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.
- SourceAvailable from: Donghua Hu
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- "etiology of IBD is unclear, the prevailing view is that it is triggered by multiple factors, including the environment, genetic variations, intestinal microbiota, and disturbances in the innate and adaptive immune responses (Vermeire et al., 2011). "
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; 738. DOI:10.1016/j.ejphar.2014.04.050 · 2.53 Impact Factor
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- "In addition to various environmental factors it is clear that genetic factors also influence susceptibility to IBD. Recent genetic based studies have identified greater than 100 genetic loci as being associated with the development of IBD , , . Of the numerous genes implicated by these studies, many are known to be integrally involved in various aspects of the immune response including, pathogen recognition, cytokine/growth factor signalling, intestinal epithelial barrier function and defense, and lymphocyte activation, among others. "
ABSTRACT: Recent genetic-based studies have implicated a number of immune-related genes in the pathogenesis of inflammatory bowel disease (IBD). Our recent genetic studies showed that RAC2 is associated with human IBD; however, its role in disease pathogenesis is unclear. Given Rac2's importance in various fundamental immune cell processes, we investigated whether a defect in Rac2 may impair host immune responses in the intestine and promote disease in the context of an infection-based (Citrobacter rodentium) model of colitis. In response to infection, Rac2(-/-) mice showed i) worsened clinical symptoms (days 13-18), ii) increased crypt hyperplasia at days 11 and 22 (a time when crypt hyperplasia was largely resolved in wild-type mice; WT), and iii) marked mononuclear cell infiltration characterized by higher numbers of T (CD3(+)) cells (day 22), compared to WT-infected mice. Moreover, splenocytes harvested from infected Rac2(-/-) mice and stimulated in vitro with C. rodentium lysate produced considerably higher levels of interferon-γ and interleukin-17A. The augmented responses observed in Rac2(-/-) mice did not appear to stem from Rac2's role in NADPH oxidase-driven reactive oxygen species production as no differences in crypt hyperplasia, nor inflammation, were observed in infected NOX2(-/-) mice compared to WT. Collectively, our findings demonstrate that Rac2(-/-) mice develop more severe disease when subjected to a C. rodentium-induced model of infectious colitis, and suggest that impaired Rac2 function may promote the development of IBD in humans.PLoS ONE 04/2013; 8(4):e61629. DOI:10.1371/journal.pone.0061629 · 3.23 Impact Factor
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- "For lack of a thorough understanding of the causes of IBD, the condition is categorised as either ulcerative colitis (UC) or Crohn's disease based on the location and duration of the inflammation, the microscopic pathology and the lack of identifiable inciting factors such as infection with enteric pathogens. Variations in more than 160 distinct genes can either increase or decrease the risk of acquiring either UC or Crohn's disease (Van et al., 2011; Vermeire et al., 2011). Many of these genes influence innate immunity, intestinal epithelial cell barrier function, bacterial clearance, immune regulation and effector cytokine pathways such as Th17/IL23/Stat3. "
ABSTRACT: Modern hygienic lifestyles are associated with the emergence of inflammatory bowel disease (IBD) which now afflicts millions of people in highly-developed countries. Meticulous hygiene interrupts conduits of transmission required for ubiquitous exposure to parasitic worms (helminths). We proposed that loss of exposure to helminths permits development of IBD. Early clinical trials suggested that exposure to helminths such as Trichuris suis or Necator americanus can improve IBD. Over the last several years, processes to "medicinalize"T. suis have been developed and use of this helminth is now being studied in large multi-center clinical trials. Concurrently, we and others have identified some of the immune regulatory mechanisms elicited by helminth exposure that suppress inappropriate intestinal inflammation. These efforts could soon result in new therapies for patients with IBD.International journal for parasitology 11/2012; 43(3-4). DOI:10.1016/j.ijpara.2012.10.016 · 3.87 Impact Factor