Increased Intestinal Permeability in Relatives of Patients With Crohn's Disease Is Not Associated With Small Bowel Ulcerations.

BACKGROUND & AIMS: Many first-degree relatives of patients with Crohn's disease (CD) have increased intestinal permeability. Video capsule endoscopy (VCE) is the most sensitive imaging test to identify small bowel mucosal lesions that could indicate subclinical CD. We aimed to estimate the association of increased intestinal permeability with small bowel ulcerations detectable by VCE in healthy first-degree relatives of patients with CD. METHODS: We conducted a cross-sectional study of 223 healthy, asymptomatic first-degree relatives of patients with CD (parents, siblings, and children; 9-45 years old) enrolled at the University of Alberta between 2009 and 2012. Patients were given the lactulose and mannitol test to measure small bowel permeability; we used high-performance liquid chromatography to measure concentrations of lactulose and mannitol in urine samples (increased permeability defined as a ratio of lactulose/mannitol 0.025 or greater). Patients with increased permeability (n = 39) and randomly selected subjects with normal permeability (n = 59) were then examined by VCE for signs of small bowel inflammation and subclinical CD. The prevalence of small bowel lesions was compared among groups. We performed logistic regression analyses to estimate odds ratios for the association of small bowel ulcerations with intestinal permeability. RESULTS: Among 223 first-degree relatives of patients with CD, 30% were found to have increased intestinal permeability; VCE examination found 24% of subjects to have 3 or more small bowel ulcers. Three or more small bowel ulcers were detected in 28% of patients with increased intestinal permeability and 20% of patients with normal intestinal permeability (P = .37). The adjusted odds ratio for the association of 3 or more small bowel ulcers with increased intestinal permeability was 1.5 (95% confidence interval, 0.6-3.8; P = .46). CONCLUSIONS: Thirty percent of healthy, asymptomatic first-degree relatives of patients with CD have increased intestinal permeability. However, a strong association of small bowel ulceration seen on VCE with increased intestinal permeability was not observed.

Therapeutic drug monitoring was helpful in guiding the decision-making process for children receiving infliximab for inflammatory bowel disease.

AIM: This study examined the impact of therapeutic drug monitoring (TDM) on clinical decision-making for children receiving infliximab for inflammatory bowel disease (IBD). METHODS: The medical records of children with IBD who had infliximab trough levels (ITLs) measured between January 2013 and December 2015 at two Canadian tertiary-care centres were examined. The indications for TDM, clinical and laboratory disease activity indices and TDM-driven treatment changes to infliximab therapy were documented. RESULTS: We included 107 consecutive serum measurements of ITLs in 73 children (40 boys), with a median age of 16.1 years, including 52 with Crohn's disease. TDM was performed due to concerns about clinical disease activity in 24/107 (22.4%) measurements and 83 (77.6%) were ordered as routine tests. Of these, 38 (35.5%) ITLs were suboptimal (<3.5 µg/mL) and 36 (34.0%) resulted in more frequent doses of infliximab, with subsequent improvements in disease biomarkers. Interval changes were implemented as a result of 34 (32.0%) ITLs, with shorter intervals in 19 (17.0%) cases, and seven (6.5%) ITLs resulted in adding or increasing doses of immunomodulators. In addition, four children were switched to adalimumab. CONCLUSION: Therapeutic drug monitoring was helpful in guiding the decision-making process for children with IBD on infliximab.

The tumor suppressor gene, RASSF1A, is essential for protection against inflammation -induced injury.

Ras association domain family protein 1A (RASSF1A) is a tumor suppressor gene silenced in cancer. Here we report that RASSF1A is a novel regulator of intestinal inflammation as Rassf1a(+/-) , Rassf1a(-/-) and an intestinal epithelial cell specific knockout mouse (Rassf1a (IEC-KO) ) rapidly became sick following dextran sulphate sodium (DSS) administration, a chemical inducer of colitis. Rassf1a knockout mice displayed clinical symptoms of inflammatory bowel disease including: increased intestinal permeability, enhanced cytokine/chemokine production, elevated nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB) activity, elevated colonic cell death and epithelial cell injury. Furthermore, epithelial restitution/repair was inhibited in DSS-treated Rassf1a(-/-) mice with reduction of several makers of proliferation including Yes associated protein (YAP)-driven proliferation. Surprisingly, tyrosine phosphorylation of YAP was detected which coincided with increased nuclear p73 association, Bax-driven epithelial cell death and p53 accumulation resulting in enhanced apoptosis and poor survival of DSS-treated Rassf1a knockout mice. We can inhibit these events and promote the survival of DSS-treated Rassf1a knockout mice with intraperitoneal injection of the c-Abl and c-Abl related protein tyrosine kinase inhibitor, imatinib/gleevec. However, p53 accumulation was not inhibited by imatinib/gleevec in the Rassf1a(-/-) background which revealed the importance of p53-dependent cell death during intestinal inflammation. These observations suggest that tyrosine phosphorylation of YAP (to drive p73 association and up-regulation of pro-apoptotic genes such as Bax) and accumulation of p53 are consequences of inflammation-induced injury in DSS-treated Rassf1a(-/-) mice. Mechanistically, we can detect robust associations of RASSF1A with membrane proximal Toll-like receptor (TLR) components to suggest that RASSF1A may function to interfere and restrict TLR-driven activation of NFκB. Failure to restrict NFκB resulted in the inflammation-induced DNA damage driven tyrosine phosphorylation of YAP, subsequent p53 accumulation and loss of intestinal epithelial homeostasis.

RASSF1 Polymorphisms in Cancer.

Ras association domain family 1A (RASSF1A) is one of the most epigenetically silenced elements in human cancers. Localized on chromosome 3, it has been demonstrated to be a bone fide tumor suppressor influencing cell cycle events, microtubule stability, apoptosis, and autophagy. Although it is epigenetically silenced by promoter-specific methylation in cancers, several somatic nucleotide changes (polymorphisms) have been identified in RASSF1A in tissues from cancer patients. We speculate that both nucleotide changes and epigenetic silencing result in loss of the RASSF1A tumor suppressor function and the appearance of enhanced growth. This paper will summarize what is known about the origin of these polymorphisms and how they have helped us understand the biological role of RASSF1A.