Single-Cell Map Reveals How Genetic Variation Drives Inflammatory Bowel Disease, Opening New Paths for Drug Development
核心洞察
Scientists at the Wellcome Sanger Institute (搜索) created IBDverse, the largest single-cell dataset from gut tissue and blood, analyzing gene expression in roughly 2.2 million individual cells from over 400 individuals.
The study identified likely effector genes at more than half of known IBD genetic risk regions, revealing that many genetic effects appear only in specific cell types like dendritic cells and epithelial cells.
Findings suggest IBD arises from a combination of immune system dysregulation through reduced Notch (搜索) signaling and failure of the gut lining to repair itself via disrupted Wnt (搜索)-regulated genes.
Researchers at the Wellcome Sanger Institute (搜索), Open Targets (搜索), and Cambridge University Hospitals NHS Foundation Trust have created the most detailed cell map to date showing how genetic variation influences inflammatory bowel disease (搜索) (IBD), revealing the specific cells and genes that drive the disease. Published June 3 in Nature, the findings lay the foundation for the development and repurposing of new treatments across many diseases.
IBD — which includes Crohn's disease (搜索) and ulcerative colitis (搜索) — is characterized by chronic inflammation of the gastrointestinal tract and affects over 4.9 million people worldwide, including more than half a million in the UK. Inherited changes in DNA are known to play a major role in determining susceptibility to IBD, yet translating this knowledge into biological understanding has proven difficult because over 90 percent of DNA changes linked to IBD lie outside regions of the genome that code for proteins.
"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," said a researcher involved in the study.
Building IBDverse: Single-Cell Sequencing at Unprecedented Scale
The team collected blood and gut samples at Addenbrooke's Hospital in Cambridge from just over 400 individuals, including 125 people with Crohn's disease (搜索). Gut samples were collected from the terminal ileum — the last portion of the small intestine — and the rectum, the most commonly affected sites in Crohn's disease and ulcerative colitis (搜索), respectively.
The researchers generated 'IBDverse', the largest single-cell dataset from gut tissue and blood from Crohn's disease (搜索) and healthy patients, containing gene expression data from roughly 2.2 million individual cells. They measured the expression level of tens of thousands of genes in each of these cells using single-cell RNA sequencing, then linked inherited genetic differences to changes in gene expression level and compared these to known genetic risk regions for IBD.
"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, involving hundreds of patients undergoing invasive biopsies specifically for this research," said Dr. Tim Raine, co-senior author and consultant gastroenterologist at CUH. "The willingness of those patients to contribute, and the extraordinary effort of the clinical and laboratory teams to collect and process samples at that scale, made this unprecedented science possible."
Cell-Type-Specific Genetic Effects Revealed
Many genetic effects linked to IBD were found to only appear in specific cell types and are missed when studying whole tissues. The team identified likely effector genes — genes most likely to drive disease — at more than half of known genetic regions associated with IBD.
The researchers found that many genetic effects occurred in immune cells, particularly in dendritic cells, which resulted in reduced Notch (搜索) signaling — a pathway involved in regulating immune responses in the gut. They also identified genetic effects in epithelial cells, where genetic changes linked to IBD dysregulated the expression of Wnt (搜索)-regulated genes that control crucial cellular functions. This leads to reduced tissue renewal that may weaken the gut lining and contribute to IBD susceptibility.
"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," said Dr. Bradley Harris, co-first author at the Wellcome Sanger Institute (搜索). "This work therefore really helps us understand the overall picture of what molecular changes cause IBD, and in which cell types and tissues."
Overall, the study demonstrates that IBD arises from a combination of immune system dysregulation and failure of the gut lining to repair itself properly.
Broader Implications for Drug Development
Among the genes identified, the researchers found 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 genetic mapping could help anticipate the tissue-specific effects of existing drugs.
Beyond IBD, the findings demonstrate a broadly applicable framework for connecting genetic risk to specific cells and pathways in any disease where relevant tissue can be sampled, with potential applications for conditions including asthma, psoriasis and endometriosis.
"The Foundation is pleased to support this important project as part of its genetics initiative. This high-resolution cell map provides more granular information on which pathways are abnormal in different cell types in IBD," said Dr. Alan Moss, Chief Scientific Officer of the Crohn's & Colitis Foundation, one of the study's funders. "Information such as this can guide researchers to disease signals in specific cell types. These data can reveal new mechanisms of disease, and potentially more targeted treatments for patients."
The researchers emphasized that the same approach can be applied broadly. "What's really exciting about this, in addition to the many lessons we've learned about IBD biology, is that the same approach can be used to unlock the biological mysteries of many different diseases. Single-cell sequencing at scale provides a high-resolution view of disease biology, and by combining that with genetic variation, we can now make the insights needed to drive better drug target identification."