Crohn's Subtype Accurately Predicted through miRNA Molecule

Crohn’s disease (CD), a chronic inflammatory condition of the intestinal tract, has emerged as a global disease, with rates steadily increasing over the last 50 years. Experts have long suspected that CD likely represents a collection of related but slightly different disorders, but until now it has not been possible to predict accurately which subtype of CD a patient is likely to develop.

Investigators at Cornell University and the University of North Carolina (UNC) have just identified that the levels of a single molecule – microRNA-31 (miR-31) – can predict whether a patient has subtype 1 or subtype 2 of CD. This is a critical discovery as patients with subtype 1, unlike subtype 2, often do not respond well to medications and develop strictures – extreme narrowing of the gut tube, requiring surgery once it develops.

Findings from the new study were published recently in JCI Insight through an article titled “Colonic epithelial miR-31 associates with the development of Crohn’s phenotypes.”

The researchers believe that markers like miR-31 could be useful in the future for clinicians to predict whether a patient should pursue pre-emptive surgery before the condition worsens.

“We are not at the point at which we can perform personalized medicine on this, but at the very least we think it can lead to better clinical trial designs,” explains co-senior study investigator Praveen Sethupathy, Ph.D., associate professor in the department of biomedical sciences at Cornell’s College of Veterinary Medicine.

Clinical trials have generally grouped all patients together when testing a new therapy for CD, and that leads to inconsistent results across the group. Using miR-31, researchers potentially could separate individuals with CD into subtypes to more accurately determine if a particular drug works for one subtype and not the other.

In the current study, the researchers also used a state-of-the-art artificial gut, called an intestinal organoid, that allowed them to culture human biopsy samples while retaining the basic physiology that exists inside a human. “This innovative system can serve as a personalized testing platform to screen therapeutic agents before administering them to patients,” notes co-senior study investigator Shehzad Sheikh, M.D., Ph.D., associate professor of medicine at UNC.

Additionally, the researchers also used cutting-edge genomic techniques to track the abundance of different molecules in the colon tissue of more than 150 pediatric and adult patients.

“We performed small RNA sequencing of adult colon tissue from CD and NIBD controls,” the study authors wrote. “Colonic epithelial cells and immune cells were isolated from colonic tissues, and microRNA-31 (miR-31) expression was measured. miR-31 expression was measured in colonoid cultures generated from controls and patients with CD. We performed small RNA-sequencing of the formalin-fixed paraffin-embedded colon and ileum biopsies from treatment-naive pediatric patients with CD and controls and collected data on disease features and outcomes.”

MicroRNAs control the extent to which a target gene is turned on. They function as negative dials – the greater the abundance of a microRNA, the more a target gene will be suppressed. Data from genomic sequencing technology allowed the researchers to make their miR-31 discovery.

“Our study hints that it’s not only that miR-31 could be a predictive indicator of clinical outcome, but also that it could be functionally relevant in driving the disease,” Dr. Sethupathy says.

Future work will explore exactly what miR-31 does and what role it might play in the integrity of the gut epithelium. “Our long-term goal, extending the work of this study, is to better understand at the molecular level why CD is so different in its presentation across patients, and to use this knowledge to develop more effective therapies,” concludes co-senior study investigator Terrence Furey, Ph.D., associate professor of genetics at UNC.