Developing a test to personalise Crohn’s treatments

What this research looked at

Everyone with Crohn’s Disease experiences the condition differently. Some people respond well to some medicines, but others don’t.

This aim of this research project was to find new biomarkers that can reliably predict who will respond best to biological medicines for Crohn’s. A biomarker is a specific biological feature or “red flag” that doctors can look for in a patient – often in a blood sample. Biomarkers are used to reliably predict how a person will respond to a treatment.

In this research, Dr Powell used a cutting-edge technology, called next-generation sequencing, to look incredibly closely at immune cells from the gut of people with Crohn’s. His research team analysed which genes are switched on or off in these cells during inflammation. The pattern of genes that are turned on or off is called the transcriptional signature.

Dr Powell also looked for transcriptional signatures in epithelial cells. Epithelial cells line the gut to form a protective barrier. Epithelial cells play a role in the development of Crohn’s - they become leaky so the protective barrier doesn’t work properly. This part of the research was done using a new technology that creates 3D 'mini guts' grown from gut tissue.

Together, these transcriptional signatures were used to build a biomarker. Dr Powell and his team then looked for these biomarkers in hundreds of people with Crohn’s who had taken a biological medicine. In this way, they hoped to test whether this biomarker could distinguish between those people who had responded well to a biologic and those who had not.

What the researchers found 

From this work, the researchers were able to show that their transcriptional signature biomarker was increased in gut biopsies of people with Crohns or Colitis. The size of this increased response was different depending on the person’s response to treatment. So, they were able to tell between those who responded to various advanced treatments and those who did not.

What the researchers think this could mean for people with Crohn's and Colitis

Finding biomarkers that can predict who will respond best to biological medicines could revolutionise the treatment of Crohn’s and Colitis. People with a specific biomarker could be given a treatment that has the greatest chance of working well at the earliest opportunity. They would no longer have to go through a trial-and-error process of taking different medicines, where some might work but others won’t. This would significantly improve their quality of life and help to prevent further complications, such as fibrosis and fistulas, that are linked to long-term untreated inflammation in the gut.

Scientific publications

• Pavlidis P, Tsakmaki A, Pantazi E, Li K, Digby-Bell J, Cozzetto D, Yang F, Lo J, Niazi U, Friedman J, Long AK, Ding Y, Carey CD, Lamb C, Saqi M, Macdonald TT, Lord GM, Bewick G, Powell N. Interleukin 22 regulates neutrophil recruitment in ulcerative colitis andis associated with resistance to ustekinumab therapy. Nature Communications 2022 Oct 3;13(1):5820. https://doi.org/10.1038/s41467-022-33331-8). PMID: 36192482
• Pavlidis P, Tsakmaki A, Treveil A, Li K, Cozzetto D, Yang F, Niazi U, Hussain Hayee B, Saqi M, Friedman J, Korcsmaros T, Bewick G, Powell N. Cytokine responsive networks in human colonic epithelial organoids unveil a novel molecular classification of inflammatory bowel disease. Cell Reports 2022 27;40(13):111439. https://doi.org/10.1016/j.celrep.2022.111439. PMID:36170836

Who lead the research: Dr Nick Powell, Imperial College London
Our funding: £119,400
Duration: 24 months
Official title of the application: Harnessing cytokine-responsive transcriptomics to deliver precision medicine in Crohn’s disease