Kay Diederen

The ATG16L1 risk allele associated with Crohn’s disease results in a Rac1-dependent defect in dendritic cell migration that is corrected by thiopurines

Thiopurines are commonly used drugs in the therapy of Crohn’s disease, but unfortunately only show a 30% response rate. The biological basis for the thiopurine response is unclear, thus hampering patient selection prior to treatment. A genetic risk factor associated specifically with Crohn’s disease is a variant in ATG16L1 that reduces autophagy. We have previously shown that autophagy is involved in dendritic cell (DC)-T-cell interactions and cytoskeletal regulation. Here we further investigated the role of autophagy in DC cytoskeletal modulation and cellular trafficking. Autophagy-deficient DC displayed loss of filopodia, altered podosome distribution, and increased membrane ruffling, all consistent with increased cellular adhesion. Consequently, autophagy-deficient DC showed reduced migration. The cytoskeletal aberrations were mediated through hyperactivation of Rac1, a known thiopurine target. Indeed thiopurines restored the migratory defects in autophagy-deficient DC. Clinically, the ATG16L1 risk variant associated with increased response to thiopurine treatment in patients with Crohn’s disease but not ulcerative colitis. These results suggest that the association between ATG16L1 and Crohn’s disease is mediated at least in part through Rac1 hyperactivation and subsequent defective DC migration. As this phenotype can be corrected using thiopurines, ATG16L1 genotyping may be useful in the identification of patients that will benefit most from thiopurine treatment.

Efficacy and safety of prucalopride in adults and children with chronic constipation

Introduction: Chronic constipation (CC) is a debilitating condition with high prevalence rates both in children and adults. Despite the broad range of medical and pharmaceutical treatments, the bowel function does not restore in a fair amount of patients. Prucalopride is a first-in-class selective, high affinity serotonin 5-hydroxytryptamine type 4 (5-HT4) receptor agonist promoting gastro-intestinal prokinetic activity and has been evaluated for the treatment of CC. Areas covered: A PubMed search (1965 – 2014) using the following terms alone or in combination: prucalopride, 5-HT4, R093877, safety, toxicity, pharmacokinetics, pharmacodynamics, transit, cardiac, human ether-a-go-go related gene (hERG), arrhythmia, potassium current, elderly, children. Expert opinion: Prucalopride, a highly selective 5-HT4 receptor agonist, stimulates gastrointestinal motility and has been proven to be effective in the treatment of CC in adults by increasing stool frequency, reducing constipation-related symptoms and improving quality of life (QoL). The safety and tolerability have been proven to be excellent. More research would be preferable on the effect of prucalopride on men, children and in other gastrointestinal motility disorders.

Complications and Disease Recurrence After Primary Ileocecal Resection in Pediatric Crohn's Disease: A Multicenter Cohort Analysis

Background: Studies on the outcome of ileocecal resection in pediatric Crohns disease (CD) have a limited follow-up and fail to assign predictors of adverse outcomes. Therefore, we aimed to investigate (I) the complication and disease recurrence rates and (II) identify risk factors for these adverse outcomes after ileocecal resection for pediatric CD. Methods: This is a retrospective cohort analysis of all children (<18 years) that underwent ileocecal resection as first intestinal resection for CD derived from 7 tertiary hospitals in the Netherlands (1990–2015). Risk factors were identified using multivariable analysis. Results: In total, 122 children were included (52% male; median age 15.5 years [interquartile range 14.0–16.0]). Severe postoperative complications rate was 10%. Colonic disease (odds ratio: 5.6 [95% confidence interval {CI}: 1.3–26.3], P = 0.024), microscopically positive resection margins (odds ratio: 10.4 [95% CI: 1.1–100.8] P = 0.043), and emergency surgery (odds ratio: 6.8 [95% CI: 1.1–42.2], P = 0.038) were risk factors for severe complications. Clinical and surgical recurrence rates after 1, 5 and 10 years were 19%, 49%, 71% and 2%, 12%, 22%, respectively. Female sex (hazard ratio [HR]: 2.1 [95% CI: 1.1–3.8], P = 0.023) was a risk factor for clinical recurrence, whereas ileocecal disease (HR: 3.9 [95% CI: 1.2–12.5], P = 0.024) and microscopically positive resection margins (HR: 9.6 [95% CI: 1.2–74.5], P = 0.031) were risk factors for surgical recurrence. Immediate postoperative therapy reduced the risk of both clinical (HR: 0.3 [95% CI: 0.1–0.6], P = 0.001) and surgical (HR: 0.5 [95% CI: 0.1–0.9], P = 0.035) recurrence. Conclusions: Ileocecal resection is an effective and durable treatment of pediatric CD, although postoperative complications occur frequently. Postoperative therapy may be started immediately to prevent disease recurrence.

Fecal Amino Acid Analysis Can Discriminate De Novo Treatment-Naïve Pediatric Inflammatory Bowel Disease From Controls

Objectives: Endoscopy remains mandatory in the diagnostic work-up of inflammatory bowel disease (IBD), but is a costly and invasive procedure. Identification of novel, noninvasive, diagnostic biomarkers remains a priority. The aim of the present study was to explore the potential of fecal amino acid composition as diagnostic biomarker for pediatric IBD. Methods: In this case-control study, treatment-naïve, de novo pediatric patients with IBD from two tertiary centers were included. Endoscopic severity of ulcerative colitis (UC) and Crohns disease (CD) was based on physician global assessment scores, substantiated by levels of fecal calprotectin and C-reactive protein at study inclusion. Patients were instructed to collect a fecal sample prior to bowel cleansing. Healthy controls (HCs) were recruited from primary schools in the same region. Dedicated amino acid analysis was performed on all samples. Results: Significant differences between 30 IBD patients (15 UC, 15 CD) and 15 age and sex-matched HCs were found in six amino acids (histidine, tryptophan, phenylalanine, leucine, tyrosine, and valine; all area under the curve >0.75 and P < 0.005), displaying higher levels in IBD. When distributing the patients according to type of IBD, a similar spectrum of amino acids differed between UC and HC (histidine, tryptophan, phenylalanine, leucine, valine, and serine), whereas three amino acids were different between CD and HC (histidine, tryptophan, and phenylalanine). Conclusions: Significantly increased levels of six different fecal amino acids were found in patients with IBD compared to controls. Whether these differences reflect decreased absorption or increased loss by inflamed intestines needs to be elucidated.