When and how bacteria colonize the intestine in early life is still a matter of scientific debate. Although the impact of delivery mode and feeding type on the development of the gut microbiota of newborns has been subject to considerable study, little is known about the extent of in utero microbial colonization.
Through the use of microbial culture and molecular approaches, Rackaityte and colleagues report limited evidence of bacterial colonization in the fetal terminal ileum, which may influence the immunological status of the intestinal epithelium.
Compared with previous research exploring tissues in contact with the fetus (e.g. placenta, amniotic fluid and meconium content collected after birth), one strength of this study is that it directly explores human intestinal fetal content collected from terminated pregnancies. The authors found bacteria-like structures in pockets of human fetal meconium at mid-gestation by scanning electron microscopy and bacterial deoxyribonucleic acid in 40 of the 50 fetal intestinal content samples studied by 16S ribosomal ribonucleic acid sequencing.
Rackaityte and colleagues report limited evidence of bacterial colonization in the fetal terminal ileum, which may influence the immunological status of the intestinal epithelium
Interestingly, three bacterial profiles were identified in the fetal intestinal content samples: one dominated by Lactobacillus, another represented by Micrococcaceae, and a third including Lactobacillus, Micrococcaceae, Bacteroides, Bifidobacterium and Prevotella. While the first two profiles were found in a minority of the samples (15/40), the third profile resembled that of the contamination controls. Ex vivo fetal intestinal transcriptomics revealed that eighteen taxa enriched in the fetal intestine were associated with distinct gene expression and distinct patterns of T cell composition.
Through culture conditions that mimicked the fetal intestine environment, the authors isolated a viable Micrococcus luteus strain from the fetal intestine with a genome that differed from that of other related M. luteus strains. In vitro experiments showed the ability of fetal M. luteus to proliferate and persist under the harsh pregnancy hormonal environment (progesterone and estradiol with nutrient limitation). Additional experiments showed its ability to survive inside phagocytes. Combined with data from independent cohorts showing that the prevalence of this bacterium decreased in meconium samples during the first months of life, these findings highlight that the fetal intestine environment might selectively boost the growth of M. luteus.
In addition, when this M. luteus strain was exposed in vitro to human fetal intestinal epithelial cells, it led to transcriptomic profiles resembling the tissue derived epithelial cell layer transcriptome of M. luteus positive specimens. While fetal intestinal immune cells can elicit an inflammatory response to bacteria, fetal M. luteus isolates promoted immune regulation by inducing tolerogenic antigen presenting cells in the lamina propria and reducing the pro-inflammatory interferon-gamma production by fetal memory T cells.
These findings highlight that the fetal intestine environment might selectively boost the growth of M. luteus
Beyond viable bacteria, bacterial cell walls and bacterial metabolites could also contribute to shaping the immune system in utero, acknowledge Maria Carmen Collado and Nicola Segata in an accompanying ‘News & Views’ article.
On the whole, this study shows some evidence for early bacterial colonization of the fetal intestine, with the presence of specific bacteria that thrive under the selective conditions posed by the intestinal environment in utero. As happened with previous studies that partially validated in utero bacterial colonization with different bacterial groups in the healthy placenta, amniotic fluid and meconium, the authors acknowledged that the study of a low-biomass sample such as the fetal gut in a culture medium could promote the growth of bacteria from the environment, which makes it difficult to rule out contamination as the source of any observed findings.
As Maria Carmen Collado and Nicola Segata conclude in the accompanying ‘News & Views’ article, further studies are thus required to better elucidate the origin of bacteria in the fetal gut and unravel the biological implications of in utero colonization for human development and long-term health outcomes.
Rackaityte E, Halkias J, Fukui EM, et al. Viable bacterial colonization is highly limited in the human intestine in utero. Nat Med. 2020; 26(4):599-607. doi: 10.1038/s41591-020-0761-3.
Collado MC, Segata N. Initial exploration of in utero microbial colonization. Nat Med. 2020; 26(4):469-70. doi: 10.1038/s41591-020-0836-1.