by For more than a century, the uterus has largely been considered a sterile environment. But even today, with advanced medical technology at hand, scientists cannot agree on whether the placenta and the amniotic fluid that bathes a fetus are truly germ-free or not.
Some researchers claim to have detected signs of microbial life in fetal samples in recent years. This has led them to argue that the human microbiome – the community of bacteria, fungi and archaea that live on and in us – is present before birth.
Others disagree. According to a group of researchers from North America, Europe and Great Britain, such studies are based on contaminated samples.
The microbes discovered in previous findings, the authors argue, were inadvertently introduced to the scene, either after vaginal birth or during a clinical procedure to remove a fetus or samples of its DNA.
The very notion of a fetal microbiome is radical. It goes against basic immunological principles and the very basis behind germ-free mammals, which presupposes that a fetus develops in a sterile environment.
While it is possible for microbes to pass from mother to fetus by crossing the placenta, these foreign invaders are usually quickly dealt with by the local immune system in the amniotic fluid. When microbes persist here, they tend to cause serious health and developmental problems for the fetus.
“Such disagreement about a fundamental aspect of human biology poses a challenge to scientific progress,” write lead author Katherine Kennedy, a microbiologist at McMaster University in Canada, and colleagues.
“Failure to address this issue risks diverting limited resources to research that does not result in advances in fetal and maternal health, and misguided attempts to therapeutically modify a non-existent fetal microbiome.”
The new paper attempts to clear up some of this confusion by reviewing the findings and methods of previous research, focusing on four recent reports published since 2020.
By directly examining the microbiology of the human fetus, the selected studies revealed subtle signs of potential microbial habitation. Half of the reports detected viable, low-density microbial populations in the fetus, while the other two only detected metabolic byproducts of microbes, or traces of bacteria commonly found on the skin.
Collecting fetal samples without introducing microbes is difficult work, and in some of these earlier studies, Kennedy and colleagues argue, critical controls were conspicuously missing.
Two of the papers mentioned above collected samples after the fetus was delivered vaginally. Another collected samples after birth by caesarean section. Each of these routes from the body can introduce the fetus to microbes from the mother’s own microflora and nearby environment. And yet only the C-section study—of which Kennedy was the lead author—accounted for this exposure.
In the two studies that claimed microbes had colonized the fetus, every single genus of microbe detected was also found at varying levels in most control samples from other research.
“The omission of vaginal checks … to determine the microbiota of vaginally delivered fetuses is a significant limitation that casts doubt on the authors’ conclusion that the microorganisms originate in the uterus,” warns the new paper.
Moreover, other researchers not involved in the analysis have pointed out that microbial colonization and a consistent microbiome are fundamentally different.
“The available work so far suggests that it is certainly possible that microbes are in the in utero environment, but I think at best these microbes come from somewhere else in the body and are not native to the in utero environment,” microbiologist Suzanne Devkota of the University of California, Los Angeles wrote in a recent comment.
“It’s hard for me to reconcile these human studies that suggest a placental microbiome with the fact that germ-free animals exist.”
Also, even if a small number of microbes do colonize the fetus before birth, how does the developing immune system stop these contaminants from taking advantage of the new life form? And how do immune cells know which microbes to let in and which to kick out in the first place?
“[F]From a clinical perspective, most interpretations in recent publications regarding the presence of microorganisms in the fetus appear to be biologically difficult to reconcile, as it is very likely that they will cause damage to or death of the fetus,” conclude colleagues.
“Through several angles of explanatory considerations, we conclude that the evidence strongly favors the ‘sterile uterus’ hypothesis.”
The study was published in Nature.
