138 Age-Dependent Intestinal Barrier Repair in Suckling Pigs: A Comparative Model to Improve Neonatal Gastrointestinal Health Across Species

Abstract

Abstract As in porcine epidemic diarrhea virus, strangulating equine colic or necrotizing enterocolitis in human infants, intestinal diseases involving ischemic injury cause mucosal barrier damage and are associated with poorer survival in neonates. The cause of age-dependent outcomes in afflicted individuals has not been fully explained and therefore novel preventatives and treatments are lacking. While traditional rodent models have not demonstrated age-dependent differences in intestinal recovery, our translational pig model is the first to demonstrate an age-dependent intestinal barrier repair defect. We have shown that, while weaned pigs recover rapidly after ischemic intestinal injury, barrier repair is markedly impaired in suckling pigs, due to complete failure of epithelial restitution. Importantly, we found that the restitution defect in suckling pigs can be rescued by the direct application of homogenized mucosa from ischemia-injured small intestine from weaned pigs. Identifying reasons for this age-dependent defect in restitution and the components of the more mature pig mucosal tissues responsible for rescue will inform novel treatment interventions for neonates suffering with intestinal injury. Our lab has associated this age-dependent defect in barrier repair with an underdeveloped enteric glial cell (EGC) network, a postnatally developing component of the enteric nervous system known to regulate the intestinal barrier. We have found sub-epithelial EGC are reduced in neonates, neonatal epithelium in co-culture with EGC restitute more efficiently in vitro, and EGC inhibition ex vivo blocks restitution in juveniles recreating the neonatal phenotype. Further, as this EGC network is known to mature postnatally in response to the microbial colonization, we have found postnatal microbiota modulation with dietary prebiotic fiber supplementation exerts important effects on EGC network development and activity, and on EGC-epithelial pro-restitution crosstalk in vitro. Ongoing work to understand the roles of diet, microbiota, and the enteric nervous system on postnatal development of epithelial barrier repair can inform novel preventatives and interventions to improve intestinal health in vulnerable neonates.