Endoplasmic Reticulum Stress Contributes to Intestinal Injury in Intrauterine Growth Restriction Newborn Piglets.

Simple Summary: Current evidence suggests that protein synthesis dysfunction within the endoplasmic reticulum (ER) of the small intestine in animals with intrauterine growth retardation (IUGR) may be a potential factor contributing to the adverse postnatal outcomes associated with intestinal growth and development. However, little is known about whether the impaired protein-folding capacity of ER triggers the adaptive cellular response known as the unfolded protein response (UPR), as well as the subsequent signaling pathways leading to cellular apoptosis in the intestines of IUGR pigs. Therefore, this study aimed to evaluate the structural integrity of the ER and elucidate the potential signaling cascade of the UPR, which may mitigate the effects of ER stress (ERS) within the intestinal mucosa of IUGR neonates. The results showed that the mitochondrial swelling and ER dilation in the intestinal mucosa, resulting from restricted intrauterine development, occur on the neonatal day. The activation of the IRE1α and PERK pathways within the UPR, in response to ERS, was observed in the intestines of IUGR newborn piglets, leading to apoptosis in intestinal cells mediated by the transcription factor CHOP. Understanding this apoptotic mechanism underlying the structural and functional impairment in the guts of animals with IUGR is crucial for identifying potential preventive strategies. Intrauterine growth retardation (IUGR) in piglets is associated with a high rate of morbidity and mortality after birth due to gut dysfunction, and the underlying mechanisms remain poorly understood. This study selected six pairs of IUGR newborn male piglets and normal birth weight newborn piglets (Large White × Landrace) to investigate differences in intestinal structure and digestive functions, intestinal ERS and apoptosis, intestinal barrier function, and inflammatory response. The results showed that IUGR significantly reduced the jejunal villi height (p < 0.05) and the ratio of villus-height-to-crypt-depth (p = 0.05) in neonatal piglets. Additionally, the microvilli in the jejunum of IUGR neonatal piglets were shorter than those in normal-weight piglets, and swelling of the mitochondria and expansion of the endoplasmic reticulum were observed. IUGR also significantly reduced serum glucose and lactase levels (p < 0.05) while significantly increasing mRNA levels of jejunal IRE1α, EIF2α, CHOP, Bax, Caspase9, Mucin2, Claudin-1, Occludin, ZO-1, Bcl-2, IL-6, and IFN-γ (p < 0.05), as well as GRP78 protein levels in neonatal piglets (p < 0.05). These findings suggest that IUGR impairs intestinal structure and barrier function in newborn piglets by enhancing intestinal inflammatory responses, activating intestinal ERS and the signaling pathways related to the unfolded protein response, thereby inducing ERS-related apoptosis. [ABSTRACT FROM AUTHOR]