The Not-so-Sterile Womb: Evidence That the Human Fetus Is Exposed to Bacteria Prior to Birth

Stinson, Lisa F.; Boyce, Mary C.; Payne, Matthew S.; Keelan, Jeffrey A.

doi:10.3389/fmicb.2019.01124

Cited by 290 publications

(289 citation statements)

References 86 publications

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“…Whether there are microbiota (live or simply DNA signatures) in the maternal-fetal interface remains mired in controversy. In the recent years, there has been a large number of studies, providing both sequencing and histological evidence, indicating microbial signatures 3,11,18,19,22,23,29 , while other studies have reported these signatures as likely DNA contaminants originating from the sample collection and/or the DNA extraction process, rather than the placenta itself [54][55][56][57] . Placenta location remains a key variable in the aforementioned studies given that that BP, PV and FM have distinct physiology and function.…”

Section: Discussionmentioning

confidence: 99%

“…These probes predominately bind to 16S rRNA and the bright staining suggests a large intact rRNA pool, which is typically a hallmark of viability. Finally, the guidelines suggest that it must be "ecologically plausible" for the detected microbes to reside in the placenta 3,58 . In this report, we show that R. insidiosa replicates within human placental samples, human BP explants cultured ex vivo, and EVT-like JEG-3 cells in culture.…”

Section: Discussionmentioning

confidence: 99%

“…Contrary to this paradigm, bacterial DNA has been identified in the amniotic fluid and meconium, suggesting that the womb may not be sterile after all [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] . More recently, studies have detected bacteria in term placentas 11,18-24 .…”

Section: Introductionmentioning

confidence: 99%

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Functional characterization ofRalstonia insidiosa, a bona fide resident at the maternal-fetal interface

Parnell

Willsey

Joshi

et al. 2019

Preprint

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Controversy about whether there are microbes in the placenta and if they have any functional importance during pregnancy and for neonatal health is ongoing. Previous work has demonstrated that the basal plate (BP), comprising maternal and fetal derived cells harbors intracellular bacteria. 16S sequencing and bacterial species-specific analysis of term placentas revealed that the gram-negative bacillus Ralstonia insidiosa, native to aqueous environments and an effective biofilm promoter, comprises the most abundant species in the BP. Here, we demonstrate whether R. insidiosa cells home to a particular niche in the BP, how they may arrive there, and whether they are associated with adverse outcomes. We developed methods to detect and study cell-specific localization of R.insidiosa using ex vivo and in vitro models. Additionally, we studied potential routes of R.insidiosa entry into the placenta. We show that R. insidiosa is a bona fide resident in human placental BP. It can access trophoblast cells in culture and within basal plate tissues where it localizes to intracellular single-membrane vacuoles and can replicate.However, the presence of R. insidiosa does not cause cell death and does not induce a pro-inflammatory immune response suggesting that it is not harmful in and of itself.Finally, we show that in a pregnant mouse model, R. insidiosa traffics to the placenta via the intrauterine route but does not induce preterm labor or preterm birth. Together, our findings provide a foundation for understanding non-pathogenic placental cell-microbe interactions and the functional importance of R. insidiosa in placental health and physiology.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Functional characterization ofRalstonia insidiosa, a bona fide resident at the maternal-fetal interface

Parnell

Willsey

Joshi

et al. 2019

Preprint

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“…Until recently, the foetus has been considered to exist in a sterile environment with initial microbial colonization of the newborn taking place during birth (51). Recent studies have reported the detection of microbes from amniotic fluid, placenta and meconium, suggesting that microbial colonization may begin in utero (52, 53). In addition, a number of studies have reported bacterial communities from meconium specimens (54).…”

Section: Discussionmentioning

confidence: 99%

Association of maternal prenatal psychological stressors and distress with maternal and early infant faecal bacterial profile

Naudé

Claassen

Gardner-Lubbe

et al. 2019

Preprint

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BackgroundFindings from animal studies indicate that the early gut bacteriome is a potential mechanism linking maternal prenatal stress with health trajectories in offspring. However, clinical studies are scarce and the associations of maternal psychological profiles with the early infant faecal bacteriome is unknown. This study aimed to investigate the associations of prenatal stressors and distress with early infant faecal bacterial profiles in a South African birth cohort study.MethodsAssociations between prenatal symptoms of depression, distress, intimate partner violence (IPV) and posttraumatic stress-disorder (PTSD) and faecal bacterial profiles were evaluated in meconium and subsequent stool specimens from 84 mothers and 101 infants at birth, and longitudinally from a subset of 69 and 36 infants at 4–12 and 20–28 weeks of age, respectively in a South African birth cohort study.ResultsInfants born to mothers exposed to high levels of IPV had significantly higher proportions of unclassified genera within the family Enterobacteriaceae detected at birth; higher proportions of the genus Weissella at 4-12 weeks; and increased proportions of genera within the family Enterobacteriaceae over time (birth to 28 weeks of life). Faecal specimens from mothers exposed to IPV had higher proportions of the family Lactobacillaceae and lower proportions of Peptostreptococcaceae at birth. Maternal psychological distress was associated with decreased proportions of the family Veillonellaceae in infants at 20-28 weeks and a slower decline in Gammaproteobacteria over time. No changes in beta diversity were apparent for maternal or infant faecal bacterial profiles in relation to any of the prenatal measures for psychological adversities.ConclusionIPV during pregnancy is associated with altered bacterial profiles in infant and maternal faecal bacteria. These findings may provide insights in the involvement of the gut bacteria linking maternal psychological adversity and the maturing infant brain.

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“…This has led to discussion in the literature on the caveats associated with studies of the microbiota of very low microbial biomass, or potentially sterile, body sites (47–54). In particular, there has been much debate over the existence of a placental microbiota (31–45, 50, 55–69) and of in utero microbial colonization of the human fetus (36, 44–46, 64, 70–72).…”

Section: Introductionmentioning

confidence: 99%

Lack of evidence for microbiota in the placental and fetal tissues of rhesus macaques

Theis

Romero

Winters

et al. 2020

Preprint

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ABSTRACTThe prevailing paradigm in obstetrics has been the sterile womb hypothesis. However, some are asserting that the placenta, intra-amniotic environment, and fetus harbor microbial communities. The objective of this study was to determine if the fetal and placental tissues of rhesus macaques harbor viable bacterial communities. Fetal, placental, and uterine wall samples were obtained from cesarean deliveries without labor (∼130/166 days gestation). The presence of viable bacteria in the fetal intestine and placenta was investigated through culture. The bacterial burden and profile of the placenta, umbilical cord, and fetal brain, heart, liver, and colon were determined through quantitative real-time PCR and DNA sequencing. These data were compared with those of the uterine wall, as well as to negative and positive technical controls. Bacterial cultures of fetal and placental tissues yielded only a single colony of Cutibacterium acnes. This bacterium was detected at a low relative abundance (0.02%) in the 16S rRNA gene profile of the villous tree sample from which it was cultured, yet it was also identified in 12/29 background technical controls. The bacterial burden and profile of fetal and placental tissues did not exceed or differ from those of background technical controls. In contrast, the bacterial burden and profiles of positive controls exceeded and differed from those of background controls. Among the macaque samples, distinct microbial signals were limited to the uterine wall. Therefore, using multiple modes of microbiologic inquiry, there was not consistent evidence of viable bacterial communities in the fetal and placental tissues of rhesus macaques.IMPORTANCEMicrobial invasion of the amniotic cavity (i.e. intra-amniotic infection) has been causally linked to pregnancy complications, especially preterm birth. Therefore, if the placenta and the fetus are typically populated by low biomass yet viable microbial communities, current understanding of the role of microbes in reproduction and pregnancy outcomes will need to be fundamentally reconsidered. Could these communities be of benefit by competitively excluding potential pathogens or priming the fetal immune system for the microbial bombardment it will experience upon delivery? If so, what properties (e.g. microbial load, community membership) of these microbial communities preclude versus promote intra-amniotic infection? Given the ramifications of the in utero colonization hypothesis, critical evaluation is required. In this study, using multiple modes of microbiologic inquiry (i.e. culture, qPCR, DNA sequencing) and controlling for potential background DNA contamination, we did not find consistent evidence for microbial communities in the placenta and fetal tissues of rhesus macaques.

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The Not-so-Sterile Womb: Evidence That the Human Fetus Is Exposed to Bacteria Prior to Birth

Cited by 290 publications

References 86 publications

Functional characterization ofRalstonia insidiosa, a bona fide resident at the maternal-fetal interface

Functional characterization ofRalstonia insidiosa, a bona fide resident at the maternal-fetal interface

Association of maternal prenatal psychological stressors and distress with maternal and early infant faecal bacterial profile

Lack of evidence for microbiota in the placental and fetal tissues of rhesus macaques

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