Gut and systemic immune responses to prenatal inflammation in preterm neonates
PhD student: Shuqiang Ren, e-mail: email@example.com
Department of Veterinary and Animal Science,
Comparative Pediatrics and Nutrition
Thesis defended: February 2020
Preterm birth is defined by the World Health Organization (WHO) as an infant who is born before 37 complete weeks of gestation, accounting for ~11 % of all live births worldwide. Complications related to preterm birth are the leading causes of neonatal mortality, and preterm birth is also associated with other causes of mortality. Probably due to the immature organs and immune system, preterm infants are vulnerable to microorganisms and other factors in the ex vivo environment. Preterm birth is also related to short- and long-term postnatal disorders. Accordingly, preterm birth is associated with multiple maternal and fetal factors, such as intrauterine inflammation, maternal age and genetics. Approximately 40-70 % of cases of preterm birth are related to prenatal inflammation and infection, including chorioamnionitis (CA). However, the molecular mechanism of CA remains unclear, and CA may also be associated with neonatal sepsis and necrotizing enterocolitis (NEC). A transcriptomic analysis is a good tool to study the differentially expressed genes (DEGs) related to systemic immunity and to investigate the corresponding mechanisms of CA. Additionally, because the milk supplied from the mother is insufficient or unavailable, a large proportion of preterm infants receive infant formula as the first milk, which exerts detrimental effects on gut maturation. Infant formula may even be worse for preterm infants with CA, thereby further increasing risks of postnatal infection and NEC.
Purpose of the project
The immature functions of the organs and immune system of preterm infants predispose them to gut and immune disorders. Growth and developmental delays in preterm neonates may affect various organ systems differently at the term-corrected age. Preterm birth is driven by multiple factors from both the mother and fetuses. Among these factors, prenatal inflammation, such as chorioamnionitis (CA), is one of the most common causes of preterm birth and may predispose the neonate to postnatal inflammatory disorders. The distinct developmental trajectories of the immune system are directly reflected by the functions of systemic immune cells in preterm infants born with prenatal inflammation potentially. Furthermore, bioactive milk components may support gut and immune maturation in preterm neonates, particularly during the first weeks of life, but the mother’s milk is often insufficient supply after a preterm birth. Using preterm pigs as models for preterm infants, we would like to investigate the effects of these factors on preterm neonates.
At birth, preterm pigs exhibited compromised blood-related parameters, gut lactase activities and villus height, and numbers of several types of immune cells compared to term pigs. Multiple intestinal and immune parameters increased significantly with age in both groups. At the same postconceptional age (PCA), preterm pigs displayed higher numbers of blood leukocyte and gut enzyme activities, but lower villus height and blood cytotoxic T cell numbers compared to term pigs.
According to the results of the blood transcriptomic analysis, preterm pigs had a relatively immature immune status compared to term pigs at birth. Moreover, almost no correlations were identified between differentially expressed genes (DEGs) and immune cell counts. The intra-amniotic (IA) LPS injection activated the innate immune system. Commonly DEGs identified in both preterm pigs with and without IA LPS indicated that they shared similar patterns of innate immune development. Finally, no alterations in cytotoxic T cell proportions and specific down-regulated genes with age in IA LPS pigs were observed, thus illustrating that IA LPS pigs maintained the immunosuppressive and showed compromised cellular metabolic activities.
IA LPS exerted modest effects with different diets on gut parameters within the first 5 days. COL feeding resulted in a lower incidence of diarrhea, NEC severity, systemic inflammation, and better gut barrier function and lactase activities than FOR feeding. CGMP promoted neonatal gut lactase activities, and decreased the IA LPS-induced increase in the IL-8 level in intestinal epithelial cells (IECs) in vitro. Finally, OPN tended to reduce diarrhea and promoted IEC proliferation in vitro.
Future perspectives of the research
A future study should be performed to compare the pigs described in Manuscript 1 with truly term pigs simulating all clinical conditions of term infants, such as vaginal delivery, no PN and no catheter, to further confirm the translational value observed in the current project. Additional preterm pig studies are also required to investigate the organ development trajectories under different conditions corresponding to human fetuses using as a desirable translational model for human infants.
For the studies of preterm births with prenatal inflammation, further studies may be performed by administering pathogens during the postnatal period to assess the responses of these preterm animals or by administering specific nutrient compositions and feeding regimens to protect these preterm animals from external insults. Furthermore, based on our meaningful findings of the impaired cellular oxidative phosphorylation and ribosomal activity in preterm neonates with prenatal inflammation. A postnatal therapeutic target that may improve the immunometabolism could be developed rather than only antibiotic treatments for those preterm infants to prevent neonatal sepsis and other infections and reduce the risks of antimicrobial resistance and perturbations in spontaneous bacterial colonization.