supposition that 'what works in one will work in the other'.Disease-specific therapies targeting these pathways should be developed and in some instances already exist but require evaluation in IBD.The utility of genetic findings in predicting who might develop IBD in the future remains limited, and given the relative infrequency of IBD in the population is likely to remain so.A more focussed application will be detection of genetic markers which when combined with other biomarkers and clinical data predict disease course.Such markers have yet to be defined but the appropriate studies are underway.Additional pharmacogenetic insights are also likely to be gleaned through use of GWAS data.
with concentrated conditioned media (CM) of E. faecalis OG1RF as well as purified proteolytically active GelE demonstrated a tremendous decrease of the transepithelial electrical resistance in human and murine colonocytes, whereas the concentrated CM of GelE lacking strains TX5264 and TX5266 did not affect the barrier integrity.The loss of barrier function could be demonstrated by increased permeability for sodium fluorescein in the transwell cultures, but also after colonic administration of GelE in Wt mice.Conclusion: E. faecalis GelE contributes to the development of intestinal inflammation in gnotobiotic IL-10 / mice.Furthermore GelE leads to a functional loss of barrier integrity in vivo and in vitro.Our data suggest that bacteria-derived proteases could contribute to intestinal inflammation through the impairment of epithelial barrier function.
In both main forms of Inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD), intestinal commensal microbiota are thought to trigger the disease in genetically susceptible individuals. Approximately one third of patients with CD have a mutation in the NOD2 gene that encodes an intracellular bacterial pattern-recognition receptor located within Paneth-cells. The maturation of Paneth cells is regulated via the canonical Wnt cascade. The Nkd1 (naked cuticle homologue 1), gene, a Wnt antagonist, is located near NOD2 at 16q12, and it has been found weakly associated with CD in WTCCC dataset (rs8047222 P<1x10-5). Aims: To investigate rs4785433, rs730055, and rs8047222 SNPs of NKD1 and to search for likely correlation with clinical phenotypes in both adult and pediatric onset IBD patients. Methods: 1185 CD patients (670 male) with a mean age at diagnosis of 27 yrs (range 1-80) (334 < 19 yrs at diagnosis), 1385 UC patients (803 male) with a mean age at diagnosis of 31 yrs (range 1-83) (246 < 19 yrs at diagnosis), and 645 healthy controls (HC), were genotyped for NKD1 gene by using the TaqMan allelic discriminationmethod. Genotype frequencies were comparedwith respect to age at diagnosis, disease localization and behaviour (Montreal classification), need of resective surgery, response to medical therapy (steroids, immunosuppressive drugs), and NOD2 status. Results: A significant allele and genotype association of the rs8047222 with UC (P=0.01, OR=0.83, CI=0.73-0.96; P=0.02, OR=0.79; CI=0.65-0.96) was shown, especially in adult-onset cohort (P<0.002). After stratifying the cohort on the basis of NOD2 genotypes (NOD2-=no major variants; NOD2+=at last one variant), a significant genotype association in NOD2patients (P=0.004; OR= 0.74; CI=0.61-0.91) was also demonstrated. No significant difference for either allele and genotype frequencies with rs8047222 was found for CD compared with controls, however, a significant genotype association in NOD2patients (P=0.03, OR=0.77, CI=0.62-0.97) was found. At genotype-phenotype evaluation, a reduced freq uency of distal (E1) vs extensive (E3) colitis in UC (47% vs 78%; P=0.006; OR=0.25, CI=0.09-0.70), and colon (56%) vs ileum localization in CD(65%)(P=0.02, OR=0.69, CI=0.49-0.95) was demonstrated. No significant difference for either allele and genotype frequencies for rs4785433, rs730055 SNPs for IBD was found. Conclusions: The rs8047222 SNP on NKD1 gene has a significant protective role in both UC and CD, possibly influenced by NOD2 status, with interaction with disease localization. Nkd1 might be responsible for the residual linkage at 16q12 locus in NOD2-negative CD patients.
high levels of Smad7 in T cells could promote inflammationrelated CC initiation and growth.Material and Methods: Wild type and T cell-specific Smad7 (tg) transgenic mice were treated with azoxymethane (AOM) and dextran sulphate sodium (DSS) to induce colitis-associated CC.Tumor number and size were assessed by endoscopy.Colitis and dysplasia were graded by histology.mRNA expression of proinflammatory cytokines and cytotoxicity markers (i.e Granzynes B, perforin-1, and FasL) were evaluated by qPCR in immune cells isolated from tumors and tumor free areas.Results: As expected Wt mice developed large and multiple tumors after AOM/DSS treatment.By contrast, only few and small tumors were seen in Smad7tg mice, even in the presence of a strong Th1-mediated colitis as indicated by the higher expression of IFN-gamma in these mice.Further flow-cytometry analysis of tumor-infiltrating T cells showed a higher expression of IFN-gamma in T cells, both CD4+ and CD8+, and NK/NKT cells from Smad7Tg in comparison to Wt mice.Analysis of CD8+ T/NK-cell-related cytotoxic molecules showed higher expression of Perforin-1, Granzyme B and FasL in both tumors and tumor-free areas of the Smad7tg in comparison to the Wt animals.Conclusions: T cell-specific Smad7 over-expression results in a more severe colitis that protects against CC.Our data suggest that high expression of IFN-gamma and cytotoxicity sustained by high Smad7 in T cells could play a role in the regulation of anti-tumor immune responses in the gut.
