Increased circulating cortisol after vaginal birth is associated with increased FGF19 secretion in neonatal pigs

Authors: VONDEROHE, CAITLIN - Children'S Nutrition Research Center (CNRC); GUTHRIE, GREG - Children'S Nutrition Research Center (CNRC); STOLL, BARBARA - Children'S Nutrition Research Center (CNRC); MELENDEZ HEBIB, VALERIA - Children'S Nutrition Research Center (CNRC); Dawson, Harry; Burrin, Douglas - Doug

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/7/2022
Publication Date: 11/23/2022
Citation: Vonderohe, C., Guthrie, G., Stoll, B., Melendez Hebib, V., Dawson, H.D., Burrin, D.G. 2022. Increased circulating cortisol after vaginal birth is associated with increased FGF19 secretion in neonatal pigs. Endocrinology. 164(1). https://doi.org/10.1210/endocr/bqac188.
DOI: https://doi.org/10.1210/endocr/bqac188

Interpretive Summary: Infants that are born prematurely are more likely to have significant health issues that prevent them from growing and developing normally. Unfortunately, thousands of infants are born prematurely in the U.S., and this number is growing every year. Most of these preterm births are also spontaneous and vaginal rather than by a planned surgical cesarean section (c-section). Bile acids are important molecules that are produced by the liver and play an important role in fat digestion and signaling between the gut and the liver. Fibroblast Growth Factor-19 (FGF19) is one of the ways that bile acids can transmit signals between the gut and liver and it may play a role in muscle growth, intestinal development and fat accumulation. We explored the impact of preterm c-section versus term c-section and vaginal birth on the development of the gut and liver using pigs as models for infants. Vaginally-born term pigs had larger birthweights and grew faster over the first three days of life than pigs born via c-section. Term pigs that were born vaginally had blood levels of FGF19 that were 35x higher than FGF19 levels in term pigs born via planned c-section and 70x higher than preterm pigs born via c-section. We also found that the blood levels of the hormone cortisol were highest in the vaginally-born term pigs and lowest in the preterm pigs born by c-section. The direct relationship between blood levels of cortisol and FGF19 led us to test if cortisol signals the gut to release FGF19. We found that when intestine and intestinal cells are treated with cortisol, they release FGF19. This lets us conclude that cortisol may impact the release of FGF19 at birth. We will next focus on better understanding the relationship between FGF19 and cortisol to see if we can make preterm pigs and babies grow and digest food more efficiently.

Technical Abstract: The influence of birth modality (scheduled cesarean or spontaneous vaginal) on the development of the newborn has been a source of controversy in neonatology. The impact of cesarean versus vaginal birth on the development of bile acid and FGF19 signaling is unknown. Our aim was to determine the effect of birth modality and gestational age (preterm vs. term) on plasma hormone levels, bile acid pool distribution, expression of genes in the bile acid-FXR-FGF19 pathway, and plasma levels of FGF19 at birth and on day 3 of life in neonatal pigs. Four sows underwent a cesarean section on gestation day 105 (n=2) and 114 (n=2; term=115d), and two additional sows were allowed to farrow at term (gestation days 112 and 118). Piglets were euthanized at birth for tissue and blood collection, and the remaining pigs were nutritionally supported on total parenteral nutrition (TPN) then fed enterally on day 3, before blood and tissue were collected. Piglets born vaginally had a markedly (30-fold) higher plasma FGF19 at birth than term pigs born via cesarean section, and 70-fold higher than preterm pigs (p<0.001). However, distal ileum FGF19 gene expression was similar in all groups (p >0.05).Plasma FGF19 positively correlated with plasma cortisol (r=0.58; p <0.05) and dexamethasone treatment increased ileal FGF19 expression in cultured pig tissue explants and human enteroids. Our findings suggest that exposure to maternal or endogenous glucocorticoids in the perinatal period may upregulate the development of the bile-acid-FGF19 pathway.