Systems medicine for bowel disease

IBD is a chronic inflammation of the gut, with ulcerative colitis and Crohn's disease being the most frequent disease manifestations. At present, there are no cures for IBD and clinicians can only provide disease management options.

The large EU-funded 'Systems medicine of chronic inflammatory bowel disease' (SYSMEDIBD) consortium is exploring a systems medicine approach to generate new treatments for IBD. By focusing on NF-kappa-B signalling, the project aims to understand disease mechanism, and develop new biomarkers for patient stratification and for the design of future personalised treatments.

To study the human pathway, scientists have generated mice with bacterial artificial chromosomes carrying two NF-kappa-B–encoding human transgenes. These genes have been fluorescently tagged to follow pathway activation in 3D gut organoid cultures under normal and inflammatory conditions. Using this system and additional biomarkers, researchers will analyse pathway activation in patient cells and progression to chronic inflammation.

A further humanised mouse model is being developed that contains human gut and could be used to simulate IBD conditions. Partners are hopeful that they could use this in vivo model to find novel therapies for IBD.

The consortium has identified a number of biomarkers following mapping of inflammation-associated genes onto the NF-kappa-B pathway. A selection of these targets will be used to screen small molecule inhibitors, while others that are potentially released in the serum could be exploited for diagnostic purposes. This will offer a less invasive way of arriving at an IBD diagnosis.

All the information generated during SYSMEDIBD will ultimately be used to construct a mathematical model to predict IBD onset and progression. In addition, the same model could be used for predicting the therapeutic outcome of various regimens and following a personalised treatment approach.