T2084 Comparison of Small Bowel and Colonic Mucosal Permeability in Diarrhea-Predominant Irritable Bowel Syndrome and Health by Urinary Saccharide Excretion

Abstract

Background: A significant proportion of patients with irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) suffer from psychological co-morbidities, i.e. depression. Recently, we identified 16 interferon (IFN)-responsive genes (ISGs) that were associated with IFN-α induced depression during therapy of chronic HCV infection as well as with severe endogenous depressive episodes. Based upon data that a large proportion of patients with chronic bowel disorders suffer from depressive disorders, we aimed to investigate, whether these “depression ISGs” may play a role in patients with IBS and IBD. Methods: 11 consecutive IBS (all constipation predominant) and 12 IBD patients (7 ulcerative colitis, 5 Crohn's disease) as well as 14 healthy controls were included. Basal expression of ISGs and the internal expression of IFN-α, -β, and -γ was analyzed in whole blood (PAXgene blood RNA tubes) using quantitative real-time PCR. Additionally, PBMC were isolated from each patient by density gradient centrifugation and were stimulated In Vitro with IFN-α (0, 100, and 1000 IU/ mL for 16h). The upregulation of ISGs was analyzed by real-time PCR. HRQOL (SF-36, physical [PCS] and mental component score [MCS]) and affective disorders (Hospital Anxiety and Depression Scale) were also assessed. Results: We found highly significant differences in the basal expression of 11 out of 14 tested ISGs (p<0.001 for 10 genes) in IBS and IBD patients vs. healthy controls. Basal expression of ISGs associated with depression and of “classical” ISGs (IFIT1, ISG15, and MX1) was significantly lower in 13/ 14 genes in IBS and IBD patients compared to healthy controls. Basal expression of IFN-β was significantly upregulated in IBS and IBD patients (p<0.001), while there was no difference in basal expression of IFN-α and IFN-γ. Comparing IBS and IBD patients, no significant differences in basal gene expression were detected. PBMC of IBS and IBD patients were hyper-responsive to exogenous stimulation with IFN-α compared to healthy controls leading to significantly higher induction of selected ISGs. Summary: In patients with refractory IBS and chronic IBD a marked activation of the type I IFN system and a hyper-responsiveness to stimulation with type I IFNs can be observed. This is associated with a response pattern that is also found in patients with depressive disorders and may thus explain at least some of the psychopathological abnormalities in these patients.