The symbiotic relationship between host and microbes starts early in life and is important not only in terms of how the neonate microbiome ultimately develops, but also its potential impact on long-term infant health.
A current ongoing debate within the scientific community is whether gut colonization starts during pregnancy or at birth. Indeed, the crucial question of when bacteria first colonize the body has yet to be answered.
Microbial transfer at the feto-maternal interface
For long time, prevailing scientific dogma stated that neonates are born sterile and only upon delivery are they populated by microorganisms. For instance, in 1900, French pediatrician Henry Tissier declared: “The fetus lies in a sterile environment.”
Things changed in 1982, however, when a study found bacteria in the placenta. That discovery prompted scientists to accurately corroborate these findings.
By using both conventional culturing techniques and 16S ribosomal RNA gene and/or metagenomic sequencing in animal studies and humans in the mid-2000s, bacteria were also detected in what had been presumed to be sterile tissue from healthy term neonates. These included the placenta, amniotic fluid and meconium.
Contrary to initial belief, therefore, the evidence of bacterial presence in fetal membranes and in newborns’ first stool would not necessarily be a sign of infection. Furthermore, no distinction is made in this regard between premature infants and matched controls, which, in turn, might support the existence of a placenta microbiome in healthy pregnancies.
Other species such as clams, tsetse flies and turtles appear to inherit a mother’s microbiome before birth. It is therefore no surprise that humans may also have microbes in utero.
Major caveats remain, however, making it difficult to prove the existence of a fetal-maternal microbiome. For instance, it is unclear which route microbes use to enter the intrauterine space, with their origin thought to be the mother. Furthermore, scientists leading this field remain uncertain about whether the organisms are viable or if free DNA is being detected, and it is unclear to what extent those bacteria are temporary passengers of the fetus or indeed residents in the fetal gut.
Contamination of the samples is also plausible. To tackle this issue, scientists have recently provided evidence of fetus exposure to bacterial DNA—it remains unclear whether this originates from viable or dead bacteria—and metabolites prior to birth beyond the level of background contamination.
How the transfer of commensal organisms from the maternal gut to blood and systemic locations mechanistically occurs has been largely explored in mice, showing that maternal gut microorganisms migrate to various locations, including the mammary gland via an endogenous cellular route (called the bacterial entero-mammary pathway), taking place mainly during late pregnancy and lactation. These findings suggesting that transporting bacterial components from the gut to both blood and breast milk cells is possible, probably in the form of non-viable bacteria vectorized by immune cells, was formerly proposed from a study in mother-infant pairs. As such, this could program the neonatal immune system to better tackle the challenge of sorting out pathogens and commensal organisms.
There is also evidence of the impact on offspring development of symbiotic interactions between the mother and gut microbiome. In this regard, Elaine Hsiao and colleagues showed that injecting pregnant dams with a mock virus yielded offspring that exhibited autism-like symptoms. Such behavioral abnormalities in the offspring of maternal immune activation in mice were accompanied by defects in intestinal integrity and alterations in gut microbiota composition.
From an evolutionary perspective, it has been hypothesized that microbes may have influenced host sociability and behavior through the known microbiota-gut-brain axis as a way to propagate their own genetic material.
Other host-related and environmental factors such as maternal obesity and weight gain and exposure to environmental factors such as a high-fat diet and non-nutritive sweeteners may also affect infant microbial colonization and health programming later in life.
Thus, gut colonization during the perinatal period, especially during the first 2 to 3 years of life, is influenced by multiple biological and environmental factors and provides a window of opportunity to potentially reduce the risk of chronic diseases in childhood and later life.
Birth as the major microbial encounter
Although data exists regarding gut colonization before birth, some scientists remain skeptical and argue that the presence of bacterial DNA in presumably sterile fetal tissues such as the placenta does not lead to the establishment of the seed of the human microbiome before birth.
It is widely accepted that humans’ first exposure to microbes occurs in the birth canal. After delivery, maternal peripheral blood mononuclear cells and human breast milk cells contain the genetic material of a wide range of gut microbes, some of which are also found in infant feces.
At birth, newborn babies experience rapid colonization by microbes from their mothers and the surrounding environment. Delivery type is a critical factor involved in establishing the infant gut microbiota. Epidemiological studies indicated that cesarean section birth may come with a slightly increased risk of developing allergies and later obesity. Recent research has revealed that, compared with vaginal delivery, cesarean sections may predispose individuals to opportunistic infections.
Scientists have found no differences in the bacterial DNA recovered from placenta samples (of preterm infants and those of babies born at term) from that found on commercial reagents. Therefore, given that the placenta has a low bacterial biomass, it is also plausible that the bacterial DNA identified may derive from contamination through dust or commercial reagents.
More recently, an analysis of placental samples from more than 537 women, with either complicated or uncomplicated pregnancies, showed that the placenta was unlikely to be the major source of the infant microbiota. An experimental approach consisting of the use of two different kits for DNA extraction and different molecular methods to detect bacterial DNA allowed to reduce the chance of false-positive results due to contamination. The fact that almost 5% of placenta samples collected before labour contained group B Streptococci, a major cause of sepsis in newborns, also reveals that bacterial infection of the placenta is not a frequent cause of adverse pregnancy outcome.
Meanwhile, the observation of a handful of microbes in the placenta, umbilical cord blood, amniotic fluid and meconium does not necessarily support the existence of a complex microbiome, like the ones found in other niches such as the gut or saliva. As with the study of the breast milk microbiome, characterizing microorganisms colonizing the fetus prior to birth requires sophisticated methodologies that distinguish resident microbes from those that temporarily colonize the sample.
On the whole, it is clear that host interaction with intestinal microbes either during pregnancy or during the immediate postnatal period may have a profound impact on the neonatal microbiome and health and disease in later life by programming immune and metabolic pathways. Compensating for the lack of exposure to maternal microbes upon cesarean section delivery by a simple gesture might prove beneficial. Targeting the development of host-microbes symbiosis in early life might also be considered as a means of preventing the uncontrolled rise in incidence of chronic diseases that current medicine is not able to cure.
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