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Crohn's Disease MicroRNA Marks Subtypes With Differing Outcomes

NEW YORK (GenomeWeb) – Gut tissue expression of a microRNA called miR-31 in individuals with Crohn's disease may help in identifying subtypes of the chronic inflammatory bowel disease that show distinct features and outcomes, new research suggests.

As they reported in the journal JCI Insight, researchers from the University of North Carolina at Chapel Hill and elsewhere did small RNA sequencing on colon samples from 18 individuals with Crohn's disease and 12 inflammatory bowel disease (IBD)-free individuals, identifying differences in miR-31 expression that corresponded with previously described Crohn's disease molecular subtypes. And in general, they noted that the miRNA had pronounced expression in intestinal epithelial cells in Crohn's patients.

In contrast, diminished miR-31 expression appeared to herald poorer outcomes in adult Crohn's patients — a finding supported by the team's analyses on still more adult cases and controls and on adult-derived colonoid cultures. Further, small RNA sequencing on formalin-fixed paraffin-embedded pre-treatment samples from more than 100 children with or without Crohn's disease indicated that pediatric Crohn's cases that were initially marked by low miR-31 were more likely to progress and require surgical intervention.

"Our study shows that miR-31 is a candidate prognostic determinant of [Crohn's disease] behavior in adult and pediatric patients and highlights the potential role of miR-31 in the pathobiology of [Crohn's disease]," senior author Shehzad Sheikh, a gastrointestinal biology and disease, genetics, and molecular biology researcher at UNC Chapel Hill, and his co-authors wrote.

The researchers isolated small RNAs from colonic epithelial and immune cells in gut tissue samples from the adult Crohn's disease cases and controls using Illumina sample prep kits and paired-end small RNA sequencing with the HiSeq 2500 instrument. In the individuals with Crohn's disease, including those who received surgery for medically refractory forms of the disease, they saw miRNA and long non-coding RNA clusters that lined up with the colon-like and ileum-like molecular subtypes reported in the past.

In particular, miR-31 showed distinct gut expression profiles, both between the Crohn's disease subtypes and between Crohn's disease cases and controls, the team reported. Although miR-31 expression was enhanced overall in samples from individuals with Crohn's disease compared to controls, especially in the epithelial cells, these differences were more modest in the colon-like disease subtype.

The researchers validated these expression differences through quantitative PCR profiling on another 40 adult cases and 29 controls, along with colonoid culture testing, while data from dozens of individuals with colon-like or ileum-like Crohn's disease pointed to poorer outcomes for those in the colon-like group marked by lower miR-31 expression.

Using 234 FFPE treatment-naïve colon and ileum tissue samples from 76 pediatric Crohn's diseases cases and 51 unaffected children, the team again saw miR-31 expression differences between samples from individuals with or without Crohn's disease, particularly in colon tissue.

Low expression of miR-31 was more common in children who went on to progress to forms of Crohn's disease that called for surgical resection, the team noted, whereas none of the pediatric patients in the low miR-31 group progressed to that point.

Consequently, the authors called miR-31 "a molecular stratifier of both pediatric and adult patient, an indicator of established disease phenotype in adult patients, and a predictor of clinical phenotype at the time of diagnosis in pediatric patients." They also concluded that their findings "represent significant progress in molecularly defining the [Crohn's diseases], moving closer toward potential personalization of therapy and improving outcomes."