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: 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
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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
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ABSTRACT: It is established that chronic spirochetal infection can cause slowly progressive dementia, brain atrophy and amyloid deposition in late neurosyphilis. Recently it has been suggested that various types of spirochetes, in an analogous way to Treponema pallidum, could cause dementia and may be involved in the pathogenesis of Alzheimer's disease (AD). Here, we review all data available in the literature on the detection of spirochetes in AD and critically analyze the association and causal relationship between spirochetes and AD following established criteria of Koch and Hill. The results show a statistically significant association between spirochetes and AD (P = 1.5 × 10-17, OR = 20, 95% CI = 8-60, N = 247). When neutral techniques recognizing all types of spirochetes were used, or the highly prevalent periodontal pathogen Treponemas were analyzed, spirochetes were observed in the brain in more than 90% of AD cases. Borrelia burgdorferi was detected in the brain in 25.3% of AD cases analyzed and was 13 times more frequent in AD compared to controls. Periodontal pathogen Treponemas (T. pectinovorum, T. amylovorum, T. lecithinolyticum, T. maltophilum, T. medium, T. socranskii) and Borrelia burgdorferi were detected using species specific PCR and antibodies. Importantly, co-infection with several spirochetes occurs in AD. The pathological and biological hallmarks of AD were reproduced in vitro by exposure of mammalian cells to spirochetes. The analysis of reviewed data following Koch's and Hill's postulates shows a probable causal relationship between neurospirochetosis and AD. Persisting inflammation and amyloid deposition initiated and sustained by chronic spirochetal infection form together with the various hypotheses suggested to play a role in the pathogenesis of AD a comprehensive entity. As suggested by Hill, once the probability of a causal relationship is established prompt action is needed. Support and attention should be given to this field of AD research. Spirochetal infection occurs years or decades before the manifestation of dementia. As adequate antibiotic and anti-inflammatory therapies are available, as in syphilis, one might prevent and eradicate dementia.Journal of Neuroinflammation 08/2011; 8(1):90. DOI:10.1186/1742-2094-8-90