Inflammatory bowel disease and colitis: new concepts from the bench and the clinic.
ABSTRACT The previous 18 months have shown important progress in unravelling the causes of inflammatory bowel disease (IBD) and in improving its management for the patients.
More genome-wide association studies and meta-analyses of these have been published and have identified more than 100 confirmed genes for IBD, and highlighted a number of novel pathways. Two of the genes, NOD2/CARD15 and the autophagy gene ATG16L1 have recently been linked into one functional pathway of bacterial sensing, invasion and elimination. From the clinical side, the previous year has been dominated mainly by the results of the SONIC study, comparing efficacy and safety of azathioprine, infliximab and the combination of azathioprine and infliximab, in patients with active Crohn's disease, naive to these drugs. International consensus guidelines on infection prevention were released last year by the European Crohn's and Colitis Organisation.
The recent findings in IBD include the increasing number of IBD susceptibility genes, the demonstration that NOD2 and ATG16L1 are linked in one functional pathway and the role of IL-33/ST2 in colitis. From the bedside, the novelties have been the results of SONIC and selecting the right patient for intensified treatment with immunomodulators and anti-tumor necrosis factor, and appropriate counselling regarding risk of infections and vaccinations.
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ABSTRACT: 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.Digestive Diseases and Sciences 05/2013; · 2.26 Impact Factor
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ABSTRACT: Artemisinin has been used to treat malaria for centuries in the context of traditional Chinese medicine. In the present study, the effects of artemisinin on pregnane X receptor (PXR)-mediated CYP3A expression and its therapeutic role in inflammatory bowel disease were investigated. LS174T cells exposed to artemisinin at various concentrations and for different periods of time were examined with respect to the specific induction of CYP3A4 and PXR mRNA expression. Transient transfection experiments showed transcriptional activation of the CYP3A4 gene through artemisinin to be PXR-dependent. An electrophoretic-mobility shift assay (EMSA) showed that artemisinin activates the DNA-binding capacity of the PXR for the CYP3A4 element. These results indicate that the induction of CYP3A4 by artemisinin is mediated through the activation of PXR. Using animal models, it was demonstrated that artemisinin abrogates dextran sulfate sodium (DDS)-induced intestinal inflammation. Preadministration of artemisinin ameliorated the clinical hallmarks of colitis in DSS-treated mice as determined by body weight loss and assessment of diarrhea, rectal bleeding, colon length, and histology. Artemisinin was found to prevent or reduce the severity of colonic inflammation by inducing CYP3A expression by activation of PXR.European Journal of Pharmacology 05/2014; · 2.68 Impact Factor
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ABSTRACT: An inflammatory bowel disease (IBD) is most common in highly industrialized Western countries but uncommon in less developed areas of the world where helminths are frequent. The hygiene hypothesis proposes that the recent increase in allergic and autoimmune diseases is due to modern highly hygienic life styles and medical conditions. Loss of routine exposure to parasitic helminths, as a result of increasing lifestyle-associated factors, may be one factor leading to the increased disease prevalence. In animal models and clinical trials of IBD, gastrointestinal nematodes colonization suppresses intestinal inflammation through multiple mechanisms including induction of innate and adaptive regulatory circuits. Studies using helminths like Trichuris suis or Necator americanus showed that these helminths are safe and may be effective therapeutic approaches for the control of IBD and other immune diseases. The aim of present review was to exploring the therapeutic use of helminths for the control of IBD.Gastroenterol Hepatol Bed Bench. 01/2014; 7(1).