More than 100 years ago, French pediatrician Henry Tissier declared that babies were bacteria-free in the womb. Colonization, he claimed, began during the birthing process, not before. While bacterial transmission to the fetus has been documented many times since then, for decades few questioned how the womb could be sterile – they just accepted that it was. However, as research on the human microbiota has progressed, this dogma has been subjected to increased scrutiny: How could any aspect of the human body truly be sterile? Finally, in the last five years, several groundbreaking studies have shattered the paradigm completely, suggesting that our first encounter with the microbial universe occurs much earlier than we thought: in utero. So what is it that dictates and differentiates the outcome of the feto-maternal-bacterial interaction?
MICROBIAL TRANSMISSION from mother to offspring is a universal phenomenon in the animal kingdom. Across the invertebrate phyla, maternal transfer of microbial symbionts occurs at various stages of development, via systems such as transovarial transmission and ‘egg-smearing’ — where the mother smears her fecal matter over the eggs. This transfer of symbionts typically occurs to aid in nutrient uptake and provide essential amino acids or vitamins. While less is known about Chordata, studies from domesticated chickens, ray-finned fish and turtles all suggest that maternal microbial transmission also occurs in vertebrates. Indeed, maternal microbial transfer is now thought to strongly influence evolutionary development. Research from the last century has uncovered several species that require the transfer of specific symbionts for proper development. By impacting on countless aspects of the host physiology, microbial transfer to new generations ultimately improves their fitness, resulting in further propagation of the mutualistic relationship.
So how and when does this transfer occur in humans? In keeping with the dogma of the sterile uterus, the placenta was thought to be free of microbes as well. However, a 2014 study by Aagaard et al. identified the placental microbiome and found it to be extremely vibrant. Based on metagenomic shotgun sequencing, the placental microbiome most closely resembled the maternal oral microbiome and had a large variety of species with specific metabolic functions. Thus, the placenta likely represents the fetus’ first encounter with bacteria and their products.
Of note, the presence of live bacteria in the placenta has not yet been identified. Sequencing-based analysis of microbial communities uses DNA isolated from tissues; so while the presence of a wide variety of bacterial DNA has been confirmed, this does not conclusively prove that live bacteria inhabit the placenta or fetus. Indeed, one of the most confounding questions in the field is how bacteria would be able to reach the fetus. The current theory proposes that maternal bacteria are picked up by various maternal blood mononuclear cells, then transported and released into the placenta. This is supported by the fact that DNA from Bifidobacteria and Lactobacilli, genera that play critical beneficial roles in early life immune regulation, has been identified in the human placenta. It is therefore possible — and exciting — to hypothesize that by introducing the fetus to bacteria in utero, maternal immune cells are inducing tolerance to specific bacterial species in preparation for their roles postpartum.
The placenta may mediate the fetus’ first encounter with bacteria, but birth provides the foundation for the microbiota. Delivery mode has long been identified as having a significant influence on the neonatal microbiome. Vaginally delivered infants possess a gut microbiota most closely resembling their mother’s vaginal microbiome, whereas infants delivered via Cesarean section acquire bacterial communities most like the maternal skin microbiome, as well as bacteria from the delivery room. This difference in founding bacteria is observed up until two years of age, with loss of bacterial richness and diversity in C-section delivered infants. Delivery via C-section has also been associated with numerous inflammatory diseases, including: asthma, type 1 diabetes, celiac disease and obesity. This suggests that interruption of the critical transfer of bacteria from mother to newborn has long-term detrimental effects on the immune system and metabolism.
Despite this, elective C-sections are still on the rise. In Rome, close to 80% of live births are elective C-sections. In North America, that number is closer to a third. Dr. Dominguez-Bello and colleagues are attempting to restore the altered microbiota of C-section newborns. They collect maternal vaginal contents prior to surgery, and “wash” the newborn immediately after birth to inoculate them with the vaginal bacteria. Although studies to determine the long-term effects are still required, preliminary results show a positive effect on the fecal, skin and oral microbiome, suggesting that doctors can “correct the C-section” with the protective vaginal microbiota.
After birth, the infant continues to be colonized with microbes from their environment and diet. Breast milk, which is strongly influenced by the maternal diet, maternal health status, mode of delivery and gestational age, is a wonderful soup of maternal antibodies, bacteria and bacterial products, promoting the colonization of the infant gut microbiota postpartum. As breast milk is the primary source of nutrition and immune protection for the infant, its bacterial composition can have significant effects. Human milk oligosaccharides (HMOs) are a critical prebiotic component of breast milk, further promoting the growth of specific bacterial groups like Bifidobacteria in the infant gut. In formula, these prebiotic HMOs are absent. Formula-fed infants have a reduced microbial diversity and a decline in Bifidobacteria compared to exclusively breast-fed infants. Recent work from Dr. McCoy’s research group has identified maternal microbial metabolites in the breast milk of reversibly colonized germ-free dams. Moreover, maternal antibodies required loading with microbial antigens in order to activate the innate immune response in the offspring. Using models such as this, we are starting to understand the profound impact of maternally derived microbes on neonatal health and development.
In conclusion, bacteria are ubiquitous both inside and outside the human body, and the idea that any part of the human body is sterile is quickly becoming implausible. Despite the long held belief that fetal development occurred in completely sterile conditions, mounting evidence suggests that microbes are present throughout the process, although to what extent live bacteria or their metabolites are required is still unknown. Maternal microbial transmission, through the mode of delivery and breast-feeding, has a profound influence on neonatal health and development. Perhaps we have underestimated its importance in utero as well.
References:
- Aagaard K et al. The Placenta Harbors a Unique Microbiome. Science and Translational Medicine 2014; 6: 237ra65.
- Bright M, Bulgheresi S. A Complex Journey: Transmission of Microbial Symbionts. Nature Reviews Microbiology 2010; 8: 218-230.
- Dominguez-Bello MG et al. Delivery Mode Shapes the Acquisition and Structure of the Initial Microbiota across Multiple Body Habitats in Newborns. Proceedings of the National Academy of Sciences 2010; 107: 11971-11975.
- Funkhouser LJ, Bordenstein SR. Mom Knows Best: The Universality of Maternal Microbial Transmission. PLoS Biology 2013; 11(8): e1001631.
- Mueller NT et al. The Infant Microbiome Development: Mom Matters. Trends in Molecular Medicine 2015; 21: 109-117.
Ashleigh Goethel
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