Project description:Premature birth and cesarean section are major perinatal factors influencing immune development and are associated with increased morbidity and inflammatory diseases. However, their impact on neonatal adaptive immunity remains incompletely understood. To determine how gestational age and mode of delivery shape early immune programming, we analyzed CD4⁺ T cells, central regulators of adaptive responses, from preterm neonates (28–36 wga) and full-term neonates delivered by cesarean section or natural birth. We performed transcriptomic profiling by mRNA sequencing, complemented by functional assessment of T cell activation, proliferation, and cytokine production following stimulation. The mode of delivery exerted a dominant effect on the CD4⁺ T cell transcriptome and function. CD4⁺ T cells from full-term neonates delivered by natural birth exhibited an immune activation signature compared with those from cesarean section and produced higher levels of multiple cytokines, but showed reduced proliferative capacity. In contrast, prematurity induced modest changes in basal gene expression relative to full-term cesarean section neonates. Despite these limited transcriptional differences, CD4⁺ Tcells from preterm neonates displayed enhanced proliferation and increased secretion of inflammatory cytokines IL-13, TNFα, IL-6, and IL-17F, indicating heightened responsiveness. Collectively, our findings suggest that CD4⁺ T cell immune programming begins in utero, as preterm neonates exhibit heightened inflammatory responsiveness. At term, the mode of delivery further refines this developmental trajectory. Cesarean section is associated with a restrained functional profile, whereas natural birth induces an immune activation signature and enhanced cytokine production. These results provide functional evidence that neonatal CD4⁺ T cell trajectories are established during fetal life and subsequently modulated at birth, underscoring the layered influence of perinatal factors on immune development.

Project description:Background: The gut microbiome, a complex community of bacteria, viruses, fungi, and protozoa, matures alongside its host. In humans, the birth mode, vaginal delivery (VD) or cesarean section (CS), is a major determinant of early microbial colonization. However, it remains unclear whether CS-associated colonization has lasting effects on microbiome-host interactions. To address this, we developed a Wistar rat model to examine how birth mode affects gut microbiome composition and the gut and plasma metabolome from weaning to adulthood. Methods: Male Wistar rats were assigned to three groups: (i) VD, born vaginally without cross-fostering; (ii) VD-CF, born vaginally and cross-fostered; and (iii) CS-CF, born via cesarean section followed by cross-fostering. Fecal samples were collected on postnatal days (PND) 25, 53, and 90 for microbiome profiling using 16S rRNA sequencing. Fecal and plasma samples collected on PND 25, 39, 53, 67, 81, and 90 were analysed by untargeted metabolomics. Results: The CS-CF group exhibited a distinct postnatal gut microbiome trajectory, characterized by lower α-diversity compared to VD and VD-CF animals, suggesting delayed microbial maturation. β-diversity analyses (unweighted and weighted UniFrac) revealed persistent birth mode-associated differences in microbial community composition, most pronounced in adulthood. Compositional analyses identified specific taxa altered by CS, including increased relative abundance of Romboutsia and Limosilactobacillus. Metabolomics analysis of fecal samples demonstrated clear differentiation between early (PND 25 and 39) and late (PND 53–90) postnatal stages in all groups with CS-CF animals showing a unique metabolic trajectory characterized by fewer temporal changes compared to VD and VD-CF groups. Specifically, the vaginal-delivered groups showed time-dependent increases in microbially derived metabolites, such as secondary bile acids and indole derivatives, a functional maturation profile that was absent in the CS-CF group. Conclusion: These findings indicate that cesarean section alters the postnatal development of the gut microbiome and metabolome, with potential long-term implications for host physiology. Importantly, this study establishes a Wistar rat model to investigate the causal effects of birth path on microbiome development and host metabolism, providing a valuable platform for future mechanistic and translational studies.

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Human metagenome

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