P859 The functional exoproteome as a driver and predictor of IBD status: Proteases from bacteria influence host health. (16th January 2018)

• Record Type: Journal Article
• Authors: Osborne, L S; Marchesi, J
• Is Part Of: Journal of Crohn's and colitis. Volume 12:Number 1(2018:Jan.)Supplement 1
• Page Start: S551
• Page End: S551
• Publication Date: 2018-01-16
• Subjects: Inflammatory bowel diseases -- Periodicals; 616.344005
• DOI: 10.1093/ecco-jcc/jjx180.986
• Languages: English
• ISSNs: 1873-9946

Abstract

Abstract: Background: From the studies of sterile rodents, it is an unequivocal fact that the gut microbiome is an essential environmental factor in the development of inflammatory bowel disease (in both ulcerative colitis and Crohn's disease). To date, no pathobionts have been identified which have been directly shown to initiate the disease, but strong correlations between the presence of some strains of Escherichia coli, specifically, the adherent and invasive E. coli (AIEC) strains and IBD have been reported. We propose that rather than reducing the pathogenesis to single organisms and trying to identify a single causative agent, we explore the source of pathogenesis in the collective system and accept an alternative model of disease initiation. Especially in light of recent reports that the genetics are consistently playing a less significant role in the disease when compared with environmental factors. Our alternative model regards the functions of the gut microbiome as responsible for driving inflammation in the gut. When this model is combined with a specific genetic predisposition, e.g. the 2 variants of NOD2, IBD may result. We propose a function-driven model which is an emergent property of the whole microbiome and not one specific organism. In our novel hypothesis, we claim that a specific function of the gut microbiome, bacterial derived proteases (BDPs) may be at least in part responsible for driving inflammation. Methods: We aimed to test whether BDPs can drive inflammation and modulate tight junction integrity using tissue culture and ex vivo models and identify the bacterial proteases that may be responsible. Using faecal samples from a large cohort of UC and CD sufferers, total protease activity was measured and compared between each cohort and linked to taxonomy and diversity. Protease inhibitor assays revealed the dominant protease types present and an FPLC pipeline was developed to enrich faecal water samples for proteases for downstream mass spectrometry protein identification. Results: Protease activity was consistently significantly higher in IBD faecal samples compared with healthy and increased activity was positively correlated with disease severity. Inhibitor studies revealed that serine- and metallo-proteases were mainly responsible for the observed activity and protein extracts from IBD patients were capable of disrupting tight junction architecture and contributing to an increase in paracellular permeability in vitro. Conclusions: Protease activity is an indicator, if not a driver of IBD severity and the gut microbiota is considerably responsible and may be a beneficial therapeutic target for maintaining remission in a UC and CD setting.