Placenta microbiome. To be or not to be?
One of the first questions to address was to discover if the placenta has a bacterial microbiome, and could it be the potential site of the genesis of this prenatal complex and dynamic ecosystem.
In 2014, Kjersti Aagaard et al. found a unique microbiome niche in the placenta, and that microbiome was consistently different from those reported in other parts of the body. Composed of non-pathogenic commensal microbiota from the Firmicutes, Tenericutes, Proteobacteria, Bacteroidetes, and Fusobacteria phyla, placenta microbiome showed a high prevalence of E. coli species. (1)
But five years later, new studies revealed that Aagaard’s team was totally wrong.
Marcus c. de Goffau and Al, after analysing hundreds of samples, showed that there was no evidence for the presence of bacteria in the large majority of placental samples, from both complicated and uncomplicated pregnancies, but that placenta does represent a potential site of perinatal acquisition of S. agalactiae, a major cause of neonatal sepsis (2).
The difference between the two studies? Contamination of samples.
A few months later, Kuperman’s team reached the same conclusion as de Goffau (3). There’s not a single piece of evidence of placental microbiome and the initial microbial colonizers of the neonatal intestine originate from the maternal perineal, vaginal, and faecal microbiota.
This is probably why Dr Nigel Field (UCL Institute for Global Health) observed such microbiome difference between C-section and vaginal delivery birth children during the Baby Biome Study (analysis of 596 babies with 314 babies who had a vaginal birth, and 282 who were born by caesarean). The study concluded that babies born by C-section had a reduced number of "favourable" Bacteroides derived from their mothers and an increased number of opportunistic pathogens, including Enterococcus, Enterobacter and Klebsiella species (4).
But curiously enough, by the time the babies were weaned at the age of 9 months, these differences had largely disappeared. In fact, a longitudinal study of 903 children between the age of 3 and 46 months, demonstrated that gut microbiome undergoes three distinct phases of microbiome progression: a developmental phase (months 3–14), a transitional phase (months 15–30), and a stable phase (months 31–46). (5)
So which factors can explain such an evolution of the microbiome in such a short period of time?
The factors influencing the infant microbiome
Since children consume approximately 800 mL of milk per day, it seems natural to first turn our survey towards breastfeeding.
Maternal milk contains its own microbiota, dominated by Staphylococci and Streptococci (Streptococcus mitis and Streptococcus salivarius groups), followed by corynebacteria, lactic acid bacteria, bifidobacteria, and propionibacteria. And milk also acts indirectly providing essential nutrients for bacterial growth (6).
Logically enough, the microbiome also differs between infants from various geographical locations. Children born in developing countries are characterized by enhanced levels of Prevotella and decreased abundance of Bacteroides in early life, as compared with infants living in western countries (De Filippo et al., 2010; Grzeskowiak et al., 2012; Yatsunenko et al., 2012; Clemente et al., 2015). In addition to geographical situation and dietary related differences, other factors may influence milk composition, including maternal stress, lactation stage, or the use of antibiotics for example (7).
But the impacts of indirect and independent factors can also be questioned, such as species interaction.
A study by the Home Microbiome Consortium, showed substantial interaction among human and pet microbiota (Lax et al., 2014). Moreover, Azad et al. (2013) observed that the presence of pets might affect infant colonization, in contrast to studies that did not find a relation between the presence of household pets and the human gut microbiota (Penders et al., 2006; Konya et al., 2014). But at the beginning of 2020, a new study conducted by Kates et al. concluded that seven operational taxonomic units were significantly more abundant in those without pets compared to those with pets, and four were significantly more abundant in those with pets (8). The influence of inter-species relationships on the evolution of the microbiome seems now to be accepted.
Of course, despite the complexity of the analysis, intrinsic factors should also be investigated.
A recent article, published in July 2020, demonstrated that hepatic function impacts directly the early intestinal microbiota maturation through the secretion of bile acids. But these findings in mice still need to be confirmed in humans (9).
Earlier in 2018, Fulde et al. demonstrated that neonatal Toll-Like Receptor 5 (TLR5) expression strongly influences the composition of the microbiota throughout life (10). Finally, if we are beginning to see multiple links between various genetic modifications and the evolution of our microbiome, we are only at the very first draft of explanations.
Wang et al. have thus established the MiBioGen consortium initiative to understand the role of human genetics in shaping gut microbiota, gathering more than 19,000 subjects and 18 population-level cohorts (11). The statistical power of this project should shed more light on our connection to the microbiome in the coming years.
(1) Aagaard K, Ma J, Antony KM, Ganu R, Petrosino J, Versalovic J. The placenta harbors a unique microbiome. Sci Transl Med. 2014;6(237):237ra65.
(2) De Goffau, M.C., Lager, S., Sovio, U. et al. Human placenta has no microbiome but can contain potential pathogens. Nature 572, 329–334 (2019).
(3) AA Kuperman, A Zimmerman, S Hamadia, O Ziv, V Gurevich, B Fichtman, N Gavert, R Straussma, Deep microbial analysis of multiple placentas shows no evidence for a placental microbiome.
(4) Shao, Y., Forster, S.C., Tsaliki, E. et al. Stunted microbiota and opportunistic pathogen colonization in caesarean-section birth. Nature 574, 117–121 (2019).
(5) Stewart, C.J., Ajami, N.J., O’Brien, J.L. et al. Temporal development of the gut microbiome in early childhood from the TEDDY study. Nature 562, 583–588 (2018). https://doi.org/10.1038/s41586-018-0617-x
(6) Katherine M. Hunt, James A. Foster, Larry J. Forney, Ursel M. E. Schütte, Daniel L. Beck, Zaid Abdo, Lawrence K. Fox, Janet E. Williams, Michelle K. McGuire, Mark A. McGuire. Characterization of the Diversity and Temporal Stability of Bacterial Communities in Human Milk.
(7) Fallani M, Young D, Scott J, Norin E, Amarri S, Adam R, et al. and Other Members of the INFABIO Team Intestinal microbiota of 6-week-old infants across Europe: geographic influence beyond delivery mode, breast-feeding, and antibiotics. J Pediatr Gastroenterol Nutr. 2010;51:77–84. doi: 10.1097/MPG.0b013e3181d1b11e.
(8) Kates AE, Jarrett O, Skarlupka JH, et al. Household Pet Ownership and the Microbial Diversity of the Human Gut Microbiota. Front Cell Infect Microbiol. 2020;10:73. Published 2020 Feb 28. doi:10.3389/fcimb.2020.00073
(9) van Best, N., Rolle-Kampczyk, U., Schaap, F.G. et al. Bile acids drive the newborn’s gut microbiotamaturation. Nat Commun 11, 3692 (2020). https://doi.org/10.1038/s41467-020-17183-8
(10) Fulde M, Sommer F, Chassaing B, et al. Neonatal selection by Toll-like receptor 5 influences long-term gut microbiota composition [published correction appears in Nature. 2018 Nov;563(7731):E25]. Nature. 2018;560(7719):489-493. doi:10.1038/s41586-018-0395-5
(11) Wang, J., Kurilshikov, A., Radjabzadeh, D. et al. Meta-analysis of human genome-microbiome association studies: the MiBioGen consortium initiative. Microbiome 6, 101 (2018). https://doi.org/10.1186/s40168-018-