Zebrafish modeling of intestinal injury, bacterial exposures and medications defines epithelial in vivo responses relevant to human inflammatory bowel disease.

Ling-Shiang Chuang,Nicole Villaverde,Shikha Nayar,Mireia Castillo-Martin,Nai-Yun Hsu,Ernie Chen,Jaime Chu,Judy H Cho,Joshua Morrison,Mamta Giri,Gilles Boschetti,Yashoda Sharma,Philippe Ronel Labrias,Jody Ann Facey,Tin Htwe Thin

doi:10.1242/dmm.037432

Ling-Shiang Chuang, Nicole Villaverde + Show 13 more

Open Access

https://doi.org/10.1242/dmm.037432

Copy DOI

Abstract

ABSTRACTGenome-wide association studies have identified over 200 genomic loci associated with inflammatory bowel disease (IBD). High-effect risk alleles define key roles for genes involved in bacterial response and innate defense. More high-throughput in vivo systems are required to rapidly evaluate therapeutic agents. We visualize, in zebrafish, the effects on epithelial barrier function and intestinal autophagy of one-course and repetitive injury. Repetitive injury induces increased mortality, impaired recovery of intestinal barrier function, failure to contain bacteria within the intestine and impaired autophagy. Prostaglandin E2 (PGE2) administration protected against injury by enhancing epithelial barrier function and limiting systemic infection. Effects of IBD therapeutic agents were defined: mesalamine showed protective features during injury, whereas 6-mercaptopurine displayed marked induction of autophagy during recovery. Given the highly conserved nature of innate defense in zebrafish, it represents an ideal model system with which to test established and new IBD therapies targeted to the epithelial barrier.This article has an associated First Person interview with the first author of the paper.

Highlights

inflammatory bowel disease (IBD) is comprised of two subtypes, Crohn’s Disease (CD) and ulcerative colitis (UC)
The most significant loci identified in genome-wide association studies (GWAS) for IBD include protein-altering alleles in IL23R, NOD2, ATG16L13, LRRK2 (Leucine-rich repeat kinase 2)[4] and CSF2RB5, as well as non-coding risk alleles near PTGER4, which increase gene expression[6]
Repeated DSS treatments prevent recovery of acidified-lysosome and mucin loss To model the chronicity of IBD, we first compared the effects of single- and threecourse dextran sodium sulfate (DSS) injury (Fig. 1A, Fig. S1A) in zebrafish

Summary

Introduction

IBD is comprised of two subtypes, Crohn’s Disease (CD) and ulcerative colitis (UC). While UC affects the superficial layers of the intestine, CD often affects deeper layers of the bowel wall. The most significant loci identified in genome-wide association studies (GWAS) for IBD include protein-altering alleles in IL23R (interleukin 23 receptor), NOD2 (nucleotide oligomerization domain 2), ATG16L1 (autophagy related 16 like 1)[3], LRRK2 (Leucine-rich repeat kinase 2)[4] and CSF2RB (colony stimulating factor 2 receptor)[5], as well as non-coding risk alleles near PTGER4 (prostaglandin E receptor 4), which increase gene expression[6]. Recent literature has defined the particular value of zebrafish in modeling innate defense and immunity[11,12,13]. Because of their transparency over the initial weeks of life, zebrafish serve as a powerful tool for performing live in vivo imaging of intestinal macrophages and epithelial responses to injury and bacterial exposure

Methods

Results

Conclusion