IBDverse database aids in cellular study that maps gene activity changes across more than 50 gut cell types in Crohn’s disease
A new comprehensive map of cellular and molecular differences in patients with Crohn’s disease may lead to lifechanging discoveries around how to stop the chronic condition.
IBDverse is an online data resource of over 1,185,000 cells isolated from small intestine samples. 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,” said Dr Monika Krzak of the Institute of Metabolic Science, University of Cambridge, and formerly of the Wellcome Sanger Institute which led study.
“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.”
The IBDverse has already led to a detailed cellular study of Crohn’s disease that has mapped how gene activity changes across more than 50 cell types in the gut.
The research, published in Nature Genetics, reveals the cell types and molecular changes involved in Crohn’s inflammation.
Inflammatory bowel disease (IBD) is an umbrella term used to describe disorders that cause chronic inflammation of the gastrointestinal tract. Between 40,000 and 50,000 people in Ireland live with IBD, which includes Crohn’s disease and ulcerative colitis.
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.
In this latest study, researchers took and analysed biopsies from 111 patients with Crohn’s and a history of current or previous terminal ileitis (inflammation of the ileum) and 232 healthy volunteers.
The team performed single-cell RNA sequencing to measure 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.
The study uncovered 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 therapies.
The study was led by researchers in the Wellcome Sanger Institute, Cambridge University Hospitals NHS Foundation Trust (CUH) and Open Targets.
“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,” said Dr Tobi Alegbe, co-first author at the Wellcome Sanger Institute and Open Targets.
“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 Tim Raine, senior author and consultant gastroenterologist at CUH, added: “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.”
Read the study: Single Cell RNA Sequencing of Terminal Ileal Biopsies Identifies Signatures of Crohn’s Disease Pathogenesis – Nature Genetics.