Researchers have created a detailed map of childhood Crohn’s disease before and after treatment to help understand progression of the disease.
A child holding a model of the human anatomy. Photo by MART PRODUCTION on Pexels.
The research, published previously as a Reviewed Preprint in eLife and appearing today as the final Version of Record, is described by the editors as an important study that substantially advances our understanding of pediatric Crohn's disease, mapping its cellular make-up and how patients respond to treatment. The editors add that the evidence is compelling, based on thorough analyses, underpinned by rigorous methodology.
Crohn’s disease is an inflammatory bowel disease (IBD) that arises when the gastrointestinal tract’s normal state is disrupted by chronic inflammation. Among IBDs, pediatric-onset Crohn’s disease is particularly common, representing 25% of all IBD cases, and is debilitating because of its early onset and the lack of treatment options for children specifically. Treatment is tailored to each child’s case, but commonly includes steroids and immune-modulating drugs, and often antibodies that work against a molecule called tumour necrosis factor-alpha (TNFα).
“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,” says co-first author Kyle Kimler, Senior Data Scientist in the Cell Discovery Network at Boston Children’s Hospital, Boston, US. “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.” Kimler is co-first author of the study alongside Benjamin Doran, now a PhD student at the University of Chicago, Alison Yu, formerly Clinical Research Manager in the Division of Pediatric Hematology/Oncology at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and Hengqi Betty Zheng, Associate Professor at Seattle Children’s and the University of Washington School of Medicine, Seattle, US.
The team made use of powerful sequencing tools called single-cell RNA-sequencing to analyse the cellular profiles of diagnostic human biopsies from the small intestines of 14 untreated children with Crohn’s disease, repeat biopsies from eight of those children after treatment, and 13 biopsies from a control group of children with non-inflammatory gastrointestinal disorders (functional gastrointestinal disorders, or FGID). They were able to separate the groups of children treated with anti-TNFα agents into subgroups who either had a complete or partial response, and could then relate these outcomes with the patients’ cell states at diagnosis.
To aid their analysis, they developed a new publicly available bioinformatics tool called ARBOL (Spanish for ‘tree’) which repeatedly splits groups of data into smaller subgroups to create trees of cell ‘states’. They used this to generate two fully described cellular atlases for childhood Crohn’s (pediCD atlas) and FGID, consisting of 94,451 and 107,432 cells, respectively. From this, they were able to identify specific cell signatures that predict disease severity and treatment outcomes.
The specific changes in cell composition associated with more severe disease were an increase in proinflammatory immune cells – including T cells, cytotoxic natural killer cells, subsets of monocytes and macrophages – and a decrease in metabolically specialized subsets of cells that line the normal, healthy intestine. The team noted significant cell changes at diagnosis underlying clinically observed disease severity, which impacted the decision whether or not to treat with anti-TNFα agents.
They then combined their pediCD atlas with the follow-up treatment data from eight children and with a single-cell atlas from adults with Crohn’s disease receiving treatment. This revealed that anti-TNF treatment pushes the childhood Crohn’s cellular ecosystem towards the more severe, treatment-resistant disease state often found in adult Crohn’s disease.
“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,” says co-senior author Leslie Kean, Director of the Stem Cell Transplant Center at Dana-Farber/Boston Children's Cancer and Blood Disorders Center, and the Robert A. Stranahan Professor of Pediatrics, Harvard Medical School, Boston, US.
Kean adds: “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.” Kean is co-senior author of the study alongside Jose Ordovas-Montanes, Associate Professor in the Division of Gastroenterology, Hepatology, and Nutrition at Boston Children’s Hospital and Harvard Medical School, and Alex Shalek, Director of the Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, US.
The authors note that there are some limitations to their work that are important to consider. For example, despite having profiled more untreated patients than previous studies at single-cell resolution, the cohort size limits their analyses to the strict inclusion/exclusion criteria used, the follow-up period, and the ability to capture untreated patients early during the diagnosis process. They are therefore unable to directly correlate in the cohort genetic and environmental influences such as the enteric microbiome, infections, and dietary factors. Additionally, the cohort is representative of the demographics of FGID and IBD in Seattle only.
As Ordovas-Montanes concludes: “It will be essential to understand how both FGID and IBD may present differently in patients across the world and the influences involved. Future studies will need to include multiple cohorts to help uncover more location-specific and generalizable insights into these diseases.”
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