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Maternal obesity influences transcriptomic and metagenomic profiles in term neonates

ABSTRACT: Maternal obesity impacts neonatal outcomes; however, its influence on fetal gene expression and early gut microbiota composition remains insufficiently characterized. This prospective study was conducted in 62 full-term neonates between 2022 and 2024, analyzing transcriptomic profiles from umbilical-cord blood and metagenomic sequencing of fecal samples at 4 months. The cohort included 31 neonates born to mothers with normal BMI (NBMI) and 31 neonates born to mothers with overweight or obesity (OBMI). Major congenital anomalies, maternal exposure to drugs or antibiotics were exclusion criteria. OBMI neonates demonstrated significant upregulation of genes related to inflammation (MPO, OLR1) and cell-cycle dysregulation (GADD45G, CCNA1). Evidence of altered lysosomal function was observed, with increased expression of CTSG and CLTCL1 and reduced expression of HYAL1. Microbiome analysis revealed a decrease in Bacteroidota and an increase in Proteobacteria in cesarean-delivered neonates. Holdemanella was enriched in vaginally delivered OBMI neonates, suggesting a potential adaptive microbial response. Enrichment of opportunistic pathogens, including Klebsiella, Morganella, and Enterococcus, was observed in cesarean-delivered neonates, indicating a combined effect of maternal obesity and delivery mode on early microbial colonization. These findings suggest that maternal obesity modifies neonatal immune and metabolic gene expression while reshaping gut microbiome composition, with potential implications for long-term health.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303891 | GEO | 2026/07/29

REPOSITORIES: GEO

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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:The rate of cesarean delivery (CD) in China has risen sharply and the high rate was reported to be associated with increased risk of disease in the offspring. However, there is little research on the molecular mechanism of critical pathways and gene signatures involved in the neonatal immunity of cesarean-born infants. This study was undertaken to identify unique gene signatures which was involved in the neonatal immunity of cesarean-born infants through large-scale RNA-sequencing. Genes differentially expressed in cesarean-born infants were identified and further validated through quantitative real-time PCR (RT-qPCR). Moreover, we employed weighted gene co-expression network analysis (WGCNA) to identify highly connected genes that were correlated with neonatal inflammation. In total, 73 differentially expressed genes (DEGs) were identified between cesarean-born infants and normal vagina childbirth. The results obtained by secondary validation indicated that GATM, MIF, IFI27, IL1B, CA1, and EPHB1 were significantly upregulated in phenotype CD, while CYP2A6 and DLK1 were significantly down regulated. Further, functional and pathway enrichment analysis reveals perturbation of several DEGs involved in signaling pathways pertaining to immunoregulation, inflammation, apoptosis, and nervous development. Additionally, HLA-DOB popped out as a core gene in the process of inflammation, which might indicate the risk of cesarean-born infants for inflammatory disease. Notably, our study for the first time has documented gene signatures PIK3CA, PTPRC, SOS1, IL6ST, and MALT1, which were found to be involved in neonatal inflammation. Taken together, the full expression repertoire including the differentially expressed gene sets and core differentially co-expressed genes should provide an excellent resource for identifying potential biomarkers of cesarean-born infants with inflammation, and formulating new hypotheses for physiological functions and the discovery of novel therapeutic targets for inflammatory disease.

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Maternal obesity influences transcriptomic and metagenomic profiles in term neonates

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