Loss of murine Paneth cell function alters the immature intestinal microbiome and mimics changes seen in neonatal necrotizing enterocolitis.

Shiloh R Lueschow,Misty Good,David K Meyerholz,Mark A Underwood,Steven J Mcelroy,Timothy G Elgin,Huiyu Gong,Karen M Kalanetra,Jessica Stumphy,David A Mills,Stacy L Kern,Melissa H Wong,Shree Ram Singh

doi:10.1371/journal.pone.0204967

Abstract

Necrotizing enterocolitis (NEC) remains the leading cause of gastrointestinal morbidity and mortality in premature infants. Human and animal studies suggest a role for Paneth cells in NEC pathogenesis. Paneth cells play critical roles in host-microbial interactions and epithelial homeostasis. The ramifications of eliminating Paneth cell function on the immature host-microbial axis remains incomplete. Paneth cell function was depleted in the immature murine intestine using chemical and genetic models, which resulted in intestinal injury consistent with NEC. Paneth cell depletion was confirmed using histology, electron microscopy, flow cytometry, and real time RT-PCR. Cecal samples were analyzed at various time points to determine the effects of Paneth cell depletion with and without Klebsiella gavage on the microbiome. Deficient Paneth cell function induced significant compositional changes in the cecal microbiome with a significant increase in Enterobacteriacae species. Further, the bloom of Enterobacteriaceae species that occurs is phenotypically similar to what is seen in human NEC. This further strengthens our understanding of the importance of Paneth cells to intestinal homeostasis in the immature intestine.

Highlights

A key regulator of small bowel homeostasis and the intestinal microbiome is the Paneth cell [1]
Loss of Paneth cells and alterations of the intestinal microbiome have both been associated with development of Necrotizing enterocolitis (NEC)
It is unclear if depletion of Paneth cells is causative of the dysbiosis seen prior to NEC or merely an associated finding

Summary

Introduction

A key regulator of small bowel homeostasis and the intestinal microbiome is the Paneth cell [1]. Paneth cells are granular secretory cells located at the base of the crypts of Lieberkuhn. These dense granules contain multiple antimicrobial peptides that are secreted constitutively. Pediatrics at the University of Iowa, and the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital. RNAseq data and analysis was supported by the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine which is partially supported by NCI Cancer Center Support Grant #P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant# UL1 TR000448 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research.

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