First-line therapies in inflammatory bowel disease

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

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

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

Pregnancy and breastfeeding in inflammatory bowel disease

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

Increased titers of anti-Saccharomyces cerevisiae antibodies in Crohn's disease patients with reduced H-ficolin levels but normal MASP-2 activity

Mannan-binding lectin (MBL) and ficolins are microbial pattern recognition molecules that activate the lectin pathway of complement. We previously reported the association of MBL deficiency with anti-Saccharomyces cerevisiae antibodies (ASCA) in patients with Crohn's disease (CD). However, ASCA are also frequently found in MBL-proficient CD patients. Here we addressed expression/function of ficolins and MBL-associated serine protease-2 (MASP-2) regarding potential association with ASCA.

Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

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.

Serological and DNA-based evaluation of Chlamydia pneumoniae infection in inflammatory bowel disease

OBJECTIVES: Chlamydia has been associated with autoimmune diseases, but a link between chlamydial infection and the aetiopathogenesis of inflammatory bowel disease (IBD) remains controversial. In this study we assessed the relationship between chlamydial infection and IBD, as evidenced by serological measurement and DNA analysis of mucosal biopsy specimens. PATIENTS AND METHODS: The sera of 78 patients with Crohn's disease (CD), 24 patients with ulcerative colitis (UC), 73 healthy family members, and 20 healthy controls were tested for anti-C. pneumoniae IgG titres. A subgroup consisting of 13 UC and 39 CD patients was screened for the presence of chlamydial DNA on 42 inflamed versus 30 non-inflamed biopsy specimens and for mutations of their NOD2/CARD15 gene. RESULTS: Anti-C. pneumoniae IgG antibodies were found in the sera of 32 (41%) patients with CD, 11 (46%) patients with UC, 35 (48%) of unaffected family members, and nine (45%) unrelated healthy controls. Thirty-five percent of the control, 18% CD and 24% UC biopsy specimens contained C. pneumoniae DNA. In CD, however, C. pneumoniae DNA was significantly more frequently found in inflamed (27%) versus non-inflamed (8%) biopsy specimens (P < 0.05, Fisher's exact test). The frequencies of NOD2/CARD15 mutations were 33% for CD patients with C. pneumoniae DNA compared to 47% for CD patients without C. pneumoniae DNA. CONCLUSION: We found no marked differences in respect to anti-C. pneumoniae serum IgG or C. pneumoniae DNA between healthy controls and patients with IBD. However, in CD patients, inflamed tissue specimens contained significantly more likely C. pneumoniae DNA compared with biopsies from unaffected areas. Thus C. pneumoniae is unlikely to be of pathogenic importance in IBD while it may still influence local clinical manifestations.

Severity of mucosal inflammation as a predictor for alterations of visceral sensory function in a rat model

Transient inflammation is known to alter visceral sensory function and frequently precede the onset of symptoms in a subgroup of patients with irritable bowel syndrome (IBS). Duration and severity of the initial inflammatory stimulus appear to be risk factors for the manifestation of symptoms. Therefore, we aimed to characterize dose-dependent effects of trinitrobenzenesulfonic acid (TNBS)/ethanol on: (1) colonic mucosa, (2) cytokine release and (3) visceral sensory function in a rat model. Acute inflammation was induced in male Lewis rats by single administration of various doses of TNBS/ethanol (total of 0.8, 0.4 or 0.2 ml) in test animals or saline in controls. Assessment of visceromotor response (VMR) to colorectal distensions, histological evaluation of severity of inflammation, and measurement of pro-inflammatory cytokine levels (IL-2, IL-6) using enzyme-linked immunosorbent assay (ELISA) were performed 2h and 3, 14, 28, 31 and 42 days after induction. Increased serum IL-2 and IL-6 levels were evident prior to mucosal lesions 2h after induction of colitis and persist up to 14 days (p<0.05 vs. saline), although no histological signs of inflammation were detected at 14 days. In the acute phase, VMR was only significantly increased after 0.8 ml and 0.4 ml TNBS/ethanol (p<0.05 vs. saline). After 28 days, distension-evoked responses were persistently elevated (p<0.05 vs. saline) in 0.8 and 0.4 ml TNBS/ethanol-treated rats. In 0.2 ml TNBS/ethanol group, VMR was only enhanced after repeated visceral stimulation. Visceral hyperalgesia occurs after a transient colitis. However, even a mild acute but asymptomatic colitis can induce long-lasting visceral hyperalgesia in the presence of additional stimuli.

Infliximab - Recommendations practiques pour le traitment de la maladie de Crohn

Infliximab is a monoclonal chimeric antibody, with high affinity and specificity for tumour necrosis factor alpha (TNFalpha) that plays a central role in the pathogenesis of immune mediated inflammatory disorders including Crohn's disease and ulcerative colitis. Globally over 600000 patients have been treated with infliximab to date. This global experience led to a better definition of the overall safety and efficacy profile of this medication. The goal of the present recommendations is to provide practical information to physicians involved in the care of patients with inflammatory bowel disease.

Role of the NFKB1 -94ins/delATTG promoter polymorphism in IBD and potential interactions with polymorphisms in the CARD15/NOD2, IKBL, and IL-1RN genes

BACKGROUND: Recently, an association of the NFKB1 polymorphism -94ins/delATTG with ulcerative colitis (UC) has been reported. This 4-bp insertion/deletion polymorphism is localized in the promoter region of the NFKB1 gene and appears to be functionally relevant. The aim of the present study was to confirm the association of the -94ins/delATTG (W/D) NFKB1 promoter polymorphism with UC in a population of German origin and to test for a potential association with Crohn's disease (CD). Furthermore, potential interactions of the -94ins/delATTG polymorphism with the IKBL and the IL-1RN genes should be determined. MATERIALS AND METHODS: The study population comprised 630 patients with CD, 365 patients with UC, and 974 healthy controls. Genotyping was performed using polymerase chain reaction and restriction fragment length polymorphism analysis. For statistical evaluation, the chi-square test and the Fisher exact test were used. RESULTS: No significant association of the W/D NFKB1 polymorphism with CD or UC was detected. In addition, no significant interactions between the -94ins/delATTG NFKB1 polymorphism and polymorphisms within the IKBL and the IL-1RN genes, respectively, were found in CD or UC. Also, no significant interactions of the NFKB1 polymorphism with mutations of the CARD15/NOD2 gene and with clinical phenotypes were detected in CD. Moreover, no associations of the NFKB1 polymorphism were found in UC depending on disease localization. CONCLUSIONS: The present study could not confirm the reported association of the -94ins/delATTG NFKB1 polymorphism with UC and also found no evidence for a role of this polymorphism in CD. The results do not give evidence for a role of this NFKB1 polymorphism in the pathogenesis of UC and CD.

Mycobacterium avium subspecies paratuberculosis and Crohn's disease: a systematic review and meta-analysis

This systematic review assesses the evidence for an association between Mycobacterium avium subspecies paratuberculosis (MAP) and Crohn's disease. We analysed 28 case-control studies comparing MAP in patients with Crohn's disease with individuals free of inflammatory bowel disease (IBD) or patients with ulcerative colitis. Compared with individuals free of IBD, the pooled odds ratio (OR) from studies using PCR in tissue samples was 7.01 (95% CI 3.95-12.4) and was 1.72 (1.02-2.90) in studies using ELISA in serum. ORs were similar for comparisons with ulcerative colitis patients (PCR, 4.13 [1.57-10.9]; ELISA, 1.88 [1.26-2.81]). The association of MAP with Crohn's disease seems to be specific, but its role in the aetiology of Crohn's disease remains to be defined.

LRH-1-mediated glucocorticoid synthesis in enterocytes protects against inflammatory bowel disease

Liver receptor homolog-1 (LRH-1) is a nuclear receptor involved in intestinal lipid homeostasis and cell proliferation. Here we show that haploinsufficiency of LRH-1 predisposes mice to the development of intestinal inflammation. Besides the increased inflammatory response, LRH-1 heterozygous mice exposed to 2,4,6-trinitrobenzene sulfonic acid show lower local corticosterone production as a result of an impaired intestinal expression of the enzymes CYP11A1 and CYP11B1, which control the local synthesis of corticosterone in the intestine. Local glucocorticoid production is strictly enterocyte-dependent because it is robustly reduced in epithelium-specific LRH-1-deficient mice. Consistent with these findings, colon biopsies of patients with Crohn's disease and ulcerative colitis show reduced expression of LRH-1 and genes involved in the production of glucocorticoids. Hence, LRH-1 regulates intestinal immunity in response to immunological stress by triggering local glucocorticoid production. These findings underscore the importance of LRH-1 in the control of intestinal inflammation and the pathogenesis of inflammatory bowel disease.