IBD-associated Colon Cancers Differ in DNA Methylation and Gene Expression Profiles Compared With Sporadic Colon Cancers.

BACKGROUND AND AIMS: As ulcerative colitis [UC]-associated colorectal cancer [CRC] and sporadic CRC differ in presentation and molecular features, we sought to evaluate differences in the impact of DNA methylation on gene expression. METHODS: DNA methylation was assessed in 11 UC-CRCs and adjacent tissue and 11 sporadic CRCs and adjacent tissue, using Illumina arrays. RNA sequencing was performed on 10 UC-CRCs and adjacent tissue and eight sporadic CRCs and adjacent tissues. Differences in DNA methylation and transcript expression, as well as their correlation in the same tissues, were assessed. Immunohistochemistry was performed for three proteins, ANPEP, FAM92A1, and STK31, all of which exhibited an inverse correlation between DNA methylation and transcript expression in UC. RESULTS: Thirty three loci demonstrated differences in DNA methylation between UC-CRC and adjacent tissue. In contrast, there were 4204 differentially methylated loci between sporadic colon cancer and adjacent tissue. Eight hundred eighty six genes as well as 10 long non-coding RNAs [lncRNA] were differentially expressed between UC-CRC and adjacent tissues. Although there were no differentially methylated loci between UC and sporadic CRC, 997 genes and 38 lncRNAs were differentially expressed between UC-CRC and sporadic CRC. In UC, 18 genes demonstrated a negative correlation between DNA methylation and transcript expression. Evaluation of protein expression related to three genes, ANPEP, FAM92A1, and STK31, confirmed down-regulation of ANPEP and up-regulation of STK31 in UC-CRC. CONCLUSIONS: Regulation of transcript expression by DNA methylation involves genes key to colon carcinogenesis and may account for differences in presentation and outcomes between inflammatory bowel disease and sporadic colon cancer.

Methotrexate Polyglutamate Monitoring in Patients With Crohn's Disease.

Methotrexate is an efficacious immunosuppressant for induction and maintenance of remission in Crohn's disease. The goal of this pilot study was to determine whether total or individual methotrexate glutamate levels (MTXGlun ) in red blood cells correlate with disease activity and adverse events in Crohn's disease. A cross-sectional study was undertaken with 12 patients on a stable dose of 25 mg weekly methotrexate (oral or subcutaneous). Clinical disease activity was assessed by the Harvey-Bradshaw Index (HBI), and biologic disease activity was measured by inflammatory markers. Concentrations of individual MTXGlun levels were measured in red blood cells (RBCs) using high-performance liquid chromatography-mass spectrometry. No association was observed between RBC individual (MTXGlun ) or total methotrexate glutamate concentrations and clinical disease activity (HBI score) or inflammatory markers or adverse events. Although Crohn's disease patients in remission appeared to generally have higher RBC total longer-chain methotrexate polyglutamate (MTXGlu3+4+5 ) concentrations compared with those with active disease, a definitive association between RBC MTXGlu3+4+5 levels and clinical disease activity could not be established. Larger longitudinal studies in patients with diverse disease activity are needed to establish the value of MTXGlun levels as indicators of treatment efficacy and clinical outcome.

Assessment of Small Intestinal Transit Times in Ulcerative Colitis and Crohn's Disease Patients with Different Disease Activity Using Video Capsule Endoscopy.

Small intestinal transit times (SITT) influence drug bioavailability. This study aimed to compare SITT in Crohn's disease and ulcerative colitis patients with non-inflammatory bowel disease (IBD) and to determine influence of disease activity on transit times, and in addition, to establish the utility of small bowel video capsule endoscopy (SB-VCE) in investigation of SITT in IBD patients. A retrospective review was performed on consecutive patients who had undergone SB-VCE at a university hospital out-patient clinic. In total, 125 non-IBD patients, 55 Crohn's disease patients, and 23 ulcerative colitis patients were included. SITT were calculated from the first duodenal image to the first cecal image. Disease activity was assessed based on endoscopy results and inflammatory markers (calprotectin, C-reactive protein, erythrocyte sedimentation rate). SITT were longer in ulcerative colitis patients compared to non-IBD patients (median 264 min vs. 216 min, p = 0.010). Patients with active Crohn's disease (n = 33) also displayed prolonged SITT compared to non-IBD patients (median 253 min vs 216 min, p = 0.017) and patients with quiescent Crohn's disease (n = 22) (p = 0.005). SITT can be prolonged in IBD patients depending on disease activity which may alter the drug release profiles and clinical response to colonic drug delivery systems. SB-VCE is a simple, non-invasive tool that can be utilized in pharmacokinetic studies to understand drug bioavailability in different patient groups. Moreover, this variability in transit times needs to be simulated in dissolution testing for in vitro in vivo correlations.

Zinc Deficiency is Associated with Poor Clinical Outcomes in Patients with Inflammatory Bowel Disease.

BACKGROUND: Zinc plays a pivotal role in wound repair, tissue regeneration, and the immune response. Although zinc deficiency is common in patients with inflammatory bowel disease (IBD), the impact of low serum zinc levels on disease course is not known. METHODS: Patients enrolled in a prospectively collected IBD registry with at least 2 serum zinc measurements were included in the analysis. Using a logistic regression model, rates of IBD-related surgeries, IBD-related hospitalizations, and IBD-related complications were evaluated after a diagnosis of zinc deficiency (serum concentration <0.66 µg/mL) compared with those with normal zinc concentrations. In patients who were zinc deficient, outcomes were also analyzed between those who had normalization of zinc levels within 12 months and those who remained deficient. RESULTS: A total of 773 patients with Crohn's disease (CD) and 223 with ulcerative colitis (UC) were included in the analysis. After adjusting for covariates, zinc deficiency was associated with an increased risk of subsequent hospitalizations, surgeries, and disease-related complications in patients with CD and UC (CD: hospitalizations, odds ratio 1.44, 95% confidence interval [1.02-2.04]; surgeries, 2.05 [1.38-3.05]; complications, 1.50 [1.04-2.15]; UC: hospitalizations, 2.14 [1.07-4.29]; surgeries, 1.64 [0.59-4.52]; complications, 1.97 [0.94-4.11]). Normalization of zinc was associated with improvement in these outcomes in patients with both CD and UC. CONCLUSIONS: Patients with IBD with serum zinc deficiency are more likely to have adverse disease-specific outcomes. As these outcomes improve with normalization of zinc, the results from this study support the role for close monitoring and replacement of zinc in patients with IBD.