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Aberrant miR-29 is a predictive feature of severe phenotypes in pediatric Crohn's disease
Alexandria J Shumway1, Michael T Shanahan1, Emilie Hollville2
1Department of Biomedical Sciences, Cornell University, Ithaca, New York, USA.
Insights
MicroRNAs (miRNAs) can predict severe pediatric Crohn's disease (CD). Elevated ileal miR-29 levels in children with CD indicate higher inflammation and Paneth cell loss, aiding in disease prediction.
Area of Science:
- Gastroenterology
- Molecular Biology
- Pediatric Inflammatory Bowel Disease
Background:
- Crohn's disease (CD) is a chronic gut inflammation with poorly understood molecular drivers.
- MicroRNAs (miRNAs) regulate gut function, but large-scale pediatric CD miRNA studies are lacking.
- Understanding pediatric CD pathogenesis is crucial for managing disease heterogeneity.
Purpose of the Study:
- To identify specific microRNAs (miRNAs) that characterize pediatric Crohn's disease (CD).
- To investigate the association of identified miRNAs with disease severity and specific clinical phenotypes.
- To explore the functional role of a key miRNA in gut inflammation and cell integrity.
Main Methods:
- Small RNA sequencing (Seq) on colon and ileum biopsies from pediatric CD patients and controls.
- Multinomial logistic regression to identify predictive miRNAs for disease severity.
- Transcriptomic and histologic analyses in transgenic mice overexpressing miR-29.
Main Results:
- 58 microRNAs (miRNAs) were significantly altered in pediatric CD patients.
- Ileal miR-29 levels strongly predicted severe inflammation and stricturing in pediatric CD.
- miR-29 overexpression in mice reduced Pmp22 gene expression and caused Paneth cell loss.
- Elevated miR-29 in pediatric CD correlated with lower Paneth cell counts, increased inflammation, and reduced PMP22.
Conclusions:
- Upregulation of miR-29 is a key feature distinguishing pediatric Crohn's disease (CD).
- miR-29 is a potent biomarker for predicting severe pediatric CD phenotypes.
- miR-29's role in Paneth cell loss and inflammation highlights its pathogenic contribution to pediatric CD.
Abstract:
Crohn's disease (CD) is a chronic inflammatory gut disorder. Molecular mechanisms underlying the clinical heterogeneity of CD remain poorly understood. MicroRNAs (miRNAs) are important regulators of gut physiology, and several have been implicated in the pathogenesis of adult CD. However, there is a dearth of large-scale miRNA studies for pediatric CD. We hypothesized that specific miRNAs uniquely mark pediatric CD. We performed small RNA-Seq of patient-matched colon and ileum biopsies from treatment-naive pediatric patients with CD (n = 169) and a control cohort (n = 108). Comprehensive miRNA analysis revealed 58 miRNAs altered in pediatric CD. Notably, multinomial logistic regression analysis revealed that index levels of ileal miR-29 are strongly predictive of severe inflammation and stricturing. Transcriptomic analyses of transgenic mice overexpressing miR-29 show a significant reduction of the tight junction protein gene Pmp22 and classic Paneth cell markers. The dramatic loss of Paneth cells was confirmed by histologic assays. Moreover, we found that pediatric patients with CD with elevated miR-29 exhibit significantly lower Paneth cell counts, increased inflammation scores, and reduced levels of PMP22. These findings strongly indicate that miR-29 upregulation is a distinguishing feature of pediatric CD, highly predictive of severe phenotypes, and associated with inflammation and Paneth cell loss.
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