P006 Correlation of small intestinal permeability, faecal calprotectin and barrier genes in multiple-affected families with inflammatory bowel disease
M. Vancamelbeke*1, V. Ballet1, A. Luypaerts1, T. Vanuytsel1, M. Ferrante1, R. Farré1, K. Verbeke1, S. Vermeire1, I. Cleynen2
1University Hospitals Leuven - KU Leuven, Department of Clinical and Experimental Medicine, Translational Research Centre for Gastrointestinal Disorders (TARGID), Leuven, Belgium, 2KU Leuven, Department of Human Genetics, Leuven, Belgium
Impaired intestinal permeability (IP) is a crucial factor in the pathogenesis of inflammatory bowel disease (IBD). However, its causal role and association with genetic and environmental determinants remain unclear. We performed an in-depth characterisation of small IP in affected and unaffected individuals from multiplex IBD families (≥ 3 affected first-degree relatives [FDR]), and correlated this with faecal calprotectin and SNPs in barrier genes.
Eleven multiplex IBD families were studied, including 26 affected IBD patients (21 Crohn’s disease; 5 ulcerative colitis), and 39 unaffected family members (33 FDR; 6 spouses). Fifteen unrelated healthy individuals (HC) served as controls. Demographic (sex, age, BMI, and smoking) and clinical (age at diagnosis, disease location and behaviour, surgery, and medication use) characteristics were collected. Small IP was measured using the 2-hour lactulose-mannitol (LM) urinary excretion test. Acute and chronic stress levels were determined by cortisol in saliva and the Perceived Stress Questionnaire, respectively. Faecal calprotectin was measured as marker for intestinal inflammation. The contribution of genetic risk factors to IP was assessed using a polygenic risk score, including SNPs (located in 128 barrier genes) that were nominally (p < 0.05) associated with IBD within the families.
Quartile analysis of the LM ratio (LMR) showed a higher proportion of IBD patients (40%) in Q4, compared with unaffected FDR (19%), spouses (17%), and HC (13%) (p = 0.05). We found high intraclass correlation for the LMR in affected members of our families (0.64), whereas this was much lower in unaffected family members (0.10), suggesting that IP is more disease-dependent than family-dependent. In addition, age was significantly positively correlated to IP in our families (r = 0.34, p = 0.01). Neither stress nor calprotectin levels were correlated with the LMR, although the median calprotectin concentration was significantly higher in affected versus unaffected family members (117 [interquartile range IQR 39–338] vs 41 [IQR 30–91] µg/g, p = 0.002). Fifty SNPs were associated with IBD in our families, comprising 9 barrier genes (MUC1, MUC21, MUC22, MAGI1, MAGI3, LAMB2, CDH1, F11R, and CXADR). The polygenic risk score, however, did not influence the LMR.
We observed higher small IP in a subset of IBD patients compared with unaffected FDR, spouses, and HC. Interestingly, calprotectin was not associated with small IP, suggesting that barrier defects also occur independent of inflammation. Our study further indicates that genetic factors are not the primary determinants for barrier dysfunction in IBD. Other serologic and environmental risk factors, including the microbiota, will be added in future analyses.