Tu1802 - Disease Demarcation in Ulcerative Colitis is Associated with Different Patterns of Gene Expression

Background: Disease extent varies in UC from proctitis (E1) to left-sided colitis (E2) and pancolitis (E3).When the extent of UC is limited (E1/E2) there is a sharp demarcation between macroscopically involved and uninvolved areas, which remains unexplained.Since 25% of patients with limited UC extend over time, we assessed molecularly the mechanisms defining the anatomic delineation between affected and unaffected colon.Method: We performed RNA-seq analysis on gut biopsies from UC patients and characterized the inflammation signature at and proximal to the endoscopic demarcation of disease.We collected biopsies from endoscopically involved rectum, sigmoid and left colon of 37, 12 and 9 UC patients, respectively.From each of these patients we also sampled uninvolved areas, either directly adjacent to the inflamed site or more proximal.The resulting 148 paired biopsies were then 'ordered' by inflammation status and gut location and a 'distance' from inflammation was assigned for each biopsy.The distance from the first adjacent region to the inflamed biopsy was defined as D=1, for example inflamed rectum and uninflamed sigmoid.A D=2, was assigned if the adjacent biopsy was 2 regions away from the inflamed biopsy (inflamed rectum and uninflamed left colon) and so on up to D=5.We modeled the gene expression changes over all the distances from inflammation.To account for molecular differences due to region, biopsies from non-IBD control patients matched for regions were used (Fig1).Results:Two striking patterns of molecular expression were observed.One included genes which progressively changed in expression as the distance from the site of inflammation increased ('slope geneset').The second included genes that abruptly changed in expression at the first adjacent region to the inflamed biopsy and did not change further ('wall geneset').Slope genes decreasing in expression included acute and chronic inflammatory processes such as IFNg, IL6 and oncostatin-M suggesting the reach of inflammation was further than observed by endoscopy.However, a subset of inflammatory genes as well as integrins and adhesion molecules had sharply decreased expression at the adjacent uninflamed region (wall genes: IL23A, IL22, TNF and IL10) suggesting these may be important for modulating the progression of extensive inflammation.Upregulated slope genes included solute carrier and homeobox genes while upregulated wall genes included glucoronidation and fatty acid binding proteins, suggesting altered gut function (Fig2a).Conclusion:We reveal a complex molecular pattern emanating from the 'visible' line of disease demarcation, of both progressive and acute changes (Fig2b), helping to understand for the first time its origin and potentially provide biomarkers of UC extension.