Researchers identify new possibilities for the treatment of inflammatory bowel disease
Two molecular pathways found to be integral to maintaining balance in the digestive system
A new study has revealed how two molecular pathways play an important role in maintaining balance in the human intestine, and how disruption of these pathways is linked to inflammatory bowel disease (IBD). The project was a collaboration between the University of Oxford, the Wellcome Sanger Institute, King’s College London and the University of Cambridge.
The study, published in the Journal of Experimental Medicine, shows that two molecular pathways, known as interleukin-10 (IL-10) and prostaglandin E2 (PGE2), are intrinsically linked and work together to maintain the balance in our gut. Any disruption to this balance impacts their ability to control the function of immune cells called macrophages, which have important consequences for maintaining immune balance in the digestive system as well as defence against infection.
Inflammatory bowel disease (IBD), encompassing Crohn’s disease and ulcerative colitis, is a chronic inflammatory condition of the gastrointestinal tract*. It affects at least five million people worldwide. Generally, inflammation is controlled by particular immune cells, such as macrophages, together with molecules such as cytokines and lipid mediators. How these molecules work together, however, has been poorly understood.
The study reveals a new relationship between two types of molecules, cytokine IL-10 and lipid mediator PGE2, that links them to intestinal inflammation. The molecules are responsible for signalling between cells and regulating cell function, including how active macrophages are in removing unwanted material, such as harmful bacteria, from our gut.
The team studied a patient with rare infantile-onset IBD, who was lacking a functional IL10RB gene. The early onset and severity of the patient’s case meant the causes of their IBD were more prominent and easier to observe than in the more common, adult-onset IBD.
Because IL-10 is an inhibitor of macrophages, the team expected them to become more effective at killing bacteria in the patient whose IL10RB gene was switched off – however, they observed the opposite. Instead, they discovered that a loss of IL-10 signalling induced an over-production of PGE2 in macrophages that in turn limited their capacity to kill bacteria, fuelling chronic intestinal inflammation.
When working copies of the IL10RB gene were introduced, PGE2 synthesis was inhibited and the macrophages became more effective at killing bacteria, highlighting the important relationship between IL-10 and PGE2 in maintaining balance in the gut.
“IL-10 molecules are known to promote gut health by preventing immune cells called macrophages from becoming overstimulated by the large number of bacteria that live in the gut. Our study reveals that IL-10 fine tunes the secretion of lipid mediator PGE2, preventing inflammatory tissue damage and ensuring that macrophages can kill harmful bacteria effectively.”
Dr Subhankar Mukhopadhyay King’s College London and the Wellcome Sanger Institute
“Increased PGE2 signalling in the intestine has been reported in inflammatory bowel disease patients and the new data suggest that PGE2 may contribute directly to the development and progression of disease. Further examination of this pathway, including the role of distinct PGE2 receptors found on macrophages may open up new therapeutic avenues.”
Professor Fiona Powrie Director of the Kennedy Institute at the University of Oxford
It had been previously known that IL-10 plays a role in IBD, but the IL-10 pathway has proven difficult to target with drugs. With the discovery of the relationship between IL-10 and PGE2, the researchers hope that new treatments can be developed using existing PGE2 targeting drugs – in effect, targeting IL-10 pathway via its relationship with PGE2.
*More information about inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis can be found here: https://www.crohnsandcolitis.org.uk/about-crohns-and-colitis/publications/crohns-disease
Subhankar Mukhopadhyay et al. (2019). Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2. Journal of Experimental Medicine. DOI: 10.1084/jem.20180649
This study was funded by Wellcome, and Fondation Louis Jeantet and supported by the NIHR Oxford Biomedical Research Centre, University of Oxford.
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS)
The Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS) is a multi-disciplinary department focusing on discovering the causes of musculoskeletal and inflammatory conditions to deliver excellent and innovative care that improves people’s quality of life. The largest European academic department in its field, NDORMS is part of the Medical Sciences Division of the University of Oxford, and is a rapidly growing community of more than 500 orthopaedic surgeons, rheumatologists and scientists all working in the field of musculoskeletal disorders.
The research work of the department takes place in several locations across the Nuffield Orthopaedic Centre, namely the Botnar Research Centre, the Kennedy Institute of Rheumatology, and the Kadoorie Centre. The co-location with NHS services puts the department in an excellent position with basic researchers working alongside clinicians. This substantially improves research capacity, improving access for researchers to patients, and facilitating the interaction between clinicians and scientists that is essential for successful medical research. https://www.ndorms.ox.ac.uk
King’s College London
King’s College London is one of the top 10 UK universities in the world (QS World University Rankings, 2018/19) and among the oldest in England. King’s has more than 31,000 students (including more than 12,800 postgraduates) from some 150 countries worldwide, and some 8,500 staff.
King’s has an outstanding reputation for world-class teaching and cutting-edge research. In the 2014 Research Excellence Framework (REF), eighty-four per cent of research at King’s was deemed ‘world-leading’ or ‘internationally excellent’ (3* and 4*).
Since our foundation, King’s students and staff have dedicated themselves in the service of society. King’s will continue to focus on world-leading education, research and service, and will have an increasingly proactive role to play in a more interconnected, complex world. Visit our website to find out more about Vision 2029, King’s strategic vision for the next 12 years to 2029, which will be the 200th anniversary of the founding of the university.
World-changing ideas. Life-changing impact. https://www.kcl.ac.uk/news
About the University of Cambridge
The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. To date, 107 affiliates of the University have won the Nobel Prize.
Founded in 1209, the University comprises 31 autonomous Colleges, which admit undergraduates and provide small-group tuition, and 150 departments, faculties and institutions. Cambridge is a global university. Its 19,000 student body includes 3,700 international students from 120 countries. Cambridge researchers collaborate with colleagues worldwide, and the University has established larger-scale partnerships in Asia, Africa and America.
The University sits at the heart of the ‘Cambridge cluster’, which employs 60,000 people and has in excess of £12 billion in turnover generated annually by the 4,700 knowledge-intensive firms in and around the city. The city publishes 341 patents per 100,000 residents. www.cam.ac.uk
The Wellcome Sanger Institute
The Wellcome Sanger Institute is a world leading genomics research centre. We undertake large-scale research that forms the foundations of knowledge in biology and medicine. We are open and collaborative; our data, results, tools and technologies are shared across the globe to advance science. Our ambition is vast – we take on projects that are not possible anywhere else. We use the power of genome sequencing to understand and harness the information in DNA. Funded by Wellcome, we have the freedom and support to push the boundaries of genomics. Our findings are used to improve health and to understand life on Earth. Find out more at www.sanger.ac.uk or follow us on Twitter, Facebook, LinkedIn and on our Blog.
Wellcome exists to improve health by helping great ideas to thrive. We support researchers, we take on big health challenges, we campaign for better science, and we help everyone get involved with science and health research. We are a politically and financially independent foundation. https://wellcome.org/
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