Researchers from Children’s Hospital of Philadelphia (CHOP) confirmed that “mini-intestines” generated from patient tissue samples and grown in a lab can accurately replicate certain features of Crohn’s disease, which will allow them to study the epithelium, the thin layer of cells lining the intestine, that is broken down in patients with inflammatory bowel disease. Additionally, the researchers also found that tissue in the rectum not affected by the disease may successfully identify patients with Crohn’s disease. If these findings are validated in a larger cohort of patients, in the future patients may not require a full colonoscopy or endoscopy for proper diagnosis.
Inflammatory bowel disease (IBD) is associated with chronic inflammation within the gastrointestinal tract and damage to the mucosa, a protective layer of epithelium lining the gastrointestinal tract. One of the most common forms of IBD is Crohn’s disease, and 25% of all cases of Crohn’s disease are diagnosed in children and teenagers.
Most treatments currently available for IBD focus on suppressing inflammation. However, mucosal healing is among the strongest predictors of whether a patient will achieve disease remission. Understanding how epithelial lining of the gastrointestinal tract is compromised in IBD, even when the inflammation is suppressed by medication, could help develop better therapeutic strategies for patients. Approximately 1 in 4 cases of Crohn’s disease is diagnosed in children and teenagers.
One tool researchers developed to study the mucosa is using patient tissues to create enteroids and colonoids, which are “mini-intestines” grown in a lab using cells from a patient’s small intestine and colon, respectively. However, not much is known about whether these lab-grown organoids faithfully represent the tissue they were established from. Therefore, researchers wanted to take an unbiased approach to see how such enteroids and colonoids share features with those of biopsies taken from the same patients, and also evaluate tissue from disease-spared areas, particularly the rectum in the patients where Crohn’s disease was limited to the small intestine.
“Colonoscopies are the gold standard for diagnosing and monitoring patients with IBD, but these are invasive procedures that require anesthesia and can cause discomfort, especially for pediatric patients,” said first study author Tatiana Karakasheva, PhD, Associate Director of the Gastrointestinal Epithelium Modeling Program at CHOP. “Our results from this study suggest there may be disease-related signals even in the rectum that appear normal on endoscopy and histopathology. This could help identify the presence of Crohn’s disease in the upper gastrointestinal tract without the need for a colonoscopy.”
In this study, researchers compared biopsies and matching enteroid or colonoid cultures from seven pediatric patients with ileal Crohn’s disease – meaning Crohn’s disease is located in the deepest part of the small bowel – and and 17 control patients. The researchers conducted RNA sequencing, bioinformatic, and machine learning analyses to study disease-related gene activity.
The researchers found that there was significant overlap of pathways with increased activity in Crohn’s disease in both enteroids and ileal biopsies as well as colonoids and rectal biopsies. Genes expressed in Crohn’s disease biopsies were also expressed in the enteroids and colonoids, Machine learning predicted the biopsy location with 100% accuracy and the donor disease status with 83% accuracy. Another test was 80% accurate when using rectal colonoids to predict which patients had Crohn’s disease in their small intestine, demonstrating that data from disease-spared tissue can still identify patients with Crohn’s disease.
“Our findings validated that patient-derived enteroids and colonoids are valuable models for studying the intestinal lining of patients with IBD, and the potential of utilizing rectal biopsies or colonoids for screening or diagnosing Crohn’s disease may be of tremendous benefit to our patient community,” said senior study author Kathryn E. Hamilton, PhD, Assistant Professor of Pediatrics in the Division of Gastroenterology, Hepatology, and Nutrition at Perelman School of Medicine and CHOP and Co-Director of the Gastrointestinal Epithelium Modeling Program at CHOP.
This study was supported by institutional grants from the Children's Hospital of Philadelphia Institutional Development Funds and the Gastrointestinal Epithelium Modeling Program, the National Institutes of Health grants R01-DK124369, and the Penn Center for Molecular Studies in Digestive and Liver Diseases (P30-DK050306).
Karakasheva et al, “Patient-derived colonoids from disease-spared tissue retain inflammatory bowel disease-specific transcriptomic signatures.” Gastro Hep Adv. Online May 25, 2023. DOI: 10.1016/j.gastha.2023.05.003.