Inflammatory bowel disease (IBD) is a term for two conditions (Crohn’s Disease and Ulcerative Colitis) that are characterised by chronic inflammation of the gastrointestinal (GI) tract. According to the European Federation of Crohn’s & Ulcerative Colitis Associations (EFCCA), there may be as many as 10 million people worldwide living with these conditions.
While the cause of the disease is not fully understood, studies indicate that the inflammation involves a complex interaction of factors, including the genes the person has inherited and the presence of foreign substances (antigens) in the immune system. These antigens may be the direct cause of the inflammation, or they may stimulate the body’s defences to produce and sustain an inflammatory response.
This response is characterised by hyperactive macrophages, white blood cells that act as the gatekeepers of balanced gut immunity. In IBD, macrophages secrete cytokines with numerous damaging effects on tissue and other cells around them. Some of the key cytokines in IBD are TNF alpha, IL-6, IL-17, IL-23.
In a healthy person, the production of these pro-inflammatory cytokines is controlled, in IBD patients it is unbalanced and leads to persistent inflammation that causes tissue damage. In addition, anti-inflammatory cytokines, such as IL-10, are actively suppressed, leading to a further immune imbalance in the gut.
Scientific Knowledge Gaps To better understand and treat IBD, genome-wide association studies (GWAS) have identified segments of DNA associated with the disease at 215 different chromosomal sites, yet scientists have only been able to pinpoint the exact mechanisms involved for four of them.
In a recently published paper in Nature, James Lee, a clinician-scientist who runs a research group at the Francis Crick Institute in London, and colleagues, used functional genomics to investigate an intergenic haplotype on a ‘gene desert’ (swathes of the genome that initially appeared to contain nothing of relevance) known as chr21q22, which has been linked to IBD and other inflammatory diseases. They identified that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and their inflammatory cytokine status and may therefore be an appropriate target for future IBD treatment, with its inhibition potentially being clinically superior to the inhibition of single cytokine targets.
Given that the complexity of IBD is nowhere near fully understood, there is also a lack of appropriate biomarkers, which hampers treatment possibilities. Diagnosis and monitoring of the disease relies heavily on invasive and expensive endoscopy and imaging techniques. Several serum biomarkers have been established as reliable measures for disease activity in IBD, however, many of them have limitations in terms of their specificity, sensitivity, responsiveness, and/or other desirable attributes. Because of this, there is a growing interest in switching from a single biomarker to a multiple panel approach specific to IBD and that can enable differential diagnosis and treatment of Crohn’s disease versus ulcerative colitis.
The identification and effective use of new biomarkers would improve diagnosis and help to predict treatment success. It would also ensure that treatment could begin before the clinical manifestation of symptoms, which could significantly improve the quality of life of patients living with this chronic disease.
