Abstract
The molecular mechanisms of IBD have been the subject of intensive exploration. We, therefore, assembled the available information into a suite of causal biological network models, which offer comprehensive visualization of the processes underlying IBD. Scientific text was curated by using Biological Expression Language (BEL) and compiled with OpenBEL 3.0.0. Network properties were analysed by Cytoscape. Network perturbation amplitudes were computed to score the network models with transcriptomic data from public data repositories. The IBD network model suite consists of three independent models that represent signalling pathways that contribute to IBD. In the “intestinal permeability” model, programmed cell death factors were downregulated in CD and upregulated in UC. In the “inflammation” model, PPARG, IL6, and IFN-associated pathways were prominent regulatory factors in both diseases. In the “wound healing” model, factors promoting wound healing were upregulated in CD and downregulated in UC. Scoring of publicly available transcriptomic datasets onto these network models demonstrated that the IBD models capture the perturbation in each dataset accurately. The IBD network model suite can provide better mechanistic insights of the transcriptional changes in IBD and constitutes a valuable tool in personalized medicine to further understand individual drug responses in IBD.
Highlights
The molecular mechanisms of Inflammatory bowel disease (IBD) have been the subject of intensive exploration
We present a new addition to the causal biological network (CBN), a suite of causal biological models that describe important molecular events involved in IBD, from epithelial barrier defence to inflammation and wound healing
The barrier defence network model visualizes the routes that lead to tight junction disruption and highlights the molecular entities involved in the balance between intestinal epithelial cell proliferation and apoptosis, which is essential for tight junction regulation
Summary
The molecular mechanisms of IBD have been the subject of intensive exploration. We, assembled the available information into a suite of causal biological network models, which offer comprehensive visualization of the processes underlying IBD. Alterations in the balance between proliferation and apoptosis are known to be involved in barrier dysfunction, which leads to IBD8 This is further supported by evidence showing that anti-tumor necrosis factor (TNF) therapies reduce IEC apoptosis in models of colitis and CD p atients[9,10]. The pathways of several genetic risk factors for IBD impair barrier function and lead to colitis, including the NOD2 (nucleotide-binding oligomerization domain containing 2) and autophagy pathways. IECs express various pattern recognition receptors such as Toll-like receptors (TLR) that are able to recognize conserved microbial components (e.g. lipopolysaccharides)[18] In response to these signals, IECs produce a variety of inflammatory cytokines, such as interleukin (IL) 819, CXCL (C-X-C motif chemokine ligand) 220, and C–C motif chemokine ligand 2 021. IL1β is highly produced in the colon of IBD patients and promotes the activation of dendritic cells, macrophages, and n eutrophils[23]
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