Network biology of inflammatory bowel diseases

Abstract

Inflammatory bowel disease (IBD) is a general term for chronic conditions caused by inflammation of the gastrointestinal tract. IBD is classified mainly into two forms namely; Crohn’s disease (CD) and Ulcerative colitis (UC). In 2017 globally total IBD cases count crossed 6.8 million. The mechanism of pathogenesis of IBD is interplay between genetic factors, environmental factors, immune response and intestinal barrier conditions. Previous studies based on isolated therapies show very little effectiveness but applying a system view perspective shows promising results. In this study we tried to find the pathways which are most affected because of mutations in genome of IBD patients. For this mutations identified in IBD patients by GWAS studies were mapped to numerous genes by D Muraro et. al. We used this gene list as candidate gene list to understand how risk polymorphisms in these associated genes play role in IBD disease development. From candidate gene list 150 top ranked genes prioritized by ENDEAVOUR tools were shortlisted. 666 genes found to be closely related to these 150 genes either in the form of complex formation or common pathways were also identified using GeneMANIA. This helped to identify the pathways in which these genes can be functionally classified. IL-12 and IL23 pathways were the top pathways in which these 816 nodes were functionally classified. From literature survey it was found that IL-23 inhibition can lower the inflammation mediated by TH-17 cells. TH-17 cells play a crucial role in inflammation caused in IBD. In the second half of the study, inhibitors for IL-23 signaling axes were found by identifying plant derived molecules found in Indian medicinal plants. The basic idea is to mask the binding site of the IL-23(cytokine) and IL-23R (receptor) and not allowing IL-23 signaling. For this targeted molecular docking experiments were done focusing on the IL-23:IL23R interacting residues. Terflavin B, Punicalin and Punicalagin were the best docked molecule to IL-23 and IL-23R both in separate docking experiments. Molecular dynamic simulation showed that these three were forming stable bond with IL-23 throughout the 10ns simulation. Only Terflavin B and Punicalagin were forming stable bond with IL-23R at the end of 10ns simulation. It is known that Terflavin B showed antibacterial activity against Bacillus subtilis and Pseudomonas fluorescen. Punicalin and Punicalagin shows strong antioxidant and anti-inflammatory properties. In this study Terflavin B has better binding stability with both IL-23 and IL-23R as compared to all the analyzed ligands. The results from this study suggest that these plant derived molecules can be further explored as potential inhibitor of IL-23 pro-inflammatory signaling axis.