Development and Characterization of a Weaned Pig Model of Shiga Toxin-Producing E. coli-Induced Gastrointestinal Disease

Abstract

Post-weaning enteropathies in swine caused by pathogenic E. coli, such as post-weaning diarrhea (PWD) or edema disease (ED), remain a significant problem for the swine industry. Reduction in the use of antibiotics over concerns of antibiotic resistance and public health concerns, necessitate the evaluation of effective antibiotic alternatives to prevent significant loss of livestock and/or reductions in swine growth performance. For this purpose, an appropriate piglet model of enterotoxigenic E. coli enteropathy is required. In this study, we attempted to induce clinical signs of post-weaning disease in a piglet model using a one-time acute or lower daily chronic dose of a Shiga toxin-producing and enterotoxigenic E. coli strain. The induced disease state was monitored by determining fecal shedding and colonization of the challenge strain, animal growth performance, cytokine levels, fecal calprotectin, histology, fecal metabolomics, and fecal microbiome shifts. The most informative analyses were colonization and shedding of the pathogen, serum cytokines, metabolomics, and targeted metagenomics to determine dysbiosis. Histopathological changes of the gastrointestinal (GI) tract and tight junction leakage as measured by fecal calprotectin concentrations were not observed. Chronic dosing was similar to the acute regimen suggesting that a high dose of pathogen, as used in many studies, may not be necessary. The piglet disease model presented here can be used to evaluate alternative PWD treatment options. Furthermore, this relatively mild disease model presented here may be informative for modeling human chronic gastrointestinal diseases, such as inflammatory bowel disease, which otherwise require invasive procedures for study. ImportancePost-weaning diarrhea remains a significant problem in swine production and appropriate models of pathogenesis are needed to test alternative treatment options. In this study, we present an E. coli induced piglet model for post-weaning diarrhea, and also explore its translational potential as a model for human intestinal inflammation. Our study here presents two firsts to our knowledge. 1) The first simultaneous analysis of the intestinal microbiome and metabolome through fecal sampling of piglets challenged with Shiga toxin-producing E. coli. This is valuable given the limited metabolomics data from swine in various disease states. 2) A comparison of the clinical signs caused by a daily chronic vs one-time dosing regimen of E. coli. This comparison is key as infection by pathogenic E. coli in real-world settings likely occurs from chronic exposure to contaminated food, water, or environment rather than the highly concentrated dose of pathogen that is commonly given in the literature.