The pioneering gut microbiome acquired via different delivery modes in neonates shapes distinct immune and metabolic environments

Background: Cesarean section (CS) delivery is associated with an increased risk of inflammatory diseases, hypothesized to be driven by differences in the microbiome acquired at birth compared to vaginally delivered (VD) infants. How delivery mode associated differences in initial colonizers directly modulate early life immune education and metabolic development is poorly understood. Objective: First, to investigate how differences in pioneering colonizers associated with delivery mode directly modulate early life immune education and metabolic programming. Second, to examine the effect of vaginal seeding, an intervention aimed to restore the microbiome of CS infants to a VD state. Design: Germ-free mice were colonized with transitional stool from VD, CS or CS-delivered and vaginally seeded neonates. Immune cell populations, serum immunoglobulin levels, and fecal microbiome and metabolome profiles were analyzed. Results: Mice colonized with stool from VD neonates displayed increased numbers of myeloid cells at barrier tissues, whereas CS microbiome colonized mice exhibited decreased Th1/Th2 ratios and increased serum IgE levels. Key amino-acid pathways including tryptophan metabolism, riboflavin co-enzymes and carbohydrate metabolites were significantly enriched in the murine VD fecal metabolome and correlate with the increased abundance of Escherichia typically observed in the VD microbiome. Mice colonized with stool from CS neonates who received vaginal seeding, resulted in increased regulatory T cells and serum IgA in mice, suggesting potential benefits of vaginal seeding. Conclusion: Collectively, our studies demonstrate the ability of pioneering colonizers to set the immune and metabolic tone that could have long-lasting effects and provide avenues for microbiome-mediated interventions.