Trophoblast-microbiome interaction: a new paradigm on immune regulation

doi:10.1016/j.ajog.2015.06.039

American Journal of Obstetrics and Gynecology

Volume 213, Issue 4, Supplement, October 2015, Pages S131-S137

https://doi.org/10.1016/j.ajog.2015.06.039 Get rights and content

The immunologic paradigm of pregnancy led to the conceptualization of pregnancy as an organ transplant that requires, for its success, suppression of the maternal immune system. Growing scientific evidence suggests that in many ways the placenta functions as a tumor rather than a transplant and the immune regulation of the maternal-fetal interface is the result of the coordinated interaction between all its cellular components, including bacteria. Examining the role of microbiota in reproduction is in its infancy, but there is growing literature that supports its relevance. We discuss a potential normal function of bacteria in the establishment of immune tolerance and compelling evidence that a viral infection might be the underlying cause of perturbation of homeostasis. There is compelling evidence that many infectious diseases of human beings are caused by >1 microorganism and are defined as polymicrobial infections. We propose that pregnancy complications, such as preterm birth, are the result of polymicrobial infections. We examine the potential cellular and molecular mechanisms by which a viral infection of the placenta might disrupt the normal interaction between the cellular component of the implantation site and bacteria. As we better understand the normal homeostasis among the maternal immune system, placenta, and commensal, we will be able to elucidate pathogenic conditions and design better approaches to treat pregnancy complications associated with infection.

Section snippets

The placenta and bacteria, friends or foes?

Bacterial infections are thought to pose a significant threat to a pregnancy and to the well-being of the fetus, by gaining access to gestational tissues, such as the decidua, the placenta, and the fetal membranes, through 1 of 3 major routes: by ascending into the uterus from the lower tract; by descending into the uterus from the peritoneal cavity; or via the maternal circulation.18, 19, 20, 21, 22, 23 There are strong clinical links between bacterial infection and preterm birth.23, 24, 25, 26

Trophoblast cells as a component of innate immune system

The placenta is in direct contact with maternal component, thus it is imperative that a high level of immune protection is present at the maternal-fetal interface to protect the fetus against any infectious agent that reaches the placenta.⁴⁹ It is well known that classic immune cells, such as macrophages and natural killer cells, are present at the interface to facilitate innate immune responses. In addition to these immune cells, previous studies demonstrated that trophoblasts, the major

The placenta is not a sterile organ

Human body harbors multiple microorganisms termed “microbiota” and they are known to interact with the host and play various important roles to benefit the host. Bacterial colonization in the placenta from the patients who delivered preterm due to intrauterine inflammation or chorioamnionitis has been well reported in numerous studies.30, 54, 55 Based on these findings, a general belief among obstetricians was that the placenta should remain a sterile organ to maintain pregnancy through term.

“Immune regulatory” cross-talk between the trophoblast and commensal bacteria

What is the role of microbiota in the context of immune modulation? Among various functions, such as metabolizing nutrients and enforcing mucosal barrier, microbiota have been found to take part in modulating the host immune response as a way to prevent undesired inflammatory response to commensal bacteria or end-products, thereby maintaining tissue homeostasis.⁵⁹ Stimulation of TLR with commensal bacteria in gut epithelium has been shown to suppress NF-κB pathway and persistent

Preterm birth as a polymicrobial disease

There is compelling evidence that many infections of human beings and animals are caused by >1 microorganism.69, 70 The mixed microbial nature of these diseases has been recognized since the early 1920s⁷¹; however, only more recently have we begun to understand the mechanisms associated with this type of disease. Polymicrobial diseases can be caused by the synergistic or sequential action of infectious agents from either the same or different kingdoms, genera, species, or strains or by

Conclusion

Examining the role of microbiota in reproduction is in its infancy, but there is a growing literature that supports its relevance. As we understand the normal homeostasis among the maternal immune system of the host, placenta, and commensal, we will be able to elucidate the pathogenic conditions and design better approaches to treat pregnancy complications associated with infection.

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There were no significant differences regarding background characteristics between women who delivered by elective cesarean and those who delivered vaginally. Quantitative measurements of bacterial content in all 3 placental layers (quantitative polymerase chain reaction of the 16S ribosomal RNA gene) did not show any significant difference among any of the sample types and the negative controls. Here, 16S ribosomal RNA gene sequencing of the maternal side of the placenta could not differentiate between bacteria in the placental tissue and contamination of the laboratory reagents with bacterial DNA. Probe-specific quantitative polymerase chain reaction for bacterial taxa suspected to be present in the placenta could not detect any statistically significant difference between the 2 groups. In bacterial cultures, substantially more bacteria were observed in the placenta layers from vaginal deliveries than those from cesarean deliveries. In addition, 16S ribosomal RNA gene sequencing of bacterial colonies revealed that most of the bacteria that grew on the plates were genera typically found in human skin; moreover, it revealed that placentas delivered vaginally contained a high prevalence of common vaginal bacteria. Bacterial growth inhibition experiments indicated that placental tissue may facilitate the inhibition of bacterial growth.
We found no evidence to support the existence of a placental microbiome in our study of 76 term pregnancies, which used polymerase chain reaction amplification and sequencing techniques and bacterial culture experiments. Incidental findings of bacterial species could be due to contamination or to low-grade bacterial presence in some locations; such bacteria do not represent a placental microbiome per se.
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N-acetylcysteine (NAC) is a widely used anti-inflammatory agent and antioxidant in vivo and in vitro. As a nutritional supplement, NAC can improve production and reproductive performances in animals through enhancing placental function and regulating hormone production. Trophoblast proliferation and steroid hormone production are two major functions in the placenta. We hypothesized that the effects of NAC on placental function is due to its direct and indirect effects on gene expression in placental trophoblast cells (pTr). To evaluate this hypothesis, we investigated the effects of NAC on steroidogenesis, gene expression, and cell proliferation in porcine pTr in vitro. pTr were treated with NAC in serum-free medium for 24 h with different concentrations (0, 0.1 μM, 1.0 μM, 10.0 μM, 0.1 mM, 1.0 mM, and 10.0 mM). Low-dose NAC (1 μM) stimulated pTr proliferation and decreased progesterone production, while increasing estradiol production (P < 0.05). High-dose NAC (10 mM) suppressed cell proliferation (P < 0.05), but had no effect on steroidogenesis. Low-dose NAC increased CCDN1 and decreased CASP3 and CASP8 mRNA levels (P < 0.05), whereas high-dose NAC decreased CDK4 and CCDN1 and increased CASP3 mRNA levels (P < 0.05). NAC had no effect on the mRNA abundance of StAR and HSD3B. Low-dose NAC upregulated CYP19A1 mRNA expression, and high-dose NAC downregulated CYP11A1 mRNA abundance (P < 0.05). Only low-dose NAC increased NOS3 mRNA abundance and tetrahydrobiopterin reduction (BH4/BH2 ratio). We conclude that NAC may act directly and indirectly on pTr with a dose-dependent manner and may regulate placental function by affecting pTr differentiation via regulating pTr steroid synthesis, cell proliferation, and apoptosis in sows.
TAM receptors in pregnancy
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Inflammation is an important part of human response to pathogen to recruit immune cells and remove infected or damaged cells from the system. However, immune response should be fine tuned as uncontrolled proinflammatory response leads to extensive tissue damage and organ failure. Immune homeostasis at the maternal-fetal interface is crucial in the maintenance of healthy pregnancy. TAM receptor tyrosine kinase is known to be present in immune, nervous, and reproductive systems and has been reported to have biological function in the immunological aspect including cell debris clearance, cytokine secretion modulation, and regulation of innate immunity. The presence of TAM receptors at the maternal-fetal interface has been reported and its role in pregnancy has been in question. In the present review, functional aspects of TAM receptors, clinical implications in other diseases in an immunological context, and what is known about association of TAM receptors in complicated pregnancy are discussed with suggestion of potential area of future research.
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: Funded in part by grant P01HD054713 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.

: The authors report no conflict of interest.

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Expert reviewObstetricsTrophoblast-microbiome interaction: a new paradigm on immune regulation

Section snippets

The placenta and bacteria, friends or foes?

Trophoblast cells as a component of innate immune system

The placenta is not a sterile organ

“Immune regulatory” cross-talk between the trophoblast and commensal bacteria

Preterm birth as a polymicrobial disease

Conclusion

Endocrinol Metab Clin North Am

Semin Fetal Neonatal Med

Curr Opin Immunol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Obstet Gynecol

Am J Obstet Gynecol

Placenta

Am J Obstet Gynecol

Am J Obstet Gynecol

Lancet

Fertil Steril

Placenta

Am J Obstet Gynecol

Semin Neonatol

Cell

Cell

Cytokine

Int J Gynaecol Obstet

Obstet Gynecol

Reprod Toxicol

Am J Obstet Gynecol

Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates

Symp Soc Exp Biol

Immunity to homologous grafted skin, III: the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye

Br J Exp Pathol

Inflammation and pregnancy: the role of toll-like receptors in trophoblast-immune interaction

Ann N Y Acad Sci

Immune mechanisms at the maternal-fetal interface: perspectives and challenges

Nat Immunol

Mucosal immunity in the male and female reproductive tract and prevention of HIV transmission

Am J Reprod Immunol

Management of human immunodeficiency virus-infected pregnant women at Latin American and Caribbean sites

Obstet Gynecol

Mechanisms of T cell tolerance towards the allogeneic fetus

Nat Rev Immunol

The immune system in pregnancy: a unique complexity

Am J Reprod Immunol

Immunology of placentation in eutherian mammals

Nat Rev Immunol

New insights into the relationship between viral infection and pregnancy complications

Am J Reprod Immunol

Placental viral infection sensitizes to endotoxin-induced pre-term labor: a double hit hypothesis

Am J Reprod Immunol

First trimester trophoblast cells secrete Fas ligand which induces immune cell apoptosis

Mol Human Reprod

Viral infection of the placenta leads to fetal inflammation and sensitization to bacterial products predisposing to preterm labor

J Immunol

Bacterially-induced preterm labor and regulation of prostaglandin-metabolizing enzyme expression in mice: the role of toll-like receptor 4

Biol Reprod

Surfactant protein (SP)-A suppresses preterm delivery and inflammation via TLR2

PLoS One

IL-10 modulates placental responses to TLR ligands

Am J Reprod Immunol

Micronutrients and intrauterine infection, preterm birth and the fetal inflammatory response syndrome

J Nutr

Intrauterine infection and preterm delivery

N Engl J Med

The role of infection in preterm labor and birth

Hosp Med

The role of inflammation and infection in preterm birth

Semin Reprod Med

Expert review
Obstetrics
Trophoblast-microbiome interaction: a new paradigm on immune regulation