Researchers at MIT’s Broad Institute and Harvard and Massachusetts General Hospital have constructed a high-resolution cell map of Crohn’s disease, a chronic condition in which an overactive immune system causes inflammation throughout the gut, leading to symptoms including abdominal pain, diarrhea and weight loss. . The disease is difficult to treat and often requires hospitalization.
The atlas is the largest single-cell study from Crohn’s patients to date, containing gene expression profiles of more than 700,000 cells from 71 healthy individuals and patients in various states of inflammation.
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Posted in immunityThe results provide a detailed cellular picture of the biological processes underlying Crohn’s disease that are unique to the small and large intestine. The data also reveals genes and pathways associated with complications of the disease, which new drugs could one day target. What’s more, the findings could help researchers anticipate and eventually prevent flare-ups of symptoms, or understand why some patients respond to treatments and others don’t.
“We’re beginning to see that Crohn’s disease is not one disease, and that it has many subtypes,” said Ramnik Xavier, senior author of the study, a core institute member and director of the Klarman Seal Observatory in Broad. Xavier is also the Kurt J. Professor of Therapeutics at MIT. Lingjia Kong, a research scientist in Xavier’s lab, was the first author of the study.
“We really wanted to build a resource for this field,” said Jacques Degen, study author and associate director of the Immunology Program at Broad University. “There have been atlases across a range of diseases, but now our field has grown enough that we can begin to address these questions in complex diseases, involving different organs. This moves the needle toward an individualized understanding of biology.”
Insights into inflammation
Previous genetic studies have identified more than 200 loci in the genome associated with Crohn’s disease. But Xavier’s team knew that to fully understand the disease, they would need a cellular map showing its full complexity. They studied inflammatory and non-inflammatory cells from both parts of the digestive tract: the large intestine and the ileum, the last part of the small intestine most often affected by Crohn’s disease.
The scientists used single-cell RNA sequencing to analyze the activity of genes in individual gut cells. They found that immune cells and the stroma — the cells within the intestine that form and support underlying connective tissue — changed in composition during disease. The lining of the intestine showed more changes in gene expression, with some changes unique to the large or small intestine. They also found that the expression of genes previously linked to disease risk was distinct in each organ.
“I think this lays the foundation for understanding why Crohn’s inflammation appears in one organ versus another, and how certain treatments can affect different disease subtypes differently,” DeJoin said.
Towards personalized medicine
About 50 to 60 percent of people with Crohn’s disease respond to medication, and some experience a relapse of symptoms. Xavier said this indicates that Crohn’s disease is caused by a variety of biological mechanisms that require treatments tailored to individual patients. He and Deguin added that many of their team’s findings point to potential targets for personalized therapies. For example, they identified three genes involved in collagen production that likely contribute to scar tissue in the intestines, which makes the intestines stiffer and less able to pass through food — a common complication of Crohn’s.
To their surprise, the researchers discovered that Crohn’s patients had certain gene expression signatures even when their tissues did not appear to be inflamed. This may indicate signs of pathology that can be detected even when the tissue appears to have healed at endoscopy. Understanding the pathways that contribute to low-grade inflammation can help predict when symptoms will flare up.
In the future, Xavier’s team plans to expand their atlas by collecting samples from patients from a range of strains. Dejoen also hopes to study patients before and after different treatments to track how their disease is progressing.
“These projects are collaborative studies involving patients, clinicians, clinical coordinators, data generators, and computational biologists,” said Xavier. “It became clear that this is the way biology had to be done to have a real impact on human disease.”
Reference: Kong L, Pokatayev V, Lefkovith A, et al. The nature of immune dysregulation in Crohn’s disease has been revealed by single cell transcriptome profiling in the ileum and colon. immunity. Posted Online Jan 2023: S1074761323000122. doi: 10.1016/j.immuni.2023.01.002
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