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Page 4 of 20 Horwell et al. Microbiome Res Rep 2025;4:1 https://dx.doi.org/10.20517/mrr.2024.32

Perhaps a nuanced slant to this, with increasing experimental data behind it, would be that immunogenic
microbial products (bacterial DNA fragments, and metabolites) from the mother’s commensal microbiota
are able to cross the placental barrier, giving the opportunity to educate the foetal immune system and
promote immune tolerance before birth [31-33] . With the rapid progress in ex-utero embryogenesis
technology , it is conceivable that in the near future, an animal model will be able to categorically prove if
[34]
these immunogenic microbial products have any demonstrable relevance to foetal immunogenic and
microbiomic development. For now, the evidence is insufficient to move away from the orthodoxy of the
sterile womb hypothesis.

Birth
The very first moment of life has direct implications for the newborn’s microbiome. Delivery by CS or
vaginal delivery (VD) has been shown to result in divergent neonatal microbiomes. This is believed to be
due to the direct contact of the neonate with the maternal vaginal and perineal microbiome, allowing direct
[43]
vertical transmission to occur. Although very few mechanistic studies have been performed, transmission to
the neonatal colon is believed to be via the oral route, a process phrased as the “bacterial baptism of
birth” [35,36] . An interesting physiological adaption arises during the third trimester that confers a survival
benefit to the child. In response to increasing oestrogen and progesterone, the mother’s vaginal microbiome
is altered, a decrease in alpha diversity occurs, and the abundance of Lactobacillus spp. increases [37,38] . These
species produce lactic acid, decreasing vaginal pH and consequentially reducing acid-sensitive pathobionts
[38]
such as Group B Streptococcus , which carry a high rate of neonatal sepsis and mortality.
This “bacterial baptism” during VD is inherently absent in CS; instead, other microbial environments
appear to play a role and lead to divergent microbiomes in the newborn. Multiple large studies have
demonstrated that VD is associated with increased abundances of Bacteroidetes (particularly
Bacteroides fragilis), Bacillota (chiefly Lactobacillus spp.), and Actinomycetota (almost exclusively from the
Bifidobacterium spp.), all of which are typically found in the vagina or recto-anal microbiomes. In contrast,
CS has been associated with species typically found on maternal skin and microbiomes found in the
hospital, with neonates having an increased abundance of Bacillota (notably Staphylococcus
spp.), Firmicutes, Enterococcus, and Klebsiella [14,39-46] .

An increasing number of epidemiological studies have demonstrated a correlation between CS and an
increased risk for negative long-term infant health outcomes. These findings are diverse and not always
consistent, but there are reported increases in risk for type 1 diabetes mellitus (T1DM) [47-49] , obesity [48,50] ,
[55]
[54]
asthma [51,52] , eczema , respiratory tract infections , coeliac disease , IBD [56,57] , attention deficit/
[53]
hyperactivity disorder , and autism . A recent meta-analysis of the paediatric consequences of CS, with
[58]
[59]
over two million subjects, demonstrated increased risks for childhood asthma [OR 1.23 (1.14, 1.33)], T1DM
[OR 1.07 (0.90, 1.27)], and obesity [OR 1.35 (1.29, 1.41) ] . With more than 25% of births being CS in
Europe and North America, the potential implications to long-term health are a significant public health
concern [60,61] . However, it is still unclear what causes these phenomena. Several explanations have been
proposed, from the lack of stress hormones during an elective CS to an absence of intraocular pressure
[62]
being suggested to alter the inflammatory response of the newborn . However, the leading hypothesis
relates to the divergent microbiomes associated with these methods of delivery . The first 24 h of life
[63]
have been shown to be a prime opportunity for bacterial colonisation of the colon, in that the pH of the
stomach is relatively neutral thanks to the ingestion of amniotic fluid in utero . This has been shown to
[43]
complement the vertical transmission during VD of Lactobacillus, Bifidobacterium, and Bacteroides. These
have been shown to regulate the developing immune system, influence the concentration of natural killer
(NK) cells, regulate the population of T-lymphocytes, increase the secretion of Immunoglobulin A (IgA)
antibodies, and aid in the metabolism of human milk oligosaccharides (HMOs) [64-70] . Furthermore,