NF-kB signalling is an important cellular pathway implicated in inflammation and cancer. It functions by regulating gene expression through the transcription factor NF-kB and accumulating evidence indicates that the pathway is dynamically controlled. As with many processes following circadian patterns, NF-kB displays sustained oscillations whose biological significance is only beginning to emerge. To investigate how NF-kB oscillations may be associated with IBD, the EU-funded SYSMEDIBD project proposed a systems medicine approach. “The overall aim was to better understand disease mechanism and to develop new biomarkers that will help stratify patients and suggest personalised treatments,″ explains project coordinator Prof. Werner Müller. Instrumental to the overall success of the project were the two small-medium enterprises GeneXplain and Lifeglimmer. SYSMEDIBD scientists developed mathematical models to describe the process of chronic inflammation, focusing in particular on the NF-kB pathway. These in silico findings were validated in animal models of the disease and also via patient samples. Visualising NF-kB dynamics To measure activation of the NF-kB pathway in vivo, the consortium generated animal models with fluorescently labelled pathway components. This approach allowed researchers to follow cells by fluorescence microscopy and determine the NF-kB oscillation frequencies in a number of cell types. “This work also enabled us to measure NF-kB signalling dynamics in primary cells from human patients", continues Prof. Müller. Researchers discovered selective mediators of inflammation among the signals that triggered NF-kB oscillation in these cell types. Impressively, they were able to identify a minimal gene set responsible for the dynamics of the NF-kB signalling pathway in humans. Clinical implications Using the SYSMEDIBD approach in the two major IBD clinical diseases, Crohn’s and ulcerative colitis, researchers were able to stratify patients into further sub-groups. By performing dynamic NF-kB activation measurements on blood cells from patients, they observed higher or lower responses compared to controls. Although SYSMEDIBD partners are working to understand the difference between the hyper- and hypo-responsive ulcerative colitis patients, data suggests a potential link of NF-kB dynamics with disease pathophysiology. Another major achievement of the project was an in silico framework for studying the interactions of NF-Kb with other pathways. Using this approach, researchers performed extensive screening of approximately 1 million natural compounds and small molecules for their potential to interfere with the NF-kB pathway. Among others, they identified a group of antibiotics called macrolides that inhibited NF-kB activation and reduced inflammation in in vitro assays. Apart from visualising the dynamics of NF-kB signalling pathway during gut inflammation, the SYSMEDIBD study identified genetic mutations associated with increased IBD susceptibility. This is expected to further aid in the characterisation and stratification of IBD patients. Prof Müller envisages “the information and tools of SYSMEDIBD to be implemented for the improved diagnosis of patients, taking into account disease comorbidities". In clinical samples and mouse models, SYSMEDIBD studies could link genetic variants in a specific cellular pathway, called autophagy to the NF-kB pathway. “This surprising finding sheds new light on the regulation of the signalling events in chronic inflammation and might be clinically actionable,” says Prof Rosenstiel, leader of the genomics analysis work package. From a therapeutic perspective, the findings of the SYSMEDIBD study indicate that interfering with the oscillation of biological pathways may provide new possibilities to influence processes like inflammation. Combined with diet intervention and the use of macrolides as therapy, the future of IBD treatment certainly looks promising.
SysmedIBD, NF-kB, inflammatory bowel disease (IBD), oscillation, macrolides