Could baby’s first bacteria take root before birth?

Most infants first come into contact with microbes during birth — or so researchers have assumed. Baby’s first bacteria S oon after conception, a human embryo begins By Cassandra Willyard nearly 200 placentas collected from women giving to assemble a remarkable organ crucial to its birth at a hospital in St Louis, Missouri. When the survival. The placenta is both a lifeline and a guardian: it shuttles researchers examined the samples under a microscope, they found bacoxygen, nutrients and immune molecules from the mother’s blood- teria in nearly one-third of them1. “They were actually inside cells there,” stream to her developing fetus, but it also serves as a barrier against says Mysorekar, a microbiologist at Washington University in St Louis. infections. For more than a century, doctors have assumed that this Bacteria often signal infection, and infections are a common cause of ephemeral structure — like the fetus and the womb itself — is sterile, premature birth. But the microbes that Mysorekar observed didn’t seem unless something goes wrong. to be pathogens. She didn’t see any immune cells near them; nor did Starting around 2011, Indira Mysorekar began questioning this she see signs of inflammation. And bacteria weren’t present only in the idea. She and her colleagues had sliced and stained samples from placentas of women who gave birth early; Mysorekar also found them . d e v r e s e r s t h g i r l l A . e r u t a N r e g n i r p S f o t r a p , d e t i m i L s r e h s i l b u P n a l l i m c a M 8 1 0 2 © 2 6 4 | N AT U R E | VO L 5 5 3 | 1 8 JA N UA RY 2 0 1 8 EDGARD GARRIDO/REUTERS THE WOMB WAS THOUGHT TO BE STERILE. SOME SCIENTISTS ARGUE IT’S WHERE THE MICROBIOME BEGINS. FEATURE NEWS in samples from women who had normal, healthy pregnancies. “That was our first hint that this may be like a normal microbiome,” she says. Studies seeking to understand how microbes help to shape human health and development have become extremely popular over the past few decades, but some researchers are concerned that a crucial question — when bacteria first colonize the body — has not yet been answered. Doctors have assumed that the first contact with colonizing bacteria occurs in the birth canal. Clinicians are even looking to see whether babies born by caesarean section might benefit from a swab of their mother’s vaginal microbes. But Mysorekar and other scientists have found evidence of bacteria in the placenta, amniotic fluid and meconium — the tar-like first stool that forms in a fetus in utero. This has led some researchers to posit that the microbiome might be seeded before birth. If that is true and bacteria are a normal — perhaps even crucial — part of pregnancy, they could have an important role in shaping the developing immune system. Scientists might be able to find ways to shift the microbial composition in the womb and possibly ward off allergies, asthma and other conditions. They might also be able to uncover microbial profiles associated with preterm birth or other complications during pregnancy, which could help to illuminate why they occur. The scientists at the centre of these discoveries argue that the dogma of a sterile womb is on its way out. Perhaps humans, like species such as clams, tsetse flies and turtles, can inherit a mother’s microbes before they are even born2. “If we do not have microbes in utero, I think we would be the only species that has been interrogated that doesn’t,” says Susan Lynch, a microbiologist at the University of California, San Francisco. But even as the number of papers supporting this idea grows, some scientists are pushing back. “I just don’t think that these microbiomes exist,” says Jens Walter, a microbiologist at the University of Alberta in Edmonton, Canada. Where some see an intriguing new avenue of research, others see biological implausibility, sloppy science and a spectre that has long haunted microbiome research — contamination. Now, studies are getting under way that could answer the question once and for all. One paediatrician likens the controversy over the placental micro biome to a scientific “knife fight”. But if fetal microbiomes do exist, that could have far-reaching implications not only for medicine, but also for basic biology. “If we start thinking of the placenta as a conduit or facilitator of maternal-fetal communication and not as a barrier, then I think we open ourselves up to very interesting perspectives on how we’ve interpreted a lot of developmental biology today,” says Kjersti Aagaard, an obstetrician at Baylor College of Medicine in Houston, Texas. infections during pregnancy. Bacteria can be difficult to culture. So, to identify what was there, they used gene sequencing. They took biopsies of the placentas in a sterile room within an hour of delivery, sliced off the surfaces to avoid contamination, and placed those samples into vials. They also analysed the contents of empty vials to rule out contamination from the environment or the DNA-extraction reagents. Not every placenta contained detectable bacterial DNA, but many did3. To get a more in-depth picture of the capabilities of these microbes, the researchers performed whole-genome sequencing on a subset of the samples. In most, they found communities dominated by Escherichia coli and a few other groups. And when they compared the bacterial DNA from placentas with that from bacteria typically found in other areas of the body, the results best matched the kinds of microbe found in the mouth. How oral bacteria would have made their way to the placenta isn’t clear, but one possibility is that they travelled through the bloodstream. Even routine tooth brushing can allow bacteria access to the blood. What’s more, the microbial signature seemed to differ in women who had experienced a preterm birth or an earlier infection. Physicians have assumed that the mere existence of bacteria in the placenta signals infection, but to Aagaard it seemed clear that which bacteria are present is much more important than whether they are there at all. The paper made a splash in the popular press, but critics argued that Aagaard was overreaching. “DNA is not bacteria,” says Mathias Hornef, head of the Institute of Medical Microbiology at the University Hospital RWTH Aachen in Germany. DNA can be used to characterize a microbiome, he says, but not to establish its existence. Aagaard’s findings weren’t an isolated event, however. Several other groups have found bacterial DNA and more in the placenta. Mysorekar, for example, saw the host of bacterial structures inside cells taken from the placenta1. And in 2016, a Finnish group managed to culture bacteria from placental tissues taken from women who had healthy pregnancies4. Researchers have also found bacteria in amniotic fluid4,5, leading them to wonder whether the fetus might occasionally ingest microbes when it swallows some of that fluid. And some researchers, including Josef Neu, a neonatologist at the (...truncated)