IBD: the perfect example of translational medicine?

The genetic and clinical heterogeneity of IBD means translational research has a key role to play. A session dedicated to translational and basic science at UEG Week 2019 highlighted the need for research into environmental triggers in IBD, and the potential of multiomics and systems biology approaches to deliver precision medicine.

Written by Maria Dalby

On behalf of Professor Arthur Kaser (University of Cambridge, UK) who was unable to attend the last day of UEG Week 2019, Professor Herbert Tilg (Medical University of Innsbruck, Austria) delivered a lecture on how the latest therapeutic options for IBD validate research into the disease mechanisms, and bear testimony to the importance of translational research. For example, vedolizumab has resulted from research which first identified a cell-surface molecule involved in organ-specific lymphocyte homing in 1983, and confirmed the ability of an anti-α4-integrin monoclonal antibody to attenuate colitis in monkeys in 1993. Likewise, ustekinumab can trace its roots back to work published in 1995 that anti-IL-12 antibodies could abrogate experimental colitis in mice. An example of failed translation is IL-17 which was found to aggravate induced colitis in mice in 2004, but a clinical study with the anti-IL-17 monoclonal antibody secukinumab in CD came out negative.

In terms of genetic factors, IBD is a very heterogenous group of disorders – more than 250 gene locations have been identified that are considered relevant for IBD. Of these, only a handful have been investigated, including the C13orf31 (FAMIN) gene which has been linked to CD and also to systemic juvenile idiopathic arthritis and leprosy, and has been shown to control immunometabolic function by interacting with fatty acid synthase and promote glucose flux into de novo lipogenesis to promote fatty-acid oxidation and glycolysis and, consequently, ATP regeneration. This process leads to controlled inflammasome activation, mitochondrial and NADPH-oxidase-dependent production of reactive oxygen species (ROS), and the bactericidal activity of macrophages. Another gene that is implicated in UC is FCGR2A which alters the binding affinity of the antibody receptor it encodes, FcγRIIA, for IgG and thereby increases the immunogenicity of IgG immune complexes.

The role of environmental triggers in the pathogenesis of IBD is less well understood. The prevalence of IBD is increasing all over the world, especially in newly industrialised countries in Asia and South America. In the last 17 years, the number of IBD cases world-wide has doubled. A recently proposed candidate in the search for environmental triggers of IBD is oxazolone, which is known to induce colitis in animals. Oxazolone interacts with natural killer T (NKT) cells to suppress IL-10, thus impairing the barrier function of the intestinal epithelium. A large number of compounds have been identified which closely resemble all or parts of the chemical structure of oxazolone and have inflammation-inducing potential. While some of these compounds derive from dietary or industrial sources, others derive from the microbiome and have been shown to induce colitis by triggering CD1d-restricted NKT cell responses. The hypothesis that environmental triggers of IBD may derive from the microbiome is further supported by the clinical finding that faecal stream diversion is a highly effective treatment for colonic inflammation. Professor Tilg stressed that identifying environmental triggers remains a key issue for translational research in IBD.

Multi-omics has become a buzzword in translational research in recent years. Professor Rinse Weersma (University Medical Center Groningen, the Netherlands), presented an overview of what is meant by the term and provided examples of how ‘omics’ techniques can be related to clinical outcomes. Multiomics is a widely used term for an approach to biological analysis which involves studying whole biological systems rather than individual markers – instead of documenting the role of eg a single gene, transcript or protein in a certain disease, studies of the entire genome, transcriptome or proteome can provide new insights as they involve collecting and processing large amounts of complex data. By finding associations with clinical phenotypes, the ultimate aim of using multiomic approaches in medical research is to be able to deliver precision medicine, through molecular profiling of patients to identify prognostic markers for disease course and response to therapy. True multiomics studies are difficult and expensive to perform – because of the large number of potential variations and the need for combining different data sets, very large cohorts are required to obtain valid findings.

To date, the only multiomics study in the field of IBD is phase 2 of the Human Microbiome Project which included a cohort of IBD patients and provided important information on biological mechanisms in IBD. One of the aims was to construct interaction networks of associations that can be mined for aggregated data. In IBD patients, a network of more than 2,900 significant host and microbial cellular and molecular interactors could be constructed which ranged from specific microbial taxa to human transcripts and small molecule metabolites (1). In Groningen, Professor Weersma and his team have established the Groningen 1000IBD cohort, which currently consists of more than 1,200 Dutch IBD patients who have provided phenotype data and had multiomics profiles generated, and will be followed prospectively with the ultimate aim of discovering molecular subtypes of IBD that can be targeted with new treatments.

An example of a clinical application of multiomics profiling data is to perform pre-treatment genotyping of IBD patients and create a pharmacogenetic passport that can be incorporated into the electronic medical records system. The pharmacogenetic passport issues an alert if a patient is at risk of developing thiopurine toxicity or immunogenicity from anti-TNF therapy. A team at Groningen found that 26 patients need to be genotyped to prevent one toxicity or  immunogenicity event . Professor Weersma pointed out that the cost of this tool is unlikely to be prohibitive, since obtaining data for over 20 million genetic variants is cheaper than performing one single faecal calprotectin measurement. Another example of the potential clinical utility of multiomic profiling is the finding that changes in the microbiome composition may predict the response to vedolizumab therapy in IBD (2). Professor Weersma predicted that interest in multiomics and systems biology approaches in relation to clinical endpoints will continue to grow, requiring multidisciplinary teams of clinicians and biologists to interpret the results and generate research hypotheses. As the field expands, molecular profiling will become part of routine clinical practice in IBD just as in other parts of medicine.

References

1. Proctor LM, Creasy HH, Fettweis JM, Lloyd-Price J, Mahurkar A, Zhou W, et al. The Integrative Human Microbiome Project. Nature [Internet]. 2019;569(7758):641–8. Available from: https://doi.org/10.1038/s41586-019-1238-8
2. Ananthakrishnan AN, Luo C, Yajnik V, Khalili H, Garber JJ, Stevens BW, et al. Gut Microbiome Function Predicts Response to Anti-integrin Biologic Therapy in Inflammatory Bowel Diseases. Cell Host Microbe [Internet]. 2017 May 10;21(5):603-610.e3. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28494241