TY - UNPB
T1 - Aberrant miR-29 is a predictive feature of severe phenotypes in pediatric Crohn’s disease
AU - Shumway, Alexandria
AU - Shanahan, Michael T.
AU - Hollville, Emilie
AU - Chen, Kevin
AU - Beasley, Caroline
AU - Villanueva, Jonathan W.
AU - Albert, Sara
AU - Lian, Grace
AU - Cure, Moises R.
AU - Schaner, Matthew
AU - Zhu, Lee-Ching
AU - Bantumilli, Surekha
AU - Deshmukh, Mohanish
AU - Furey, Terrence S
AU - Sheikh, Shehzad Z.
AU - Sethupathy, Praveen
PY - 2022/12/19
Y1 - 2022/12/19
N2 - 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-sequencing of patient-matched non-inflamed colon and ileum biopsies from treatment-naïve 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 genePmp22and classic Paneth cell markers. The dramatic loss of Paneth cells was confirmed by histologic assays. Moreover, we also found that pediatric CD patients with elevated miR-29 exhibit significantly lower Paneth cell counts, increased inflammation scores, and reduced levels ofPMP22. These findings strongly indicate that miR-29 up-regulation is a distinguishing feature of pediatric CD, highly predictive of severe phenotypes, and associated with inflammation and Paneth cell loss.
AB - 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-sequencing of patient-matched non-inflamed colon and ileum biopsies from treatment-naïve 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 genePmp22and classic Paneth cell markers. The dramatic loss of Paneth cells was confirmed by histologic assays. Moreover, we also found that pediatric CD patients with elevated miR-29 exhibit significantly lower Paneth cell counts, increased inflammation scores, and reduced levels ofPMP22. These findings strongly indicate that miR-29 up-regulation is a distinguishing feature of pediatric CD, highly predictive of severe phenotypes, and associated with inflammation and Paneth cell loss.
U2 - 10.1101/2022.12.16.520635
DO - 10.1101/2022.12.16.520635
M3 - Preprint
BT - Aberrant miR-29 is a predictive feature of severe phenotypes in pediatric Crohn’s disease
PB - bioRxiv
ER -