Scientists have created the most detailed cellular map yet of how genetic variations affect inflammatory bowel disease (IBD), revealing the specific cells and genes that cause the disease.
It was released today (June 3rd). natureResearch carried out at the Wellcome Sanger Institute, Open Target and Cambridge University Hospitals NHS Foundation Trust (CUH) has identified key genetic and cellular drivers of IBD risk, demonstrating the power of single-cell approaches for understanding the complex nature of human disease.
This discovery laid the foundation for the development and repurposing of new treatments across many diseases.
IBD, which includes Crohn’s disease and ulcerative colitis, is characterized by chronic inflammation of the gastrointestinal tract and affects more than 4.9 million people worldwide1, including more than 500,000 people in the UK2.
Genetic changes in your DNA are known to play an important role in determining your susceptibility to IBD. However, translating this knowledge into biological understanding is difficult because more than 90 percent of the DNA changes associated with IBD lie outside of protein-coding regions of the genome. These DNA changes are therefore thought to influence disease by altering the strength with which certain genes are switched on or off, known as gene “expression” levels.
However, identifying the specific genes and cell types that are dysregulated by these DNA changes has proven difficult. This is because most cell studies of diseases analyze whole tissue samples that are a mixture of many cell types, masking effects that only work in specific cells.
In the new study, researchers at the Sanger Institute, Open Target, and CUH and their collaborators sought to understand whether studying the expression levels of genes in individual cell types can better explain how genetic risk contributes to IBD.
The research team collected blood and intestinal samples from just over 400 people, including 125 with Crohn’s disease, at Addenbrookes Hospital in Cambridge, UK. Intestinal samples were collected from the terminal ileum (the last part of the small intestine) and the rectum. The terminal ileum and rectum are the most commonly affected sites in Crohn’s disease and ulcerative colitis, respectively.
Researchers have generated ‘IBDverse’, the largest single-cell dataset from intestinal tissue and blood from healthy patients with Crohn’s disease, containing gene expression data from approximately 2.2 million individual cells. They measured the expression levels of tens of thousands of genes in each of these cells using a method called single-cell RNA sequencing. They then correlated genetic differences with changes in gene expression levels and compared these to known IBD genetic risk areas.
Many genetic effects associated with IBD have been found to be present only in specific cell types and are missed when studying whole tissues. The research team identified likely effector genes (genes most likely to cause the disease) in more than half of the known genetic regions associated with IBD.
Researchers also found that a number of genetic effects occur in immune cells, particularly dendritic cells, resulting in a decrease in Notch signaling, a pathway involved in regulating immune responses in the gut.
They also identified genetic effects in certain types of cells that line the internal and external surfaces of the body, known as epithelial cells. Genetic alterations associated with IBD dysregulated the expression of Wnt-regulated genes that control important cellular functions. 5 This results in decreased tissue regeneration and weakens the intestinal lining, which may contribute to IBD susceptibility.
Overall, this study demonstrates the power of single-cell sequencing and genetics to unravel disease mysteries. The findings suggest that IBD results from a combination of dysregulation of the immune system and failure of the intestinal lining to repair itself properly.
The study also points to broader implications for drug development. Among the genes identified, researchers discovered a potential explanation for why metformin, one of the most widely prescribed drugs for type 2 diabetes, commonly causes gastrointestinal side effects, suggesting that single-cell gene mapping may help predict tissue-specific effects of existing drugs. The findings present a broadly applicable framework for linking genetic risk to specific cells and pathways in any disease beyond IBD for which relevant tissue can be sampled, and could also be applied to diseases such as asthma, psoriasis and endometriosis.
“Surprisingly, many of the newly named effector genes control pathways that have previously been underappreciated in relation to IBD risk. These associations are also enriched in specific cell types in the intestine that are not normally associated with the disease, such as dendritic cells and intestinal stem cells. This study therefore greatly contributes to our understanding of the overall picture of what molecular changes cause IBD and in which cell types and tissues.”
– Dr. Bradley Harris, Co-lead author, Wellcome Sanger Institute
“The Foundation is pleased to support this important project as part of its genetics efforts. This high-resolution cellular map provides more detailed information about which pathways are abnormal in different cell types in IBD. Such information can lead researchers to disease signals in specific cell types. These data may reveal new mechanisms of disease and reveal more targeted treatments for patients.”
– Dr. Alan Moss, Chief Scientific Officer, Crohn’s and Colitis Foundation, one of the research funders
“When we began planning this study, single-cell sequencing projects typically involve dozens of individuals. We knew that to have a real ability to answer these questions, we would need to obtain much larger tissue samples, including hundreds of patients undergoing invasive biopsies specifically for this study. The willingness of those patients to contribute, and the extraordinary efforts of our clinical and laboratory teams to collect and process samples at that scale, made this unprecedented science possible.”
– Dr. Tim Lane, Associate Senior Author, CUH Gastroenterology Consultant
“Genome-wide association studies have told us where IBD risk resides in the genome, but this study now tells us which genes these risk mutations disrupt and in which cell types the risk occurs. What’s really interesting about this study is that in addition to the many lessons we’ve learned about IBD biology, “Large-scale single-cell sequencing now provides a high-resolution view of disease biology, which, when combined with genetic variation, can provide the insights needed to drive the identification of better drug targets.”
– Dr. Karl Anderson, Co-Senior Author, Wellcome Sanger Institute and Open Target
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Reference magazines:
Aregbe, T. others. (2026). Genetic variations determined by cell type determine the risk of inflammatory bowel disease. nature. DOI: 10.1038/s41586-026-10627-z. https://www.nature.com/articles/s41586-026-10627-z
