Vaginal Birth Alters Gut Transcriptome of Neonatal Pigs

Background: Women at risk of preterm birth are routinely administered prenatal doses of glucocorticoids to facilitate lung maturation and improve pulmonary outcomes in preterm infants. Additionally, preterm infants are often administered low doses of glucocorticoids postnatally for prevention of bronchopulmonary dysplasia. However, there is limited understanding about the impact of perinatal glucocorticoid exposure on the gut and liver in preterm infants. In pigs, there is a spike in plasma cortisol in newborns during parturition. We previously showed in pigs that plasma cortisol levels positively correlate with plasma fibroblast growth factor 19 (FGF19), a gut hormone that negatively regulates hepatic bile acid synthesis. FGF19 is secreted by epithelial cells predominantly in the distal ileum in response to bile acids. However, in vaginally-born pigs, FGF19 mRNA levels were higher in the proximal jejunum. This led us to hypothesize that exposure to glucocorticoids in the perinatal period has a profound impact on the transcription of genes involved in the development of gut and liver. Objective: The objective of this study was to characterize the impact of spontaneous vaginal birth and the exposure to elevated cortisol on the transcriptome in gut and liver tissue of neonatal pigs Methods: Two sows underwent a cesarean section on gestation day 114 (“Term”; term=115 day), two sows underwent a cesarean section on gestation day 105 (“Preterm”) and two additional sows were allowed to farrow at term gestational age (“Vaginal”). Small intestine tissue and plasma was collected from newborn pigs (n= 10 Preterm; n=8 Term; n=6 Vaginal). RNA-seq analysis was performed on intestinal samples mapped to the latest Sus scrofa Sscrofa11.1 reference genome (NCBI). Results: Cortisol levels were statistically highest in the vaginally-born pigs (139 ng/mL), followed by the Term (101 ng/mL) and lowest in the Preterm (61 ng/mL) pigs. Gene Ontology (GO) analysis showed significant enrichment in pathways of upregulated genes involved in response to toxic substances, stress, detoxification and inorganic substances in the jejunum of Vaginal pigs compared to Preterm and Term pigs. KEGG analysis of the proximal jejunum indicated enrichment in pathways of upregulated genes in steroid hormone biosynthesis, bile secretion, TNF signaling and IL-17 Vaginal, compared to Term and Preterm pigs. The same pattern was not the same in the distal ileum where GO analysis showed pathway enrichment of upregulated genes in oxidation-reduction processes, and transition metal ion binding in Vaginal compared to Term and Preterm pigs. KEGG analysis of the distal ileum identified pathway enrichment of upregulated genes in complement and coagulation, bile acid synthesis and secretion, fatty acid metabolism, and amino acid metabolism in Vaginal pigs. Conclusion: Genes in metabolic and cellular signaling pathways associated with cortisol are upregulated in vaginally-born pigs. This work was supported in part by federal funds from the USDA, Agricultural Research Service under Cooperative Agreement Number 3092-51000-060-01, and grants from the National Institutes of Health Grant DK-094616 (D.G.B), and the Texas Medical Center Digestive Diseases Center (NIH Grant P30 DK-56338). Caitlin Vonderohe was supported by T32 DK007664 and Greg Guthrie was supported by K01 DK129408. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.