MicroRNA 29 targets nuclear factor-κB-repressing factor and claudin 1 to increase intestinal permeability

Qiqi Zhou, Stefan Costinean, Carlo M. Croce, Alan R. Brasier, Shehzad Merwat, Scott A. Larson, Sarpreet Basra, G. Nicholas Verne

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

BACKGROUND & AIMS: Some patients with irritable bowel syndrome with diarrhea (IBS-D) have intestinal hyperpermeability, which contributes to their diarrhea and abdominal pain. MicroRNA 29 (MIR29) regulates intestinal permeability in patients with IBS-D. We investigated and searched for targets of MIR29 and investigated the effects of disrupting Mir29 in mice. METHODS: We investigated expression MIR29A and B in intestinal biopsies collected during endoscopy from patients with IBS (n = 183) and without IBS (controls) (n = 36). Levels were correlated with disease phenotype. We also generated and studied Mir29-/- mice, in which expression of Mir29a and b, but not c, is lost. Colitis was induced by administration of 2,4,6-trinitrobenzenesulfonic acid; intestinal tissues were collected and permeability was assessed. Microarray analysis was performed using tissues from Mir29-/- mice. Changes in levels of target genes were measured in human colonic epithelial cells and small intestinal epithelial cells after knockdown of MIR29 with anti-MIRs. RESULTS: Intestinal tissues from patients with IBS-D (but not IBS with constipation or controls) had increased levels of MIR29A and B, but reduced levels of Claudin-1 (CLDN1) and nuclear factor-κB-repressing factor (NKRF). Induction of colitis and water avoidance stress increased levels of Mir29a and Mir29b and intestinal permeability in wild-type mice; these increased intestinal permeability in colons of far fewer Mir29-/- mice. In microarray and knockdown experiments, MIR29A and B were found to reduce levels of NKRF and CLDN1 messenger RNA, and alter levels of other messenger RNAs that regulate intestinal permeability. CONCLUSIONS: Based on experiments in knockout mice and analyses of intestinal tissue samples from patients with IBS-D, MIR29 targets and reduces expression of CLDN1 and NKRF to increase intestinal permeability. Strategies to block MIR29 might be developed to restore intestinal permeability in patients with IBS-D.

Original languageEnglish (US)
Pages (from-to)158-169.e8
JournalGastroenterology
Volume148
Issue number1
DOIs
StatePublished - Jan 1 2015

Keywords

  • Gene Regulation
  • Intestinal Barrier Function
  • Mouse Model
  • mRNA Processing

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Zhou, Q., Costinean, S., Croce, C. M., Brasier, A. R., Merwat, S., Larson, S. A., Basra, S., & Verne, G. N. (2015). MicroRNA 29 targets nuclear factor-κB-repressing factor and claudin 1 to increase intestinal permeability. Gastroenterology, 148(1), 158-169.e8. https://doi.org/10.1053/j.gastro.2014.09.037