Inflammatory bowel disease

Scientists discover network of cells and genes involved in Crohn’s disease complication

adicorat — Wed, 25 Jun 2025 09:00:10 +0000

Scientists discover network of cells and genes involved in Crohn’s disease complication

By Allessandra DiCorato June 25, 2025

Scientists discover network of cells and genes involved in Crohn’s disease complication

Spatial mapping reveals genes contributing to fibrosis, or scarring, in the gut, laying the foundation for better treatments.

By Allessandra DiCorato

June 25, 2025

Credit: Xavier and Smillie labs

Microscopy image shows intestinal tissue from a Crohn’s patient with fibrosis. Colored dots indicate clusters of different cell types, with red dots representing inflammatory fibroblasts and blue dots epithelial cells.

Up to half of patients with Crohn’s disease, an inflammatory bowel disease, develop a complication called fibrosis, where the gut becomes scarred and obstructed, causing pain and bloating. Currently, the only treatment option for these gut “strictures” is surgery.

To better understand the biological processes at play in strictures, ӳ��ý and Massachusetts General Hospital researchers analyzed individual cells from the intestinal tissue of Crohn’s disease patients, measuring gene activity and mapping the cells’ location in the tissue. The team identified key cell populations involved in this stricturing process, including different kinds of fibroblasts that may contribute to stricture formation and inflammation. The team also pinpointed certain genetic variants expressed in these cells that increase a person’s likelihood of developing Crohn’s.

The scientists suggest that new therapies that target these genes could directly address fibrosis and potentially be more effective for this complication than existing drugs, which are primarily focused on reducing inflammation.

Appearing today in Nature Genetics, the work was led by senior authors Ramnik Xavier and Christopher Smillie, associate member at the ӳ��ý and an assistant professor at Harvard Medical School. Xavier is a ӳ��ý core institute member and the director of ӳ��ý’s Klarman Cell Observatory, the Kurt J. Isselbacher Professor of Medicine at Harvard Medical School, and director of the Center for Computational and Integrative Biology and core member in the Department of Molecular Biology at Massachusetts General Hospital. Lingjia Kong, a research scientist in the Xavier lab, is the first author on the study.

“Fibrosis affects every organ in the body, but generally the therapies that are available to correct or reverse fibrosis work poorly,” Xavier said. “Connecting genetics to spatial structures of the gut and assembling a map of Crohn’s disease risk genes allows us to begin to identify new therapeutic targets and potentially intervene earlier with drugs tailored to individual patients."

Cell network

In 2023, Xavier’s lab used single-cell RNA sequencing to create the largest known atlas of single cells from routine biopsies of Crohn’s patients. When spatial mapping techniques became more advanced, the researchers decided to extend the work to deeper parts of the intestine, such as areas that might be removed during surgery to treat strictures. Though other scientists had studied how these features develop, they did not fully understand the intricate network of cell populations involved. Drugs targeting strictures have failed in clinical trials, suggesting the need for a deeper look.

In the new study, Xavier’s team analyzed 61 tissue samples from 21 patients with Crohn’s — from both routine biopsies and surgeries — and 10 people without inflammatory bowel disease. They used a combination of single-cell RNA sequencing, which profiles gene expression in individual cells, and spatial transcriptomics, which provides additional information about the cells’ location and surroundings in gut tissue. In all, they identified 68 cell types.

“Having single-cell and spatial data to complement each other was a really important and unique part of this work that allowed us to uncover populations of cells that people didn’t know were involved in the disease,” Kong said.

One group of cells, a subpopulation of fibroblasts deep in the intestine, expressed particularly high levels of collagen and were present in patients with strictures. The team thinks these cells and the collagen they produce could be responsible for making the stricture that contracts intestinal tissue.

Another group of fibroblasts clustered near the surface of the intestine and expressed immune-signaling molecules, suggesting that the cells help coordinate immune responses during an injury to gut tissue and may promote the long-term inflammation that ultimately contributes to stricture formation. The team also uncovered neurons associated with Crohn’s that were embedded deep in the organ and had been difficult to detect previously with single-cell methods or in biopsy samples.

In the future, the researchers hope that a better understanding of these populations could help scientists develop more personalized therapies for Crohn’s disease patients with specific symptoms and genetic features. It could also help doctors better treat patients with existing drugs. For example, if a patient had a certain cellular network indicating they might develop resistance to anti-inflammatory drugs called anti-TNF therapies, their doctor could consider different treatments without waiting for the patient to develop resistance.

“Most of the arsenal of therapeutics we have for inflammatory bowel diseases either target the microbes involved or inflammation itself,” said Jacques Deguine, an author on the study and the scientific director of the Immunology Program at the ӳ��ý. “But now we can potentially think about additive therapies that more directly target the fibrotic process.”

Until then, the researchers hope to collect more samples from a broader range of patients to uncover how these populations of cells change over the course of an illness and in response to treatments. The team also plans to develop cell models to study these populations and potential drugs in the lab.

“These maps of gene programs were enabled by a robust collaboration between patients and the physicians and surgeons who care for them,” said Xavier. “I’m hopeful that this type of team science can be used to tackle other hard-to-treat complications in patients.”

Funding

This work was supported in part by the National Institutes of Health and The Leona M. and Harry B. Helmsley Charitable Trust.

Paper cited

Kong L et al. Single-cell and spatial transcriptomics of stricturing Crohn’s disease highlights a fibrosis-associated network. Nature Genetics. Online June 25, 2025. DOI: 10.1038/s41588-025-02225-y.

Tags:

Immunology Program

Xavier Lab

Inflammatory bowel disease

Spatial -omics

Ramnik Xavier

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arinavetta — Tue, 15 Oct 2024 18:32:38 +0000

Scientists discover network of cells and genes involved in Crohn’s disease complication

By Allessandra DiCorato June 25, 2025

Scientists discover network of cells and genes involved in Crohn’s disease complication

Spatial mapping reveals genes contributing to fibrosis, or scarring, in the gut, laying the foundation for better treatments.

By Allessandra DiCorato

June 25, 2025

Credit: Xavier and Smillie labs

Cell network

Funding

This work was supported in part by the National Institutes of Health and The Leona M. and Harry B. Helmsley Charitable Trust.

Paper cited

Tags:

Immunology Program

Xavier Lab

Inflammatory bowel disease

Spatial -omics

Ramnik Xavier

Scientists identify a unique combination of bacterial strains that could treat antibiotic-resistant gut infections

adicorat — Wed, 18 Sep 2024 14:51:33 +0000

Scientists discover network of cells and genes involved in Crohn’s disease complication

By Allessandra DiCorato June 25, 2025

Scientists discover network of cells and genes involved in Crohn’s disease complication

Spatial mapping reveals genes contributing to fibrosis, or scarring, in the gut, laying the foundation for better treatments.

By Allessandra DiCorato

June 25, 2025

Credit: Xavier and Smillie labs

Cell network

Funding

This work was supported in part by the National Institutes of Health and The Leona M. and Harry B. Helmsley Charitable Trust.

Paper cited

Tags:

Immunology Program

Xavier Lab

Inflammatory bowel disease

Spatial -omics

Ramnik Xavier