A novel method for combining laboratory work into a systems biology mathematical model unravels possible mechanisms for the failure of glucocorticoid therapy in ulcerative colitis

- Research

Researchers from the Digestive Inflammatory Pathology Research Group at the IGTP and the Spanish Network for Hepatic and Digestive Diseases (CIBEREHD) have identified key elements of the mechanism behind the failure of steroid treatments for ulcerative colitis in some patients. Treatment failure is one of the main obstacles in the management of this disease and the new findings could help prevent treatment failure and allow for more efficient rescue therapies when needed. The study also identifies a possible biomarker to predict which patients might suffer treatment failure.  The research was led by Dr. Eugeni Domènech and Dr. Josep Manyé, and published recently in the Journal of Crohn's and Colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease the cause or causes behind the disease are still unknown, but there have been more cases and it has become more widespread in recent decades. Despite advances in new therapies, glucocorticoids (GC) remain the first-line treatment for moderate to severe attacks of the disease. However, the failure of steroid therapy is a major drawback in the treatment of UC, as it occurs in 40-60% of patients who then require rescue therapies. Despite plenty of available data, there is not enough current evidence to allow for an in-depth understanding of the molecular mechanism associated with this steroid therapy failure in UC. "Many studies have tried to address this issue, but most of them are unconnected and fail to provide a solution", Manyé explains.

"The aim of our research was to organize all the current knowledge using mathematical criteria to be able to integrate this knowledge computationally with experimental data from our patients' miRNA and mRNA", explains Manyé, "using both mathematical and biological criteria we can get a more complete picture of what is happening".

A mathematical and biological approach

The laboratory phase of this work consisted of taking samples from two rectal biopsies of patients with moderately-to-severe active UC, one obtained before therapy started and the other on the 3rd day of steroid treatment. The samples were tested for miRNA and mRNA expression by sequencing and microarrays, respectively. These differential results were integrated into the mathematical models generated by Systems Biology methods. The overall computational approach identified 18 proteins that stood out either for being associated with the mechanism of action or because they provided a way to classify the patients according to how they will respond to steroids. The biological functions of these proteins have been linked with inflammation, glucocorticoid-induced transcription and angiogenesis. All the selected proteins except ANP32E had previously been associated with UC and/or the biological effects of using glucocorticoid therapies. This work confirmed the implication of ANP32E in steroid failure in patients with active UC.

"With the computational approach we have been able to identify a comprehensive mechanism of action for steroid treatment failure. This highlights the key role of steroid-induced transcription and the potential implication of some key proteins in this phenomenon, providing potential biomarkers that could predict steroid refractoriness in UC", concludes Manyé

"Addressing clinical problems is one of the main objectives of our research group", says Domènech, group leader and Head of the Gastroenterology & Hepatology Department at the Germans Trias i Pujol Hospital and leader of the CIBEREHD group. The group has carried out cutting-edge research over the last 25 years reaching a level of excellence in intestinal healthcare and has set a national and international benchmark for the treatment of ulcerative colitis and Crohn's disease.  "This combined methodology has shown that it is a very promising tool to tease out the complex mechanisms behind the failure of some patients to respond to the standard therapy.  We aim to continue work to develop new diagnostic and therapeutic tools to manage this very distressing disease and improve the quality of life of our patients," he concludes.

Reference article

ANP32E, a protein involved in steroid-refractoriness in ulcerative colitis, identified by a systems biology approach. V Lorén A Garcia-Jaraquemada J E Naves X Carmona M Mañosa A M Aransay J L Lavin I Sánchez E Cabré J Manyé et al.  Journal of Crohn's and Colitis, jjy171,   17 October 2018