Not Sterile, After All: The Placenta’s Microbiome

Pregnant woman smiling and pointing to her tummy

Credit: Chad Cohen

When thinking about your health, or the health of your children, you’re probably not thinking of the placenta. This often neglected, yet vital, pancake-shaped organ develops during pregnancy. It adheres to the inside surface of the uterus and guides development; partly maternal, partly fetal, it delivers food and oxygen to the growing fetus via the umbilical cord and removes waste products—among other vital functions. Yet, the placenta may be even more important to the health of mother and child than we’ve previously imagined.

Until recently, the uterus and the placenta were thought to be germ-free and sterile—to keep the baby safe from infection. But at just one week old, babies have a complex collection of microbes in their guts. Where do those bacteria come from? It was thought that a baby received its first dose of bacteria as it passed through the vagina—or from the mother’s skin, if the child was born via C-section. But Kjersti Aagaard, a 2007 recipient of a NIH Director’s New Innovator Award and an obstetrician and associate professor of gynecology at Baylor and the Texas Children’s Hospital, began to suspect there was more to the story.

Aagaard’s suspicions were, in part, fuelled by evidence provided by the NIH-led Human Microbiome Project [HMP]. Launched in 2007, the HMP seeks to identify the microbes living in our nasal passages, oral cavities, skin, gastrointestinal tract, and urogenital tract. It has already taught us a great deal about the microbial populations characteristic of each location. But when Aagaard studied the infant microbiome, she found that microbes in babies’ intestines didn’t resemble the collections seen on the skin or in the vagina.

Then, Aagaard read an NIH-funded study by a team at Washington University in St. Louis, revealing the presence of microbes in the placenta [1]. Perhaps, thought Aagaard, the placenta had its own microbial population—and babies received their first dose of microbes directly from the placenta, while still in the mother’s womb.

To test the idea, she and her team collected tissue samples from 320 placentas and isolated the bacteria present in each. Rather than using a traditional microscope and petri dishes to identify the bacteria, as the Washington University researchers had done, she and her team focused on the DNA. Her team collected DNA from the placentas and sequenced the genetic material, which revealed the identity of the microbial inhabitants. When they compared the placental microbes with those in the mouth, nose, skin, vagina and gut of non-pregnant women, they found they most closely resembled the microbes that lived in the mouth [2].

The finding was unexpected. How would oral microbes from the mother end up in the placenta? Aagaard turned to earlier animal studies for possible answers. A mouse study suggested that one of the oral microbes, Fusobacterium nucleatum, could alter the structure of blood vessels, enabling the infiltration of other microbes into the blood [3]. Once in the bloodstream, these oral microbes could presumably find their way to the placenta. Aagaard reasoned that in humans, oral microbes would similarly enter the bloodstream from the oral cavity and “seed” the placental microbiome. Her team provided further support for this idea by showing that women who had suffered a bacterial infection (such as a bladder infection) during the first or second trimester had “microbial fingerprints” of this infection in their placenta.

They also found that the microbes from placentas from babies born earlier than 37 weeks (preterm births) had a significantly different collection of microbes compared to those of babies carried for the full term of 40 weeks. That’s an intriguing observation, with possible clinical significance. Every year, 500,000 babies—1 in 8—are born preterm. These early arrivals can be dangerous, because the baby is still developing vital brain and lung functions in the womb until 39 weeks. While most preterm babies do well with the kind of support now available in hospitals, they are at greater risk of breathing and feeding difficulties, cerebral palsy and vision deficits, and neurological problems later in life.

Aagaard and her colleagues are now beginning a NIH-sponsored longitudinal study of 526 women to determine whether microbes may actually play a causative role in preterm births. It may be that specific microbes, or predictable shifts in the bacterial community, may explain why some infants are more likely to be born preterm. If these possibilities are confirmed, early diagnostic testing may help identify women at risk—and ultimately there might even be ways to reset the microbiome to encourage full term pregnancies.

Aagaard’s findings are just the tip of the iceberg. It may surprise you to know that when the placenta malfunctions, the mother’s health also suffers—with problems like insulin resistance, preeclampsia, gestational hypertension, and even heart disease later in life. Yet, because the placenta is difficult to study during pregnancy, most research occurs after delivery; but that doesn’t tell us much about how the organ grew and functioned, or malfunctioned, while fetus was developing. That’s why Alan Guttmacher, director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, has proposed the Human Placenta Project [HPP] [4]. Next week, researchers from NIH will convene with international experts in placental biology to develop a research agenda for the HPP. This is a project with the potential to have a profound impact on the health of current and future generations worldwide. Perhaps the HPP will also bring long overdue attention and respect to the importance of this amazing organ.

References:

[1] Identification of intracellular bacteria in the basal plate of the human placenta in term and preterm gestations. Stout MJ, Conlon B, Landeau M, Lee I, Bower C, Zhao Q, Roehl KA, Nelson DM, Macones GA, Mysorekar IU. Am J Obstet Gynecol. 2013 Mar;208(3):226.

[2] The Placenta Harbors a Unique Microbiome. Aagaard K, Ma J, Antony KM, Ganu R, Petrosino J, Versalovic . Sci Transl Med. 2014 May 21;6(237).

[3] Transmission of diverse oral bacteria to murine placenta: evidence for the oral microbiome as a potential source of intrauterine infection. Fardini Y, Chung P, Dumm R, Joshi N, Han YW. Infect Immun. 2010 Apr;78(4):1789-96.

[4] The Human Placenta Project: placental structure, development, and function in real time. Guttmacher AE, Maddox YT, Spong CY. Placenta. 2014 May;35(5):303-4.

Links:

High-Risk, High-Reward Research. (NIH Common Fund)

NIH Director’s New Innovator Award Program

Human Microbiome Project

The Human Placenta Project: Placental Structure and Function in Real Time

Kjersti Aagaard-Tillery, Baylor College of Medicine, Project Title: Characterization of the Fetal Primate Epigenome and Metabolome Under In Utero Conditions of Maternal Obesity

Kjersti M. Aagaard Lab

NIH support: Common Fund; National Human Genome Research Institute; National Institute of Nursing Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development