PT - JOURNAL ARTICLE AU - Katie Lloyd AU - Stamatia Papoutsopoulou AU - Emily Smith AU - Philip Stegmaier AU - Francois Bergey AU - Lorna Morris AU - Madeleine Kittner AU - Hazel England AU - Dave Spiller AU - Mike HR White AU - Carrie A Duckworth AU - Barry J Campbell AU - Vladimir Poroikov AU - Vitor AP Martins dos Santos AU - Alexander Kel AU - Werner Muller AU - D Mark Pritchard AU - Chris Probert AU - Michael D Burkitt AU - the SysmedIBD consortium TI - Identification of a novel therapeutic agent for Inflammatory Bowel Disease guided by systems medicine AID - 10.1101/513838 DP - 2019 Jan 01 TA - bioRxiv PG - 513838 4099 - http://biorxiv.org/content/early/2019/01/07/513838.short 4100 - http://biorxiv.org/content/early/2019/01/07/513838.full AB - Inflammatory bowel diseases cause significant morbidity and mortality. Aberrant NF-κB signalling is strongly associated with these conditions, and several established drugs influence the NF-κB signalling network to exert their effect.To identify drugs which may be repositioned for inflammatory bowel disease, the SysmedIBD consortium combined text-mining and network development tools to enhance published NF-κB signalling network diagrams.Up-stream network analysis identified novel therapeutic targets, which were analysed using in-silico drug discovery software to identify candidate drugs with the potential for repositioning for use in inflammatory bowel disease. The highest-ranked candidate drug was clarithromycin.Clarithromycin’s effects were validated in several experimental contexts: it influenced NF-κB mediated transcription in murine peritoneal macrophages and intestinal enteroids, it suppressed NF-κB protein shuttling in murine reporter enteroids, it suppressed NF-κB (p65) DNA binding in the small intestine of mice exposed to LPS, and it reduced the severity of dextran sulphate sodium-induced colitis in C57BL/6 mice. Clarithromycin also suppressed NF-κB (p65) nuclear translocation in human intestinal enteroids.These findings demonstrate that in-silico drug repositioning algorithms can viably be allied to laboratory validation assays in the context of inflammatory bowel disease; and that further clinical assessment of clarithromycin in the management of inflammatory bowel disease is required.One sentence summary Novel bioinformatic analyses and laboratory validation demonstrate the anti-inflammatory effects of clarithromycin and suggest that it may be repositioned for the management of inflammatory bowel diseases.