients underwent MRE at week 2 and 15 patients at weeks 2 and 26 as scheduled. Inflammatory components of the MRE index decreased by >/=2 points and by >/=50% at week 26 (primary endpoint) in 40% and 32% of patients (per protocol and intention to treat analysis, respectively). The MRE index improved in 44% at week 2 and in 80% at week 26. Complete absence of inflammatory lesions was observed in 0/18 at week 2 and 13% (2/15) at week 26. The obstructive elements did not change. Clinical and CRP improvement occurred as early as wk 2, but only CDAI correlated with the MRE index. CONCLUSION: Improvement of MRE occurs from 2 weeks after infliximab therapy onwards and correlates with clinical response but normalization of MRE is rare. [less ▲]Detailed reference viewed: 6 (1 ULg)
Prognostic Value of Serologic and Histologic Markers on Clinical Relapse in Ulcerative Colitis Patients With Mucosal Healing
; ; et al
in American Journal of Gastroenterology (2012), 11(107), 1684-92Detailed reference viewed: 38 (4 ULg)
Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.
; ; et al
in Nature (2012), 491(7422), 119-24
Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome ... [more ▼]
Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD. [less ▲]Detailed reference viewed: 48 (20 ULg)
Management of inflammatory bowel disease in pregnancy.
; ; et al
in Journal of Crohn’s and Colitis [=JCC] (2012), 6(8), 811-23
BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a chronic disease affecting mainly young people in their reproductive years. IBD therefore has a major impact on patients' family planning ... [more ▼]
BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a chronic disease affecting mainly young people in their reproductive years. IBD therefore has a major impact on patients' family planning decisions. Management of IBD in pregnancy requires a challenging balance between optimal disease control and drug safety considerations. This article aims to provide a framework for clinical decision making in IBD based on review of the literature on pregnancy-related topics. METHODS: Medline searches with search terms 'IBD', 'Crohn's disease' or 'ulcerative colitis' in combination with keywords for the topics fertility, pregnancy, congenital abnormalities and drugs names of drugs used for treatment of IBD. RESULTS: IBD patients have normal fertility, except for women after ileal pouch-anal anastomosis (IPAA) and men under sulfasalazine treatment. Achieving and maintaining disease remission is a key factor for successful pregnancy outcomes in this population, as active disease at conception carries an increased risk of preterm delivery and low birth weight. Clinicians should discuss the need for drug therapy to maintain remission with their patients in order to ensure therapy compliance. Most IBD drugs are compatible with pregnancy, except for methotrexate and thalidomide. If possible, anti-TNF therapy should be stopped by the end of the second trimester and the choice of delivery route should be discussed with the patient. CONCLUSIONS: Disease control prior to conception and throughout pregnancy is the cornerstone of successful pregnancy management in IBD patients. [less ▲]Detailed reference viewed: 36 (4 ULg)
Rheumatoid arthritis and pregnancy: evolution of disease activity and pathophysiological considerations for drug use
; ; Geenen, Vincent et al
in Rheumatology (2011)
It has long been known that pregnancy and childbirth have a profound effect on the disease activity of rheumatic diseases. For clinicians, the management of patients with RA wishing to become pregnant ... [more ▼]
It has long been known that pregnancy and childbirth have a profound effect on the disease activity of rheumatic diseases. For clinicians, the management of patients with RA wishing to become pregnant involves the challenge of keeping disease activity under control and adequately adapting drug therapy during pregnancy and post-partum. This article aims to summarize the current evidence on the evolution of RA disease activity during and after pregnancy and the use of anti-rheumatic drugs around this period. Of recent interest is the potential use of anti-TNF compounds in the preconception period and during pregnancy. Accumulating experience with anti-TNF therapy in other immune-mediated inflammatory diseases, such as Crohn’s disease, provides useful insights for the use of TNF blockade in pregnant women with RA, or RA patients wishing to become pregnant. [less ▲]Detailed reference viewed: 55 (3 ULg)
Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.
; ; et al
in Nature Genetics (2011), 43(3), 246-52
Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association ... [more ▼]
Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 x 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. [less ▲]Detailed reference viewed: 19 (5 ULg)
Mucosal gene expression of cell adhesion molecules, chemokines, and chemokine receptors in patients with inflammatory bowel disease before and after infliximab treatment.
; ; et al
in Acta Gastro-Enterologica Belgica (2011), 106(4), 748-61
OBJECTIVES: Inflammatory bowel disease (IBD) is characterized by a continuous influx of leukocytes into the gut wall. This migration is regulated by cell adhesion molecules (CAMs), and selective ... [more ▼]
OBJECTIVES: Inflammatory bowel disease (IBD) is characterized by a continuous influx of leukocytes into the gut wall. This migration is regulated by cell adhesion molecules (CAMs), and selective antimigration therapies have been developed. This study investigated the effect of infliximab therapy on the mucosal gene expression of CAMs in IBD. METHODS: Mucosal gene expression of 69 leukocyte/endothelial CAMs and E-cadherin was investigated in 61 IBD patients before and after first infliximab infusion and in 12 normal controls, using Affymetrix gene expression microarrays. Quantitative reverse transcriptase-PCR (qRT-PCR), immunohistochemistry, and western blotting were used to confirm the microarray data. RESULTS: When compared with control colons, the colonic mucosal gene expression of most leukocyte/endothelial adhesion molecules was upregulated and E-cadherin gene expression was downregulated in active colonic IBD (IBDc) before therapy, with no significant colonic gene expression differences between ulcerative colitis and colonic Crohn's disease. Infliximab therapy restored the upregulations of leukocyte CAMs in IBDc responders to infliximab that paralleled the disappearance of the inflammatory cells from the colonic lamina propria. Also, the colonic gene expression of endothelial CAMs and of most chemokines/chemokine receptors returned to normal after therapy in IBDc responders, and only CCL20 and CXCL1-2 expression remained increased after therapy in IBDc responders vs. control colons. When compared with control ileums, the ileal gene expression of MADCAM1, THY1, PECAM1, CCL28, CXCL1, -2, -5, -6, and -11, and IL8 was increased and CD58 expression was decreased in active ileal Crohn's disease (CDi) before therapy, and none of the genes remained dysregulated after therapy in CDi responders vs. control ileums. This microarray study identified a number of interesting targets for antiadhesion therapy including PECAM1, IL8, and CCL20, besides the currently studied alpha4beta7 integrin-MADCAM1 axis. CONCLUSIONS: Our data demonstrate that many leukocyte/endothelial CAMs and chemokines/chemokine receptors are upregulated in inflamed IBD mucosa. Controlling the inflammation with infliximab restores most of these dysregulations in IBD. These results show that at least part of the mechanism of anti-tumor necrosis factor-alpha therapy goes through downregulation of certain adhesion molecules. [less ▲]Detailed reference viewed: 36 (10 ULg)
Mucosal gene expression of cell adhesion molecules, chemokines, and chemokine receptors in patients with inflammatory bowel disease before and after infliximab treatment.
; ; et al
in American Journal of Gastroenterology (2011)Detailed reference viewed: 21 (9 ULg)
Genetic variation in the autophagy gene ULK1 and risk of Crohn's disease
; ; et al
in Inflammatory Bowel Diseases (2011), 17(6), 1392-1397Detailed reference viewed: 23 (5 ULg)
Outcome of pregnancy in women with inflammatory bowel disease treated with antitumor necrosis factor therapy.
Schnitzler, François ; ; Boukerroucha, Meriem et al
in Inflammatory Bowel Diseases (2011), 17(9), 1846-1854
BACKGROUND:: Infliximab (IFX) and adalimumab (ADA) are attractive treatment options in patients with inflammatory bowel disease (IBD) also during pregnancy but there is still limited data on the benefit ... [more ▼]
BACKGROUND:: Infliximab (IFX) and adalimumab (ADA) are attractive treatment options in patients with inflammatory bowel disease (IBD) also during pregnancy but there is still limited data on the benefit/risk profile of IFX and ADA during pregnancy. METHODS:: This observational study assessed pregnancy outcomes in 212 women with IBD under antitumor necrosis factor alpha (TNF) treatment at our IBD unit. Pregnancy outcomes in 42 pregnancies with direct exposure to anti-TNF treatment (35 IFX, 7 ADA) were compared with that in 23 pregnancies prior to IBD diagnosis, 78 pregnancies before start of IFX, 53 pregnancies with indirect exposure to IFX, and 56 matched pregnancies in healthy women. RESULTS:: Thirty-two of the 42 pregnancies ended in live births with a median gestational age of 38 weeks (interquartile range [IQR] 37-39). There were seven premature deliveries, six children had low birth weight, and there was one stillbirth. One boy weighed 1640 g delivered at week 33, died at age of 13 days because of necrotizing enterocolitis. A total of eight abortions (one patient wish) occurred in seven women. Trisomy 18 was diagnosed in one fetus of a mother with CD at age 37 under ADA treatment (40 mg weekly) and pregnancy was terminated. Pregnancy outcomes after direct exposure to anti-TNF treatment were not different from those in pregnancies before anti-TNF treatment or with indirect exposure to anti-TNF treatment but outcomes were worse than in pregnancies before IBD diagnosis. CONCLUSIONS:: Direct exposure to anti-TNF treatment during pregnancy was not related to a higher incidence of adverse pregnancy outcomes than IBD overall. (Inflamm Bowel Dis 2011;). [less ▲]Detailed reference viewed: 56 (24 ULg)
Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease.
Momozawa, Yukihide ; Mni, Myriam ; Nakamura, Kayo et al
in Nature Genetics (2011), 43(1), 43-7
Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most approximately 20 ... [more ▼]
Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most approximately 20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability, including rare risk variants not adequately tagged thus far in GWAS. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer, plasma high-density lipoprotein cholesterol levels, blood pressure, type 1 diabetes, hypertriglyceridemia and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease. [less ▲]Detailed reference viewed: 79 (31 ULg)
Tolerability of shortened infliximab infusion times in patients with inflammatory bowel diseases: a single-center cohort study.
; ; et al
in American Journal of Gastroenterology (2011), 106(4), 778-85
OBJECTIVES: Scheduled maintenance therapy with infliximab decreases the risk of infusion reactions. Many centers have accelerated infusion times to 1 h in selected patients who tolerate 5 mg/kg infliximab ... [more ▼]
OBJECTIVES: Scheduled maintenance therapy with infliximab decreases the risk of infusion reactions. Many centers have accelerated infusion times to 1 h in selected patients who tolerate 5 mg/kg infliximab infusions. The aim of this study was to compare the tolerability of 1-h and 2-h infliximab infusions in patients with inflammatory bowel disease (IBD) in a large single-center cohort. The primary end point was the incidence of infusion reactions in both groups. METHODS: A retrospective chart analysis of all IBD patients treated with infliximab was performed. Infusions in scheduled maintenance for at least 6 months from December 1994 until March 2009 were included. All patients were treated at the infusion unit or during hospitalization under standard operating procedures. Infusion parameters were prospectively recorded. From 2004, in patients tolerating at least four 2-h infusions, infusions were given over 1 h. RESULTS: As of March 2009, 953 patients with IBD (77.6% Crohn's disease, 22.4% ulcerative colitis) had been treated with infliximab. A total of 474 patients met the criteria of scheduled maintenance therapy. In total, 9,155 maintenance infusions were administered (4,307 over 1 h). No severe infusion reactions were documented. Mild acute reactions occurred in 0.6% (27/4,307) of the 1-h-infusion group and in 1.7% (80/4848) of the 2-h infusion group (P=0.0034). Delayed infusion reactions occurred in 0.2% of 1-h and 0.5% of 2-h infusion group patients (P=0.277). Loss of tolerability due to infusion reactions (1-h group 2.9% versus 2-h group 4.1%) was evenly distributed (P=0.34). None of the prespecified variables were predictive of infusion reactions in a multivariate analysis. CONCLUSIONS: In patients with IBD tolerating 2-h infusions of infliximab scheduled maintenance therapy, the infusion time can be shortened to 1 h with good tolerability. No severe reactions were observed and no predictors of infusion reactions were identified. [less ▲]Detailed reference viewed: 25 (9 ULg)
High-throughput method for comparative analysis of denaturing gradient gel electrophoresis profiles from human fecal samples reveals significant increases in two bifidobacterial species after inulin-type prebiotic intake.
; ; Van Steen, Kristel et al
in FEMS Microbiology Ecology (2011), 75(2), 343-9
Denaturing gradient gel electrophoresis (DGGE) is one of the most commonly used molecular tools to study complex microbial communities. Despite its widespread use, meaningful interpretative analysis ... [more ▼]
Denaturing gradient gel electrophoresis (DGGE) is one of the most commonly used molecular tools to study complex microbial communities. Despite its widespread use, meaningful interpretative analysis remains a major drawback of this method. We evaluated the combination of computer-assisted band-matching with nonparametric statistics for comparative analysis of DGGE banding patterns. Fecal samples from 17 healthy volunteers who consumed 20 g of the prebiotic compound oligofructose-enriched inulin (OF-IN) for 4 weeks were analyzed before and after treatment. DGGE fingerprinting profiles were analyzed using bionumerics software version 4.6., which resulted in a data matrix that was used for statistical analysis. When comparing DGGE profiles before and after OF-IN intake with a Wilcoxon nonparametric test for paired data, two band-classes increased significantly after OF-IN intake (P<0.003 and <0.02). These two band-classes could be assigned to the species Bifidobacterium longum and Bifidobacterium adolescentis by band-sequencing analysis, and their significant increase was quantitatively confirmed with real-time PCR using species-specific primers (respectively P<0.012 and <0.010). Therefore, the nonparametric analysis of a data matrix obtained by computer-assisted band-matching of complex profiles facilitated the interpretative analysis of these profiles and provided an objective and high-throughput method for the detection of significant taxonomic differences in larger numbers of complex profiles. [less ▲]Detailed reference viewed: 37 (5 ULg)
Levels of C-reactive protein are associated with response to infliximab therapy in patients with Crohn's disease.
; Mahachie John, Jestinah ; et al
in Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of The American Gastroenterological Association (2011), 9(5), 421-71
BACKGROUND & AIMS: Infliximab is an antibody against tumor necrosis factor-alpha that is used to treat patients with moderate to severe Crohn's disease (CD). C-reactive protein (CRP) is a marker used to ... [more ▼]
BACKGROUND & AIMS: Infliximab is an antibody against tumor necrosis factor-alpha that is used to treat patients with moderate to severe Crohn's disease (CD). C-reactive protein (CRP) is a marker used to identify and follow individuals with CD. We analyzed changes in levels of CRP in a large cohort of patients with CD undergoing treatment with infliximab. METHODS: Serial levels of CRP were analyzed in 718 CD patients. Blood was collected before each infusion; a total of 8845 CRP levels were available for analysis. The correlations between CRP levels and need for dose adjustment, outcomes, and mucosal healing (based on endoscopic analysis of 253 patients) were evaluated. Therapy adjustment was considered successful if therapy continued without need for change. Subgroup analysis was performed by using data from 268 patients who received 8 weeks of maintenance therapy. RESULTS: More patients with high baseline levels of CRP responded to infliximab than patients with normal levels (90.8% vs 82.6%; P = .014). Early normalization of CRP levels correlated with sustained long-term response (P < .001). CRP levels remained significantly higher among patients who lost their response to infliximab, compared with those with a sustained response (P = .001). At time of loss of response, CRP levels were significantly increased (median, 11.2 mg/L) and did not return to baseline levels (median, 18.2 mg/L; P = .039). CRP correlated with mucosal healing (P = .033). CONCLUSIONS: CRP is a good marker of disease activity in patients treated with infliximab. Increased levels of CRP indicate mucosal inflammation and a likelihood of clinical relapse. [less ▲]Detailed reference viewed: 21 (3 ULg)
Identification of a novel autoantigen in inflammatory bowel disease by protein microarray.
; ; et al
in Inflammatory Bowel Diseases (2011), 17(6), 1291-300
BACKGROUND: Patients with inflammatory bowel disease (IBD) display immunoreactivity to self-antigens and microbial antigens. We used a protein microarray approach to identify novel autoantigens in IBD ... [more ▼]
BACKGROUND: Patients with inflammatory bowel disease (IBD) display immunoreactivity to self-antigens and microbial antigens. We used a protein microarray approach to identify novel autoantigens in IBD. METHODS: ProtoArray Human Protein Microarray v4.0 containing 8268 human proteins from Invitrogen (La Jolla, CA) was used. RESULTS: Twenty-five IBD patients and five healthy controls were screened for candidate autoantigens. For 256 antigens, IBD patients had a higher seroreactivity than controls. Twenty antigens were selected for further evaluation in a larger cohort (60 ulcerative colitis [UC] patients, 60 Crohn's disease [CD] patients, 60 healthy controls, and 60 gastrointestinal-diseased controls) by means of a customized protein microarray. Out of these 20 antigens, one antigen, family with sequence similarity 84 member A (FAM84A), was identified as a target antigen in IBD. Antibodies to FAM84A were significantly more prevalent in IBD patients (19%) than in gastrointestinal-diseased controls (1.7%) (P = 0.0008) and healthy controls (5%) (P = 0.01). Anti-FAM84A antibodies were found in 26.6% of UC patients and in 11.7% of CD patients. FAM84A was confirmed as target antigen in IBD by means of Western blotting in a large independent cohort (100 UC patients, 106 CD patients, 102 healthy controls, and 100 gastrointestinal-diseased controls). Antibodies to FAM84A were significantly more prevalent in IBD patients (20%) than in gastrointestinal-diseased controls (5%) (P = 0.0004) and healthy controls (0%) (P < 0.0001). Anti-FAM84A antibodies were found in 18% of UC patients and in 22% of CD patients. CONCLUSIONS: We identified FAM84A as a novel autoantigen in IBD. (Inflamm Bowel Dis 2011;). [less ▲]Detailed reference viewed: 16 (3 ULg)
Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci.
; ; et al
in Nature Genetics (2010), 42(12), 1118-25
We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in ... [more ▼]
We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 x 10). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease. [less ▲]Detailed reference viewed: 67 (9 ULg)