The development of a newborn’s immune system is a complex process influenced significantly by the early-life microbiome. This critical phase of immune system maturation is affected by various factors, including the maternal immune system, microbial metabolites during pregnancy, microbial transfer at birth, and the transfer of microorganisms, maternal immune factors, and metabolites via breastfeeding. Among these, the mode of birth delivery plays a pivotal role in shaping the neonatal microbiome and, subsequently, the development of the immune system. The two methods of birth delivery are vaginal birth and Cesarean birth (C-section), which consists of delivering a baby through a surgical incision made in the mother’s abdomen and uterus.
Birth mode is a main driver of compositional differences in the infants’ gut microbiota. Infants born via C-section acquire more oral and skin microbes due to reduced exposure to their mother’s vaginal and fecal microbiota. Whether or not most vaginal and skin bacteria can successfully establish themselves in the infant gut is still debated, a study has shown that infants born by C-section share 41% of gut microbes with the mother, whereas infants born by vaginal delivery share 72% of gut microbes with the mother. Moreover, different birth modes influence the colonization of other microbes. Studies have shown that infants born by C-section have less intestinal colonization by probiotic microorganisms, whereas the colonization of C. difficile, a type of bacteria that causes diarrhea and colitis, was increased at one month of age. Interestingly, a study has shown that maternal antibiotic administration before C-section does not further impair microbiome colonization of the infants, suggesting that the initial lack of exposure to maternal vaginal and gut microbiota is the primary concern. Moreover, C-section has been associated with an increased risk for immune disorders, such as asthma, allergic rhinitis and celiac disease.
How does delivery mode affect the development of immune cells? Microbes shape the infant immune landscape by engaging molecular receptors in various gut immune cells and activating signalling cascades that control cell differentiation and inflammation. For example, immune cells, such as regulatort T cells (Treg) and invariant natural killer T (iNKT) cells, can only be “educated” by microbes during a specific postnatal time window called the “neonatal window of opportunity”. This critical time period in a newborn’s life is when environmental factors drive immune and tissue maturation and influence susceptibility to diseases in adult life, helping the body develop tolerance to subsequent environmental exposures. Thus, the immune cell repertoire established during this critical period under the influence of the gut microbiota can potentially affect host immunity and disease vulnerability. In studies with mice, those born via C-section had a different microbiota composition which impacted their immune systems in various ways, including having fewer Treg and dendritic cells that help control immune responses. Therefore, C-section can potentially have lasting effects on the body’s ability to regulate immune responses.
The process by which the intestines become accustomed to bacteria shortly after birth is also affected by delivery method. For example, intestinal epithelial cells (IECs), which line the intestine and are important for protection against microbial infections, need to be critically regulated to maintain intestinal homeostasis. During vaginal birth, IECs are quickly activated by bacteria-associated molecules such as lipopolysaccharides (LPS), which helps prepare the body to defend against harmful microbes. The activation of IECs by LPS is only transient and is lost hours after birth, with no detectable inflammation, suggesting that tolerance towards microbes is acquired to facilitate microbial colonization of the fetal intestine. This activation is a delicate balance that, if disrupted, could lead to higher risk of inflammatory diseases. The reduced bacterial exposure from C-section might impair this critical early-life immune training, leading to decreased tolerance. This evidence points to the complex interplay between the mode of delivery, microbial exposure, and the developing immune system, underscoring the importance of understanding the long-term health implications of C-sections.
C-section significantly influences both the gut microbiota and immune system development, and these effects may lead to various long-term immune health issues. To address potential dysbiosis associated with C-sections, new treatments, such as fecal microbiota transplantation (FMT), are being investigated for restoring neonatal microbiota following C-section births. A recent proof-of-concept study has demonstrated that the gut microbiota of infants born via C-section can be restored postnatally by maternal FMT. However, careful microbiological screening is mandatory to eliminate harmful bacteria. Further research is needed to understand the complex interactions and the long-term impacts of C-section delivery on immune system development. Such mechanistic understanding may provide the basis for the development of preventative approaches for negative health effects in C-section infants in the future.
Tianning Yu
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