A new single-cell map of childhood Crohn’s disease offers a closer look at how the disease progresses and why some children respond better to treatment than others. The study, published in eLife, provides a detailed view of the cellular changes associated with disease severity and treatment response in pediatric patients.
“Our study addresses a critical unmet need in the fields of IBD with the creation of an atlas of newly diagnosed untreated disease tissue, coupled with detailed clinical follow-ups to link diagnostic cell types to disease progression,” said Leslie Kean, MD, PhD, professor of pediatrics at Harvard Medical School and director of the Stem Cell Transplant Center at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.
“That the severity of pediatric Crohn’s disease is not uniquely predicted by a singular cell subset or gene reflects the complex genetic and environmental factors that are implicated. But with this study we have discovered precisely which changes in Crohn’s disease cell composition anticipate both disease severity and treatment response.”
Although pediatric-onset Crohn’s disease accounts for about 25% of all IBD cases, treatment options specifically designed for children remain limited. Across both children and adults, Crohn’s is commonly treated with antibodies that block tumor necrosis factor alpha (TNF-α). However, most patients eventually relapse.
“While targeting TNF is shared across many autoimmune and inflammatory conditions, it is not successful in all patients, and many go on to develop TNF-resistant disease,” said Kyle Kimler, senior data scientist in the Cell Discovery Network at Boston Children’s Hospital. “It’s of tremendous importance to understand for which patients TNF therapy is not necessary, in which patients it may help to control disease, and which patients are not likely to benefit at all.”
The researchers used single-cell RNA sequencing to profile intestinal biopsies from 14 children with newly diagnosed, untreated Crohn’s disease. They also analyzed repeat biopsies from 8 of the children following treatment, and samples from 13 children with non-inflammatory gastrointestinal disorders as a control group. This allowed the scientists to stratify children treated with anti-TNFα agents into groups with either a complete or partial response and link these outcomes to their cell states at the time of diagnosis.
Using this data, the team developed a computational tool called ARBOL that systematically identifies distinct cellular states. They then used it to generate two cellular atlases for childhood Crohn’s and functional gastrointestinal disorders (FGID), which helped reveal cellular signatures that predict disease severity and treatment response.
Children with more severe disease had higher levels of pro-inflammatory immune cells, including T cells, natural killer cells, and certain subsets of monocytes and macrophages, along with reduced numbers of metabolically specialized epithelial cells. Combining the atlas with single-cell data from adults receiving treatment showed that anti-TNFα treatment pushes cells in children with Crohn’s disease towards a more severe, treatment-resistant disease state often found in adults.
Although the study profiled more untreated patients at single-cell resolution than previous research, larger studies will be needed to better understand the underlying biology of the condition. Still, by mapping cellular networks associated with disease severity, the atlas identified potential therapeutic targets, including CD40L blocking antibodies, IL-22 agonists and targeted anti-proliferative agents.
“Future studies will need to include multiple cohorts to help uncover more location-specific and generalizable insights into these diseases,” said Jose Ordovas-Montanes, PhD, associate professor in gastroenterology, hepatology, and nutrition at Boston Children’s Hospital and Harvard Medical School. “It will be essential to understand how both FGID and IBD may present differently in patients across the world and the influences involved.”
