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

*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

Publication:

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

Funding:

This study was funded by Wellcome, and Fondation Louis Jeantet and supported by the NIHR Oxford Biomedical Research Centre, University of Oxford.