A landmark study reading gene activity in 2.2 million individual cells has identified, for the first time, the specific genes and cell types most likely to be driving inflammatory bowel disease. The findings point to two mechanisms that weren’t previously on the IBD radar and suggest new targets for treatment.
Inherited Markers of Inflammatory Bowel Disease
Somewhere in the genome of most people with Crohn’s disease or ulcerative colitis lies a set of DNA variants. These are inherited differences that correlate to your risk of developing inflammatory bowel disease. Scientists have known about these variants for years. What they haven’t known is what those variants actually do: which genes they switch on or off, which cells and how that leads to inflammation.
A new study published in Nature on 3 June 2026 has answered those questions for more than half of the known IBD genetic risk regions, and the answers were surprising.
Dr Carl Anderson, co-senior author, Wellcome Sanger Institute, explained in a press release, ‘Genome-wide association studies have told us where in the genome IBD risk resides, but this study tells us which genes these risk variants disrupt and in which cell types this occurs.’
Researchers at the Wellcome Sanger Institute, Open Targets, and Cambridge University Hospitals built what they call IBDverse: the largest single-cell dataset of gut tissue ever assembled. Analysing gene activity in roughly 2.2 million individual cells from gut biopsies and blood samples of 421 people, including 125 with Crohn’s disease, the team were able to pinpoint the specific cells in which genetic risk variants have their effects and unmask the genes they are most likely to be disrupting.
For the first time, researchers have flagged 74 gene regulatory regions related to inherited IBD genetic risk variants, opening the door to new research avenues. They have also identified some unexpected cell types and key cellular processes that could be candidates for pharmacological intervention.
Mapping the Gut
Over 90 per cent of the genetic variants linked to IBD, and to most other complex diseases, lie outside the parts of the genome that code for proteins. This makes them very difficult to interpret. A variant might sit in a stretch of DNA that does nothing obvious, yet somehow increase disease risk. Researchers suspected these variants were altering how strongly certain genes are switched on or off (i.e. their ‘expression’ level), but identifying which genes, and in which cells, had proven extraordinarily challenging.
The problem with previous approaches was that they measured gene activity in chunks of mixed tissue, which involves blending together dozens of different cell types. Any effect that only occurs in one specific cell type was drowned out by the average. In contrast, single-cell RNA sequencing solves this by reading gene activity in each cell individually, producing a detailed atlas of what every cell type is doing. The Wellcome Sanger team would try to map the genetic activity of cells in the gut on a scale never before attempted.
As Dr Tim Raine, co-senior author and consultant gastroenterologist at Cambridge University Hospitals, put it, ‘When we started planning this study, single-cell sequencing projects typically involved tens of individuals. We knew that to have any real power to answer these questions, we would need to obtain tissue samples at a far larger scale.’ – The success of this project would rely on those 421 participants who provided blood and tissue samples for analysis. Would 421 samples deliver enough of each of those specialized cells?
Secrets Hidden Deep in Our Genome
The researchers managed to retrieve over two million gut cells from the samples provided by the participants. This sounds enormous, but because there are so many different cell types doing distinct things in the gut and all the people involved in the study had their own genetic quirks, every cell was precious.
Each cell was individually probed to see which genes were switched on at the time of collection in patients with inflammatory bowel disease. The scientists used a supercomputer to spot repeated motifs of gene activity that would identify each cell type. Every cell that was analysed was matched to a cell type, and this is where the project got interesting. They were able to find groups of cells doing different jobs and map out the diverse combinations of gene expression in each cell type. Now they could compare what was going on in the gut of an IBD patient with what they would expect to see in a healthy gut.
The researchers searched for unusual patterns of gene expression that might be a clue to what was causing the inflammation. Would a particular cell type be tagged as a trouble maker? Would they find any genes activated unexpectedly? Most importantly, would any of the unusual gene activity correspond to areas of the genome that inheritance studies had hinted were involved?
Casting a Deep Net For Genes and Cells Involved in Inflammatory Bowel Disease
The first big catch brought in by the team was that they found active gene regulatory sequences in 180 of 321 genetic regions that geneticists had previously linked to IBD. What’s more, they didn’t just uncover a hint that the region was involved. The researchers were able to identify specific genes that were most probably responsible for the risk. In 104 of those genetic regions, the investigators already had some suspicions about which genes could be related to IBD. This experiment closed the net. As for the other 74? This was the real haul. Until now, nobody had figured out which genetic regulatory sequences in those regions might have anything to do with IBD. Finally, they had some clues. Next the researchers looked to see what those genes the 180 regulatory regions were controlling were doing. Where were they active? What were they used for?
The scientists hunted for each regulatory region of interest in their new map of the IBD gut. Did they show up more in one cell type than another? It turned out that yes, there were actually two cell types that lit up when they searched for those sequences.
Notching Up Results In Immune Cells
To their surprise, a cell type that kept coming up in their searches was one that doesn’t usually make headlines in IBD research: dendritic cells. These specialized immune cells patrol the gut, recognize threats, and direct the immune system’s response.
The Inflammatory Bowel Disease risk variants that act in dendritic cells appear to reduce the activity of genes involved in the notch signalling pathway, a molecular communication system that helps regulate immune responses in gut tissue.
Two specific genes in this pathway, MAML2 and ZMIZ1, showed particularly strong associations with the regulatory regions. Both encode proteins that activate notch signalling; IBD risk variants appear to reduce their expression in dendritic cell subtypes. This might impair the gut immune system’s ability to maintain the delicate balance between attacking real threats and tolerating harmless food and bacteria. The study more than doubled the number of notch pathway genes implicated in IBD, providing a feast of new therapeutic targets.
A more unusual finding involved PSEN2, a gene best known for causing early-onset Alzheimer’s disease. PSEN2 encodes a component of an enzyme complex called gamma-secretase, which is required for notch signalling to work. The team found that IBD risk variants increase PSEN2 expression in gut epithelial and endothelial cells. This may help explain something that has puzzled Alzheimer’s disease researchers for years: why gamma-secretase inhibitors, developed to treat Alzheimer’s by blocking this enzyme, consistently caused gut side effects in clinical trials.
Protecting the Barrier
The second major finding involves the cells that line the inside of the gut, the epithelial cells, responsible for forming and maintaining the gut’s protective barrier. The researchers found that the cells most likely to be using the genetic regulatory elements were colonocytes (the cells of the large intestine) and gut stem cells, which constantly renew the gut lining.
This set of elements controls genes that disrupt the Wnt signalling pathway. Wnt signalling is a collection of molecular signals that decide how cells grow, divide, and replace themselves. The gut lining uses Wnt signalling to turn over completely every few days; it relies on a population of stem cells at the base of intestinal crypts (small pockets in the gut wall) to generate fresh cells continuously. A key finding is that the gene MYC, a well-known regulator of cell proliferation and a target of Wnt signalling, shows increased expression linked to Crohn’s disease risk in these gut stem cells.
The authors speculate that these regulatory elements impair the gut’s ability to renew and repair its own lining, making it more susceptible to the inflammatory cascade that follows. As Dr Bradley Harris, co-first author, notes, this represents a possible new axis of IBD risk: not just immune dysfunction, but a failure of the gut to maintain itself.
‘To our surprise, many of the newly nominated effector genes regulate pathways that were previously underappreciated in the context of IBD risk. These associations also accumulated in specific cell types of the gut, such as dendritic cells and gut stem cells, which are not commonly associated with the disease.’
A Map for Drug Makers – And a Clue About Metformin
The study’s implications for drug development are substantial. Among the genes and cell types that the team identified, several are already targeted by existing Inflammatory Bowel Disease drugs. Vedolizumab addresses the protein made by ITGA4, and tofacitinib targets JAK2. Finding these genes independently via genetic mapping provides human genetic support for their mechanism of action, and increases confidence in other drug candidates that emerge from the same approach.
The team also found genes targeted by drugs used in other diseases that may be contenders for repurposing in IBD. Among them: PRKCB, a kinase already being tested in early-phase IBD clinical trials, which now has genetic support from this study.
Setting Sail Again
Researchers have created a map of gene expression in the IBD gut, and linked 180 hereditary markers with specific genes that can now be investigated.
We know that the mix of gene variants we have gives us different risk profiles for IBD. Even if you have gene variants that often show up in IBD patients, it doesn’t necessarily mean you will go on to develop Crohn’s disease, colitis or other inflammatory bowel disease.
Genetic markers are often simply chunks of DNA that always get carried along with another piece of DNA that encodes for the real factor of interest. Just because that DNA sequence shows up a lot doesn’t mean it has anything to do with causing a disease. The special thing about this study is that scientists were finally able to match which genetic markers might actually increase your risk of IBD, rather than just correlating to your risk. Now we know which cellular processes are worth looking into for clues about what triggers the condition.
The team discovered that out of 321 genetic markers that often show up in people with IBD, 180 can be linked to genes that are active in the gut. What’s more, they were able to link many of those genes to important processes involving the immune system and the lining of the intestines.
What this project has done is give researchers a new understanding of what underlying cellular processes might make people vulnerable to developing IBD. Now it’s time for Crohn’s and colitis scientists to get to work to see whether notch signalling in dendritic cells or inhibited cell renewal really does have something to do with the progression of IBD.
References
Alegbe T, Harris BT, et al. Cell-type-resolved genetic variation shapes inflammatory bowel disease risk. Nature. 2026. DOI: 10.1038/s41586-026-10627-z
Wellcome Sanger Institute / EurekAlert press release (3 June 2026): ‘Study of millions of cells reveals new way to understand genetic risk of disease.’ https://www.eurekalert.org/news-releases/1130513
Crohn’s & Colitis UK (2022). New research shows over 1 in 123 people in UK living with Crohn’s or Colitis. https://crohnsandcolitis.org.uk
Nelson MR, et al. The support of human genetic evidence for approved drug indications. Nat Genet. 2015;47:856–860.
