Using organoids derived from adult stem cells in the gut tissue of patients with Crohn’s disease, researchers from the University of California, San Diego (UCSD) have discovered that the condition consists of two distinct molecular subtypes. The discovery of these distinct molecular subtypes, published in Cell Reports Medicine, promises to improve diagnostic approaches and create more personalized treatment options for patients based on their disease subtype.
Crohn’s disease affects more than 500,000 Americans, often striking younger people and causing a range of debilitating gastrointestinal symptoms. Current treatment options are limited, and there is no cure. One major challenge in developing effective therapies has been the lack of accurate preclinical animal models and the heterogeneity among patients in the clinic.
For this study, researchers collected gut tissue samples from 53 Crohn’s disease patients during routine colonoscopies at the Inflammatory Bowel Disease Center at UC San Diego Health. By creating a biobank of patient-derived organoid cultures, the scientists were able to study organoids derived from adult stem cells in the gut tissue, which more accurately reflect the characteristics of the disease compared to those derived from pluripotent stem cells that were reprogrammed to become gut cells.
“The pluripotent stem cells—whether derived from blood or skin cells—carry the genetic traits of the patient, but have no way to know the inflamed environment inside the patient’s gut,” said senior author Pradipta Ghosh, MD, a professor in the department of cellular and molecular medicine at UC San Diego School of Medicine. This contrasts with the adult stem cells, which retain an epigenetic memory of the gut environment including a history of bacterial colonization, inflammation, and altered oxygen and pH.
“We show here that adult stem cell-derived organoids accurately mimic the inflamed gut, but the pluripotent cells fail, which reminds me of what Maya Angelou once said: ‘I have great respect for the past. If you don’t know where you’ve come from, you don’t know where you’re going,’” Ghosh added.
The researchers discovered that, despite the diverse clinical presentations among Crohn’s patients, the organoids consistently fell into two discrete molecular subtypes. The first subtype, Immune-deficient infectious-Crohn’s disease (IDICD), is characterized by challenges in clearing pathogens and insufficient cytokine immune responses. Patients in this subtype often form fistulas with pus discharge. The second subtype, Stress and senescence-induced fibrostenotic-Crohn’s disease (S2FCD), is characterized by cellular aging and stress, resulting in fibrosis or scarring of the gut tissue.
Ghosh noted that these finding should eventually lead to both a shift in the understanding of Crohn’s disease and instead of classifying patients based on the broad array of clinical presentations, they will instead be classified by their molecular subtype.
“Currently, because of a lack of understanding of these fundamentally different subtypes, they are all being given the same treatment—a cookie-cutter therapy. This combination of anti-inflammatory drugs helps a fraction of the patients, but only temporarily,” Ghosh said.
The research suggests that patients with IDICD might benefit from therapies aimed at clearing bacterial infections, while those with S2FCD could respond better to treatments targeting cellular aging.
Efforts are now underway to genotype the two subtypes, which could lead to the development of a simple test to quickly identify a patient’s subtype.
“It’s my hope that when the genetics are completed, Crohn’s disease will be viewed as two molecular subtypes that should be treated in two completely different ways,” Ghosh concluded. “Traditionally, we have been treating this disease with anti-inflammatory drugs, an approach that can be likened to putting out fires. With this study, we hope to target the arsonist who is responsible for the fire in the first place.”
