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P088. Delineating lipopolysaccharide signalling pathway in ulcerative colitis through mucosal gene expression analysis

A. Balfe1, G. Lennon1, K. Killick2, C. Spillane3, A. Lavelle1, G. Blackshields4, N. Docherty5, C. Coffey6, K. Sheahan1,7, D. Winter8, R. O'Connell1,8, 1University College Dublin, School of Medicine and Medical Science, Dublin, Ireland, 2University College Dublin, Systems Biology Ireland, Dublin, Ireland, 3Trinity College Dublin, Molecular Pathology Research Group, Department of Pathology, Dublin, Ireland, 4Trinity College Dublin, Department of Histopathology and Morbid Anatomy, Dublin, Ireland, 5University College Dublin, Conway Institute of Biomolecular and Biomedical Sciences, School of Medicine and Medical Science, Dublin, Ireland, 6Graduate Entry Medical School, University Hospital Limerick, University of Limerick Ireland, Limerick, Ireland, 7St. Vincent's University Hospital, Department of Histopathology, Dublin, Ireland, 8St. Vincent's University Hospital, Centre for Colorectal Disease, Dublin, Ireland


Bacterial derived lipopolysaccharide (LPS) is known to initiate inflammatory responses both in in-vitro and in-vivo. Numerous animal models of ulcerative colitis (UC) have shown inflammation to be propagated by exposure to LPS [1,2]. Despite this, extensive knowledge of the molecular mechanisms by which LPS has the potential to induce inflammation remains to be defined. This study aimed to delineate the LPS signalling pathway in the colonic mucosa of patients with UC.


Snap frozen mucosal biopsies were collected from four colonic regions (cecum, transverse, left and rectum) in healthy controls (n = 3) and patients with acutely active UC (n = 4). Global gene expression analysis was performed using the Affymetrix GeneChip Human ST2 array. Differentially expressed genes (FDR < 0.05) were used for system biology analysis through Ingenuity Pathway Analysis (IPA) software which identified significantly over-represented functional categories, canonical pathways and up-stream regulators.


Systems analysis identified LPS as the dominant up-stream activator of differential gene expression between health and UC (Table 1). A total of 263 genes were identified as being influenced by LPS, with IFN-γ, IL-1 β, IL-4, and TNF being identified as the dominant inflammatory networks defined by these genes. These networks were predicted to have a subsequent activating downstream effect on NFkB complex.

Table 1. Altered UC and LPS mediated gene expression
LocationGene expression changes, healthy control v acutely active UC aLPS associated gene expression activationP value
Increased expression (n)Decreased expression (n)Genes associated (n)Regulation Z-score bP value
a Gene expression changes were determined by an FDR < 0.05.
b A Z-score of >+2 predicts significant activation and <−2 indicates significant inhibition.


These data support previous studies that LPS has the potential to induce UC associated inflammation. Furthermore, this study demonstrates the potential to elucidate complex gene expression pathways and their regulators through a systems biology approach.

1. Ruemmele, F.M., et al., (2002), Lipopolysaccharide modulation of normal enterocyte turnover by toll-like receptors is mediated by endogenously produced tumour necrosis factor alpha., Gut, 842–8.

2. Caradonna, L., et al., (2000), Enteric bacteria, lipopolysaccharides and related cytokines in inflammatory bowel disease: biological and clinical significance, J Endotoxin Res, 205–14.