Breakthrough Gut Map Reveals the Exact Cells Driving Crohn’s Disease Inflammation

A detailed cellular study of Crohn’s disease has mapped how gene activity changes across more than 50 cell types in the gut. The study provides an open resource of the genes that characterize each cell type and those whose activity shifts in disease, uncovering new molecular and cellular signatures of immune activity in the gut lining.

Researchers from the Wellcome Sanger Institute, Cambridge University Hospitals NHS Foundation Trust and Open Targets analyzed over a million gut cells from people with Crohn’s and healthy controls, comparing changes in the gut lining and identifying immune cells that drive inflammation. 

The research, published today (15 June) in Nature Genetics reveals the cell types and molecular changes involved in Crohn’s inflammation. It is one of two complementary studies built on IBDverse, alongside a paper recently published in Nature,¹ which together use the resource to investigate different aspects of the disease. 

Inflammatory bowel disease (IBD) is an umbrella term used to describe disorders that cause chronic inflammation of the gastrointestinal tract. Over half a million people in the UK are estimated to be living with IBD, which includes Crohn’s disease and ulcerative colitis.² 

Crohn’s is a chronic condition that causes inflammation and ulcers in the digestive tract, from the mouth to the anus, often affecting the small intestine and colon. Although inflammation is most commonly observed in the terminal ileum –  the final section of the small intestine – Crohn’s is found in many locations of the body and with variation in severity both between patients and within patients over time.  

The biological basis of Crohn’s is not thoroughly understood, although it is thought to be caused by an overactive response by the immune system to the good gut bacteria in people with higher risk of Crohn’s due to their genetics. While therapies targeting immune cells have improved clinical outcomes for some patients, non-response to treatment remains high, with 15 per cent of Crohn’s patients requiring surgery within five years of diagnosis.³ Therefore, there is an urgent need to better understand the genetics of IBD in order for research to lead to more effective therapies. 

In a new study, researchers from the Sanger Institute, CUH and their collaborators took and analyzed biopsies from 111 patients with Crohn’s and a history of current or previous terminal ileitis - inflammation of the ileum - and 232 healthy volunteers.⁴ The team performed single-cell RNA sequencing, which is a powerful tool that measures gene activity, known as gene expression, in individual cells. Using the data, they identified genes that are abnormally expressed in Crohn’s and those where expression is specific to given cell types and cellular processes. 

One of the study’s most striking findings was a ‘molecular scar’ in the gut lining. Even after visible inflammation had healed, genes that help send messages to the immune system stayed switched on in the gut’s stem cells – the cells that constantly renew the lining. This suggests that an episode of inflammation leaves a lasting mark on these cells, which may shape how the gut responds to inflammation in future.

The researchers also identified a population of macrophages – immune cells that engulf and digest cellular debris – with high expression of the gene ITGA4. These cells were key drivers of inflammation through the JAK/STAT pathway, which carries signals from the cell surface to the nucleus to switch genes on and off. Drugs that block this pathway, known as JAK inhibitors, are already used to treat IBD, which points to these macrophages as a likely target of such therapies.

By creating a comprehensive map of cellular and molecular differences in Crohn’s compared to healthy controls, the researchers established IBDverse as a result - an online data resource of over 1,185,000 cells isolated from small intestine samples.⁵ The large IBDverse dataset will serve as an open resource for future research.

Crohn’s disease is complex, variable and deeply personal to every individual living with it, which is why understanding it at the level of single cells is so important. By creating this unprecedented map of more than one million gut cells, we are giving researchers around the world a powerful new tool to uncover how inflammation begins, persists and may one day be stopped. This is the kind of open science that can accelerate discoveries and bring us closer to better treatments for patients.”

Dr Monika Krzak, Wellcome Sanger Institute, University of Cambridge

“For inflammatory bowel diseases like Crohn’s and ulcerative colitis, it’s still unclear what is going wrong in the gut cells to cause inflammation. We have been able to compare gut cells of hundreds of people with and without IBD. This has given us new insight into the genes and cell types that are involved during active disease, and lays the groundwork for similar approaches to understand diseases of other major organs like eczema and asthma.” - Dr Tobi Alegbe, co-first author at the Wellcome Sanger Institute and Open Targets.

“There is an urgent need for increased understanding of the biology of Crohn’s disease if we are to develop more effective and safe medications for people living with this condition. The patients who contributed to this research have helped us build insight into the different ways that gut function and immune function are disrupted in the disease, and with the insight comes immediate new avenues for drug development and targeted therapies.” - Dr Tim Raine, senior author and consultant gastroenterologist at Cambridge University Hospitals NHS Foundation Trust.

“What makes this study different is that we designed replication in from the start and found that even with hundreds of patients and standardized protocols, fewer than half of the gene expression changes we detected in one cohort replicated in the other. That’s a sobering finding for the field. The biology that did replicate consistently points to the gut lining itself as a key player in Crohn’s with a molecular signature in epithelial cells that persists even after inflammation has resolved. We don’t yet know what that persistence means, but it likely influences how the gut responds to future inflammatory insults.” - Dr Carl Anderson, senior author at the Wellcome Sanger Institute.