Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Colonic epithelial miR-31 associates with the development of Crohn’s phenotypes
Benjamin P. Keith, … , Praveen Sethupathy, Shehzad Z. Sheikh
Benjamin P. Keith, … , Praveen Sethupathy, Shehzad Z. Sheikh
Published October 4, 2018
Citation Information: JCI Insight. 2018;3(19):e122788. https://doi.org/10.1172/jci.insight.122788.
View: Text | PDF
Clinical Medicine Gastroenterology Genetics

Colonic epithelial miR-31 associates with the development of Crohn’s phenotypes

  • Text
  • PDF
Abstract

BACKGROUND. Crohn’s disease (CD) is highly heterogeneous, due in large part to variability in cellular processes that underlie the natural history of CD, thereby confounding effective therapy. There is a critical need to advance understanding of the cellular mechanisms that drive CD heterogeneity. METHODS. We performed small RNA sequencing of adult colon tissue from CD and NIBD controls. 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 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. RESULTS. Small RNA-sequencing and microRNA profiling in the colon revealed 2 distinct molecular subtypes, each with different clinical associations. Notably, we found that miR-31 expression was a driver of these 2 subtypes and, further, that miR-31 expression was particularly pronounced in epithelial cells. Colonoids revealed that miR-31 expression differences are preserved in this ex vivo system. In adult patients, low colonic miR-31 expression levels at the time of surgery were associated with worse disease outcome as measured by need for an end ileostomy and recurrence of disease in the neoterminal ileum. In pediatric patients, lower miR-31 expression at the time of diagnosis was associated with future development of fibrostenotic ileal CD requiring surgery CONCLUSIONS. These findings represent an important step forward in designing more effective clinical trials and developing personalized CD therapies. FUNDING. This work was supported by CCF Career Development Award (SZS), R01-ES024983 from NIEHS (SZS and TSF), 1R01DK104828-01A1 from NIDDK (SZS and TSF), P01-DK094779-01A1 from NIDDK (SZS), P30-DK034987 from NIDDK (SZS), 1-16-ACE-47 ADA Pathway Award (PS), UNC Nutrition Obesity Research Center Pilot & Feasibility Grant P30DK056350 (PS), CCF PRO-KIIDS NETWORK (SZS and PS), UNC CGIBD T32 Training Grant from NIDDK (JBB), T32 Training Grant (5T32GM007092-42) from NIGMS (MH), and SHARE from the Helmsley Trust (SZS). The UNC Translational Pathology Laboratory is supported, in part, by grants from the National Cancer Institute (3P30CA016086) and the UNC University Cancer Research Fund (UCRF) (PS).

Authors

Benjamin P. Keith, Jasmine B. Barrow, Takahiko Toyonaga, Nevzat Kazgan, Michelle Hoffner O’Connor, Neil D. Shah, Matthew S. Schaner, Elisabeth A. Wolber, Omar K. Trad, Greg R. Gipson, Wendy A. Pitman, Matthew Kanke, Shruti J. Saxena, Nicole Chaumont, Timothy S. Sadiq, Mark J. Koruda, Paul A. Cotney, Nancy Allbritton, Dimitri G. Trembath, Francisco Sylvester, Terrence S. Furey, Praveen Sethupathy, Shehzad Z. Sheikh

×

Figure 3

miR-31 is specifically upregulated in intestinal epithelial cells.

Options: View larger image (or click on image) Download as PowerPoint
miR-31 is specifically upregulated in intestinal epithelial cells.
RT-qP...
RT-qPCR for miR-31 (A), APOA1 (B), and CEACAM7 (C) in an independent adult cohort displays colon-like (blue; n = 27–28) and ileum-like (red; n = 12) clustering patterns for CD samples compared with NIBD samples (black; n = 18–29). (D) RT-qPCR of 5 colon-specific cell types reveal significant miR-31 upregulation in intestinal epithelial cells isolated from CD patients (n = 11–20) relative to NIBD controls (n = 8–16). (Eight NIBD matched and 6 CD matched across all cell types). (E) Relative miR-31 expression by qPCR of colonoid cultures generated from NIBD controls (n = 4) compared with CD patients (n = 4). miR-31 expression is increased in fresh crypts and remains higher at day 2 and day 6 of colonoid culture. miRNA levels are relative to RNU-48 expression compared with fresh NIBD crypts. Significance values determined by a 2-tailed unpaired Student’s t test. Data are presented as mean ± SEM.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts