Viable bacterial colonization is highly limited in the human intestine in utero

Rackaityte, Elze; Halkias, Joanna; Fukui, Elle; Mendoza, V. F.; Hayzelden, Clive; Crawford, Emily; Fujimura, Kei E.; Burt, Trevor D.; Lynch, Susan V.

doi:10.1038/s41591-020-0761-3

Cited by 214 publications

(217 citation statements)

References 66 publications

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“…Finally, to confirm that first-trimester HBCs have microbicidal capacity, we cultured HBCs with Lactobacillus crispatus (a microbe reported to be found in very low abundance within the second trimester fetal intestine; Rackaityte et al, 2020 ) and E. coli (not found in the fetus; Rackaityte et al, 2020 ). We find that HBC are as efficient as PAMM1a at killing both L. crispatus and E. coli when cultured at a multiplicity of infection (MOI) of 1 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Phenotypic and functional characterization of first-trimester human placental macrophages, Hofbauer cells

Thomas

Appios

Zhao

et al. 2020

Journal of Experimental Medicine

124

166

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Hofbauer cells (HBCs) are a population of macrophages found in high abundance within the stroma of the first-trimester human placenta. HBCs are the only fetal immune cell population within the stroma of healthy placenta. However, the functional properties of these cells are poorly described. Aligning with their predicted origin via primitive hematopoiesis, we find that HBCs are transcriptionally similar to yolk sac macrophages. Phenotypically, HBCs can be identified as HLA-DR−FOLR2+ macrophages. We identify a number of factors that HBCs secrete (including OPN and MMP-9) that could affect placental angiogenesis and remodeling. We determine that HBCs have the capacity to play a defensive role, where they are responsive to Toll-like receptor stimulation and are microbicidal. Finally, we also identify a population of placenta-associated maternal macrophages (PAMM1a) that adhere to the placental surface and express factors, such as fibronectin, that may aid in repair.

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Section: Resultsmentioning

confidence: 99%

Phenotypic and functional characterization of first-trimester human placental macrophages, Hofbauer cells

Thomas

Appios

Zhao

et al. 2020

Journal of Experimental Medicine

124

166

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“…We recently reported that bacteria are variably present in the fetal intestine through high resolution scanning electron microscopy, sequencing, and viable isolation methods. The presence of Micrococcus luteus in fetal meconium was correlated with a higher proportion of intestinal PLZF + CD161 + memory T cells and limited their ability to produce IFNγ as compared to non-fetal M. luteus species (101). This finding is supported by a study that demonstrated the requirement of a microbiome for the development of PLZF + T cells in mice (139).…”

Section: In Utero Environment Contributes To the Regulation Of Fetalmentioning

confidence: 60%

“…Production of IFNγ by fetal T cells may be limited by intestinal macrophages expressing high levels of LLT1, the natural ligand of CD161 (29). Exposure to fetal-specific M. luteus induces LLT1 on fetal antigen presenting cells (101), suggesting that commensal fetal bacteria may modulate this axis to promote intestinal immune tolerance. Further, suppressive functions of intestinal macrophages are well-described in adults (102)(103)(104) and it is likely that similar mechanisms are also employed by the fetal immune system.…”

Section: Cell-extrinsic Mechanismsmentioning

confidence: 99%

Mechanisms of Fetal T Cell Tolerance and Immune Regulation

2020

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The developing human fetus generates both tolerogenic and protective immune responses in response to the unique requirements of gestation. Thus, a successful human pregnancy depends on a fine balance between two opposing immunological forces: the semi-allogeneic fetus learns to tolerate both self-and maternal-antigens and, in parallel, develops protective immunity in preparation for birth. This critical window of immune development bridges prenatal immune tolerance with the need for postnatal environmental protection, resulting in a vulnerable neonatal period with heightened risk of infection. The fetal immune system is highly specialized to mediate this transition and thus serves a different function from that of the adult. Adaptive immune memory is already evident in the fetal intestine. Fetal T cells with pro-inflammatory potential are born in a tolerogenic environment and are tightly controlled by both cell-intrinsic and-extrinsic mechanisms, suggesting that compartmentalization and specialization, rather than immaturity, define the fetal immune system. Dysregulation of fetal tolerance generates an inflammatory response with deleterious effects to the pregnancy. This review aims to discuss the recent advances in our understanding of the cellular and molecular composition of fetal adaptive immunity and the mechanisms that govern T cell development and function. We also discuss the tolerance promoting environment that impacts fetal immunity and the consequences of its breakdown. A greater understanding of fetal mechanisms of immune activation and regulation has the potential to uncover novel paradigms of immune balance which may be leveraged to develop therapies for transplantation, autoimmune disease, and birth-associated inflammatory pathologies.

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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%

“…Fifth, the taxonomic data of the detected bacteria should be ecologically plausible (50, 62). There have been many studies that may have met one or two of these criteria (31–46, 78–80), but no study has yet attempted to simultaneously meet all criteria and ultimately conclude that there is widespread colonization of the placenta and/or fetus by viable microbial communities (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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Viable bacterial colonization is highly limited in the human intestine in utero

Cited by 214 publications

References 66 publications

Phenotypic and functional characterization of first-trimester human placental macrophages, Hofbauer cells

Phenotypic and functional characterization of first-trimester human placental macrophages, Hofbauer cells

Mechanisms of Fetal T Cell Tolerance and Immune Regulation

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

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