Once a newborn leaves the safety of the womb, they enter a whole new environment teeming with microbial life. Many of these microorganisms will be ‘friends’ such as those present in the mother’s vaginal flora. But there will also be foes—potentially pathogenic microbes that pose a serious risk to vulnerable infants with naive immune systems.
Luckily, in a process called immune priming, babies’ immune defenses get a head start even before the baby is born. Previous studies have demonstrated that as early as the second trimester in pregnancy, fetuses have surprisingly competent immune systems. Until now, however, the underlying mechanisms involved in immune priming have remained elusive.
In a first-of-its-kind study published in the journal Cell, a group of researchers co-led by Florent Ginhoux, a Senior Principal Investigator at A*STAR’s Singapore Immunology Network (SIgN), made the unexpected discovery that early contact with microbes in the womb drive immune development in the developing fetus.
Ginhoux and collaborators, including Jerry Chan and Salvatore Albani at the KK Women’s and Children’s Hospital and SingHealth as well as Naomi McGovern from the University of Cambridge, analyzed gut, skin, lung, thymus, spleen and placental tissue samples from human fetal tissues using high-throughput 16S rRNA gene sequencing. To ensure accuracy, the researchers implemented a series of stringent controls to ensure that any bacterial genes detected in their results did not come from contaminants.
Fascinatingly, a diverse range of live microbes was found to be present in fetal organs, including several bacterial genera typically found in the adult gut such as Gardnerella, Lactobacillus and Staphylococcus. Tissue imaging and electron microscopy data helped piece together a map of the distribution of these microbes, showing that bacteria were localized to particular areas of the gut tissues.
Next, the researchers designed an in vitro assay to measure fetal T cells’ responses to microbial contact. The team reported a significant increase in total T cell count and proliferation of CD45RO+ and CD69+ T cells. This indicated that fetal tissues were capable of immune memory, or the ability to recognize previously encountered antigens and launch an appropriate immune response.
“Our study demonstrates for the first time that human fetal organs harbor microbes that may prime the fetal immune system, thereby putting early microbial memory in the context of fetal immune priming—a concept not explored before in fetal immunity,” said Archita Mishra, a postdoctoral fellow at Ginhoux’s lab and first author of the study.
Their work lays the foundation for a myriad of future studies, including understanding where fetal bacteria come from, how they colonize the fetus and how microbial diversity changes throughout gestation. In the future, the team plans to address some of these questions by taking a deeper dive into the nature of microbe-immune priming in human fetal organs.
The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN) and Genome Institute of Singapore (GIS).
