In the secondary analysis
Kinase Inhibitor Library supplier increased levels of genera Parabacteroides and Collinsella were observed comparing PSC-UC with UC samples. Conclusions: This is the first study, to our knowledge, to characterise the intestinal microbiota of patients with UC with and without PSC. The genus level analysis revealed differences comparing PSC-UC and UC subjects which may reflect microbial representatives of PSC pathogenesis. Increased levels of genus Collinsella observed in primary and secondary analyses are of interest due to the role of these organisms in bile acid metabolism. Functional annotations of the genus level findings and replication in independent panels are presently ongoing. Disclosures: David Kevans – Speaking and Teaching: Abbvie The following people have nothing to disclose: Andrea D. Tyler, Kristian Holm, Kristin K. Jørgensen, Morten H. Vatn, Tom H. Karlsen, Dirk Gevers, Johannes R. Hov, Mark S. Silverberg Background/aims: Vascular adhesion protein (VAP)−1 is an adhesion molecule which possesses potent amine oxidase activity, and deaminates dietary amines resulting in the production of H2O2.Through this function, VAP-1 leads to activation of NFқB in hepatic sinusoidal endothelium (HSEC) resulting in expression of mucosal-vascular cell-adhesion
molecule-1 (MAdCAM-1); a mechanism proposed to contribute to the homing of gut-tropic lymphocytes expressing α4β7 to the liver. Given the putative role this pathway has in hepatic diseases complicating inflammatory bowel disease PLX3397 cost (IBD), we set out to quantify circulating/soluble (sVAP-1) and intrahepatic VAP-1 enzyme activity in primary sclerosing cholangitis (PSC), and evaluate the functional consequence of its inhibition on MAdCAM-1 dependent lymphocyte recruitment to HSEC. Methods: Total VAP-1 concentration was measured by ELISA. VAP-1 amine oxidase activity was
quantified in human serum and explanted liver tissue using the amplex red assay. Flow-based adhesion assays were performed using human HSEC isolated from almost liver explants, activated with TNFα and methylamine (VAP-1 substrate), and treated with VAP-1 antibody or semicarbazide (VAP-1 enzyme inhibitor). FAC-sorted peripheral blood leucocytes expressing α4β7 were perfused over HSEC under flow rates simulating physiological shear (0.05Pa) and adhesion and transmigration quantified. Results: Patients with PSC had significantly higher circulating median VAP-1 enzyme activity (114.5pmol H2〇 2 produced/min/ml serum, IQR 100.6-134.7) than patients with IBD (60.3, IQR 38.5-73.0; P=0.006), normal controls (84.0, IQR 77.7-105.7; P=0.020) and individuals with PBC (53.9, IQR 33.0-90.9; P=0.006), and trended higher than AIH (77.6, IQR 51.0-124.5; P=0.200) (Mann-Whitney). Total sVAP-1 concentration correlated well with sVAP-1 enzyme activity (R2=0.75). Intrahepatic median VAP-1 activity was also significantly higher in PSC (97.