Microbiota and Pregnancy

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1		Flaminia Bardanzellu	+ 2956 word(s)	2956	2021-03-15 03:42:07	\|
2	format correction	Peter Tang	Meta information modification	2956	2021-03-16 02:50:34	\|

This entry is adapted from the peer-reviewed paper 10.3390/life11020148

Human bacterial colonization starts during fetal life, in opposition to the previous paradigm of the “sterile womb”. Placenta, amniotic fluid, cord blood and fetal tissues each have their own specific microbiota, influenced by maternal health and habits and having a decisive influence on pregnancy outcome and offspring outcome. The maternal microbiota, especially that colonizing the genital system, starts to influence the outcome of pregnancy already before conception, modulating fertility and the success rate of fertilization, even in the case of assisted reproduction techniques. During the perinatal period, neonatal microbiota seems influenced by delivery mode, drug administration and many other conditions. Special attention must be reserved for early neonatal nutrition, because breastfeeding allows the transmission of a specific and unique lactobiome able to modulate and positively affect the neonatal gut microbiota.

neonatal microbiota microbiome placenta delivery breastfeeding neonatal nutrition perinatal programming

1. Introduction

The term “microbiota” defines the whole set of microorganisms that colonize organs and tissue of an individual from the beginning to the end of their life ^[1] and also persisting after death with the establishment of postmortem microbial communities also called “thanatomicrobiome” ^[2]^[3]^[4].

Placenta, amniotic fluid and fetal tissues, such as skin, lung and gastrointestinal tract, are colonized by these microorganisms since prenatal life ^[5]^[6]^[7]^[8].

Over the past decade, the human microbiota has been recognized as a new entry in human health; its importance is defined by numerous aspects, allowing us to classify it as a “new organ”. Microbiota’s essential role is determined by its ability to support the biochemical, metabolic and immunological balance of the host organism, necessary for health maintenance ^[9].

Since birth, our immune system is predisposed to distinguish and destroy invading microbes, and in this context, the human microbiota plays a fundamental role in preventing the growth of pathogens and modulating immunity pathways ^[1].

Throughout one’s life, microbiota can be influenced and modified by various factors, including maternal health ^[10]^[11]^[12], pregnancy complications, peripartum antibiotic administration ^[13], mode and place of delivery ^[14] and breastfeeding ^[11]^[15]^[16]^[17]^[18]^[19]^[20].

Before conception, female genital tract microbiota seems to influence fertility, pregnancy outcome, post-abortion infection rate and the success rate of assisted reproduction technologies (ART), including embryo-transfer (ET) ^[21]^[22]^[23]^[24]^[25]^[26]^[27]. The Human Microbiome Project allowed us to expand our knowledge on the characterization, physiology and significance of the microbiota in multiple body sites, as well as on its relationship with the host ^[28]^[29].

One of most intriguing themes is the "sterile womb" paradigm, which has been analyzed, during the last ten years, in many studies reporting the presence of bacteria even in sites traditionally considered sterile (uterus, placenta, amniotic fluid, fetus), in physiological conditions as well ^[5]^[30]. Even for placenta, the idea of the “sterile” fetus is already outdated ^[5]^[6]^[8].

As is well established in the literature and discussed in this paper, the human microbiota, due to complex and continuous interactions with the host, affects health as a whole and can contribute to the onset of many pathological conditions, even chronic ones. A particularly important function is that performed by the intestinal microbiota, which hosts the most abundant bacterial population.

2. Female Tract Microbiota

2.1. Vaginal Microbiota and Fertility

The female urogenital tract microbiota represents only 9% of the whole human microbiota, while that of the gastrointestinal tract represents about 29% ^[28]^[31]^[32].

Thanks to the Human Microbiome Project, we know that the physiological vaginal microbiota is characterized by a relatively low degree of microbial diversity, with the predominance of Lactobacillus spp. The vaginal microbiota can be classified into five groups (I–V), a.k.a. “community state types” (CST), based on the presence and types of Lactobacilli: CST I (Lactobacillus crispatus predominant), CST II (Lactobacillus gasseri predominant), CST III (Lactobacillus iners predominant) and CST V (Lactobacillus jenseri predominant). CST IV is characterized by the presence of non-Lactobacillus spp., such as Prevotella spp., Gardnerella and other bacteria (Corynebacterium, Atopobium, Megasphera, Sneathia) ^[28]^[33]^[34]. Successively, CST IV was further divided into type IV-A characterized by low proportions of Lactobacillus iners or other Lactobacillus spp.; various species of anaerobic bacteria including Anaerococcus, Corynebacterium, Finegoldia or Streptococcus; and type IV-B, showing a higher proportion of the genera Atopobium, Prevotella, Parvimonas, Sneathia, Gardnerella, Mobiluncus, Peptoniphilus and several other taxa ^[35].

During the healthy reproductive life and during pregnancy, the composition of vaginal microbiota changes according to the cyclic fluctuations of estrogen and progesterone levels. However, the variations in composition are slight and only consist of a relative predominance of one lactic acid-producing bacterium over another. In fact, estrogen and progesterone both help to ensure adequate availability of glycogen, metabolized by Lactobacillus spp., into lactic acid, which guarantees the normal acid vaginal pH ^[34]^[35]^[36]^[37]^[38].

The presence of Lactobacilli and a normal vaginal acid pH protect against a possible pathological growth of anaerobic species, such as Gardnerella vaginalis, Mycoplasma hominis, Atopobium vaginale and Mobiluncus curtisii. These bacteria prevail in the so-called bacterial vaginosis (BV), which is characteristic of pre-menopausal age and pathological conditions ^[39]^[40]^[41]^[42]. BV is well known to be associated with adverse outcomes in obstetrics and gynecology, such as preterm birth and post-surgery infections ^[21]^[22]^[23]^[24]. On the other hand, there are only a few studies concerning the relationship between the female genital tract microbiota and infertility.

The Human Microbiome Project demonstrated that the vaginal microbial diversity is very low in comparison to other sites (e.g., oral cavity), with a higher diversity being associated with BV ^[29]^[43].

Usually, in a microbial ecosystem, a high biodiversity is synonymous with health, while a significant decrease in biodiversity is defined as a status of dysbiosis, associated with several pathologies ^[44]^[45]^[46]. The unique exception is the vaginal ecosystem, dominated by Lactobacilli, where high biodiversity is linked to an unhealthy status, as reported above ^[29]^[43].

Two metanalyses pointed out that 19% of infertile patients had BV; on the other hand, according to the same metanalyses, BV does not significantly impair conception rate but increases the rate of early pregnancy loss ^[47]^[48]. The analyzed studies also show the association between anomalies in the vaginal microbiota and tubal infertility, probably due to the ascent of pathogens through the cervix (e.g., Chlamydia trachomatis), triggering inflammation ^[47]^[48]^[49]^[50].

However, all these studies were performed using the classical culture-based technology and the so-called Nugent score, based on the bacterial classification by Gram staining ^[26]^[51]. Culture-based technology has significant methodological limitations: some bacteria cannot be cultured nor identified; moreover, it can be difficult to distinguish the bacteria from each other. These limitations lead to a risk of both underestimating and overestimating the presence of pathogenic bacterial species ^[52]^[53]. Recently, sequencing and metagenomic methods have considerably enriched our knowledge on the relationship between vaginal microbiota, infertility and the outcome of pregnancies from ART.

The study carried out by Campisciano and colleauges showed that, comparing infertile women to fertile ones, Lactobacillus gasseri, Veillonella spp. and Staphylococci were over-represented, while Lactobacillus iners and Lactobacillus crispatus were under-represented ^[54].

The composition of the vaginal microbiota also impacts the outcome of ET. Hyman et al. demonstrated that the probability of a live birth is related to the diversity of species and to the presence of Lactobacilli on the ET day ^[55]. Other authors ^[25]^[26] reported the negative (although not statistically significant) effect of BV on the implantation rate.

2.2. Uterine Microbiota and Fertility

Traditionally, it was believed that the uterine cavity was sterile, and bacterial colonization was considered a pathological finding ^[56]. However, the existence of an intrauterine microbiota, characterized by remarkable stability between the follicular and luteal phase, was only recently demonstrated ^[57].

Mitchell et al. ^[49] confirmed that the upper genital tract is not sterile, uncovering the presence of at least one bacterial species in that site.

The bacteria located in the endometrial cavity and in the upper part of the cervix resemble those present in the vagina (L. iners, L. crispatus, Prevotella spp.), albeit in a smaller quantity (about 4 times less), although many more bacterial species are present in the vagina ^[58]. The relative bacterial scarcity in the uterine cavity, compared to the vaginal environment, could be due to the partial barrier action carried out by the endocervix or to the endometrial immune response ^[49].

One of the biggest criticisms aimed at these findings is the possible contamination during the collection of the uterine samples by the cervico-vaginal microbiota. However, Chen et al. showed a high degree of similarity between the uterine microbiota collected directly by surgery and that collected trans-cervically ^[58]. On the contrary, in a very recent study, the samples were taken with a particular method based on the combined use of two specific catheters and accurate tissue disinfection; thus, the procedure could be considered almost sterile. The absent contamination by the vaginal flora, as a result, highlighted a characteristic heterogeneous endometrial microbiota (also including newly identified genital bacteria such as Kocuria dechangensis and the absence of Lactobacilli) different from the vaginal one (dominated by the Lactobacillus genus) ^[59]. Although interesting, these results should be confirmed in future studies based on the same sampling technique.

The uterine microbiota is also likely to affect fertility ^[60]. Using traditional bacterial cultures, many authors demonstrated an association between the presence of pathogenic endometrial bacteria from the ET catheter and low pregnancy rates after ART ^[61]^[62]^[63]^[64]^[65]. The presence of pathogenic bacteria was shown to decrease with the preventive use of antibiotics ^[62].

In the last decade, the use of next-generation sequencing of bacterial 16S rRNA gene provided a better characterization of the microbiota during ART and allowed 278 genera to be isolated, among which Lactobacillus spp. and Flavobacterium spp. are predominant ^[66]. Another larger study conducted by Moreno et al. identified two microbiota profiles, one of which is Lactobacillus spp.–dominated (LD), while the other is non-Lactobacillus spp.–dominated (NLD): the latter has been associated with a lower implantation rate ^[57].

On the contrary, according to Riganelli et al., endometrial colonization by vaginal flora, especially Lactobacillus species by translocation, seems to have a negative impact on the outcome of ART ^[59], suggesting that the subject, still characterized by controversies, deserves clarification through future studies.

Other authors used mRNA analysis to identify less abundant bacteria, and therefore isolating, in addition to Lactobacillus spp., also Corynebacterium spp., Bifidobacterium spp., Staphylococcus spp. and Streptococcus spp. However, the authors did not make any comparison with traditional culture techniques ^[67].

It has not been clarified through which mechanisms the microbiota influences the implantation rate. It has been speculated that a positive action of Lactobacillus spp. could be mediated by the acidification of vaginal pH, which inhibits pathogenic bacteria: however, no difference was found between endometrial microbiota and endometrial pH. Instead, an abnormal endometrial microbiota could trigger an inflammatory cascade with detrimental effects on the implantation. This hypothesis needs to be supported by further studies ^[47]^[68].

At present, the results of the studies (including meta-analyses) concerning the relationship between microbiota and fertility in ART, while suggesting a negative influence by an abnormal microbiota, do not allow definitive conclusions. Further studies would be needed, with adequate sample size and comparison between new sequencing methods and traditional culture techniques. Interventional studies are also lacking, especially considering the ethical problems related to them; however, coming from the assumption that the composition of the microbiota influences fertility, it would be highly useful to identify how to modify it and therefore to demonstrate whether these interventions could be effective ^[47]^[48]^[68].

In Table 1, major bacterial taxa found at each colonization site of reproductive age women, and their impact on fertility, are reported.

Table 1. Major bacterial taxa found at each colonization site of reproductive age women, and their impact on fertility, according to the studies discussed in the review. ART = assisted reproductive technique.

Physiological	Bacterial Vaginosis	Infertility	ART Outcome
Vagina	- dominated by Lactobacillus spp. - Classified into five community state types (CST): CST I (Lactobacillus crispatus predominant), CST II (Lactobacillus gasseri predominant), CST III (Lactobacillus iners predominant), CST IV (non-Lactobacillus spp.). Type IV-A: low proportions of Lactobacillus iners or other Lactobacillus spp., various species of anaerobic bacteria including Anaerococcus, Corynebacterium, Finegoldia, or Streptococcus. Type IV-B: higher proportion of the genus Atopobium, Prevotella, Parvimonas, Sneathia, Gardnerella, Mobiluncus, Peptoniphilus and other taxa. CST V (Lactobacillus jenseri predominant) ^[28]^[33]^[34]^[35]	- Prevalence of Gardnerella vaginalis, Mycoplasma hominis, Atopobium vaginale and Mobiluncus curtisii ^[39]^[40]^[41]^[42] - higher bacterial diversity than physiological conditions ^[29]^[43]	- (Chlamydia trachomatis) ascending through the cervix ^[47]^[48]^[49]^[50] - higher percentage of Lactobacillus gasseri, Veillonella spp. and Staphylococci and lower content of Lactobacillus iners and crispatus ^[54]	- the diversity of bacterial species and the presence of Lactobacilli on the ET day improved the outcome ^[55]
Uterus	- Lactobacillus iners, Lactobacillus crispatus, Prevotella spp. ^[58]	-	- Lactobacillus spp. could improve fertility by inhibiting pathogenic bacteria ^[47]^[68]	- uterine microbiota lower in Lactobacillus spp., and non-Lactobacillus spp. dominated was associated with a lower ART success ^[57] and, on the contrary, Lactobacilli were associated with a negative impact ART outcome ^[59]

3. Microbiota and Pregnancy

Pregnancy produces a series of changes involving the entire maternal and fetal dyad ^[69]^[70]^[71]. The maternal microbiota also experiences changes in the various sites (gut, oral cavity, vagina); the findings are not homogeneous because of the wide variability of characteristics of populations included in the studies (ethnicity, gestational age-GA, geographic and environmental factors, lifestyle habits) ^[72]^[73]^[74].

There are many factors influencing maternal microbiota changes, such as maternal diet ^[75]^[76]^[77]^[78], pre-pregnancy weight, weight gain and some pathological conditions, such as diabetes and obesity ^[79]^[80]^[81]^[82]. During pregnancy, and especially in the third trimester, the maternal gut microbiota experiences a reduction in bacterial diversity, with an increase of Proteobacteria, Streptococci and some specific Lactobacilli types: this composition, necessary and beneficial for the normal course of pregnancy, highlights host–microbial interactions that impact host metabolism. Specifically, insulin resistance is increased, promoting energy storage for fetal growth. However, the future implications of these metabolic changes on maternal and fetal health are mostly unknown ^[72].

In Table 2, we summarized the major bacterial taxa found at each colonization site during pregnancy and its complications.

Table 2. Major bacterial taxa found during pregnancy and its complications, at each colonization site, according to the studies discussed here.

	Pregnancy
Gut	- especially in the third trimester, reduction in maternal gut microbiota diversity, with the increase of Proteobacteria ^[72]^[83], Streptococci, Lactobacilli ^[72] Bifidobacteria and species producing lactic acid ^[83] - in overweight women, reduction in Bifidobacterium spp. and Bacteroides, and increase in Enterobacteriaceae, Staphylococcus spp., Escherichia coli ^[81]^[84] - higher percentage of pathogenic bacteria, such as Clostridium perfringens and Bulleidia moorei, and a reduction in the Coprococcus catus in mothers affected by preeclampsia, while healthy controls were mostly characterized by Bacteroidetes spp. ^[85]
Oral cavity	- during the third trimester, increase in bacterial diversity and total amount ^[72]^[86]^[87]
Vagina	- progressive reduction in anaerobic bacteria and increase in Lactobacillus spp. ^[88]^[89]
Placenta	- prevalence of E. coli ^[5] - similarities with the oral microbiota ^[5] - Lactobacilli, Propionibacteria, Enterobacteriaceae ^[30] - in women who undergoing elective Cesarean section, lower diversity index and prevalence of Proteobacteria ^[90] - higher percentage of Acinetobacter spp. in women with gestational diabetes mellitus ^[91]

4. Impact of Maternal–Fetal Microbiota on Development

It is likely that maternal and fetal microbiota, interacting with each other, can exert a fundamental effect on fetal growth in general and in particular on the development of the immune system and nervous system ^[71]^[92]^[93].

The influence of the maternal microbiota is probably exerted by two mechanisms. First, the maternal intestinal microbiota can act directly on growth and development processes, in particular of the immune and nervous systems, through the production of metabolites that can reach the fetus through the placenta ^[71]^[93]^[94]^[95]. The second mechanism could be played by the fetal microbiota, especially the intestinal one, which would exert its action on development and programming directly on-site ^[92]^[96]^[97]^[98].

The action of colonization in utero would therefore be fundamental in determining long-term health, even in adulthood ^[99]^[100]^[101]^[102]. One of the fundamental actions of bacterial exposure in utero would be to modulate the programming of the immune and metabolic system: the primitive immune system requires interaction with bacteria in order to learn to distinguish the harmful ones from the useful ones ^[92]^[103]^[104]^[105].

What are the effectors of the immunomodulating action has been the subject of numerous studies in the last decade: an important role is played by SCFAs produced by the microbiota, which can act locally by regulating the production of T-cells and IL-10 ^[106]^[107]^[108] or by inducing an anti-inflammatory action by reaction with metabolite sensing G-proteins coupled receptors (GPRs). However, the SFCAs themselves could also enter the circulation and exert their action at a distance, for example on dendritic cells and on bone marrow macrophages ^[109]. Other molecules could be implicated in the primer action by the fetal microbiota, such as toll-like receptors (TLR), present on macrophages, dendritic cells, mast cells), capable of recognizing bacterial antigens and therefore influencing the fetal immune system ^[110]^[111].

The gut microbiota is also thought to be essential in bi-directional communication between the gastrointestinal tract and the central nervous system. A particularly fascinating hypothesis, studied especially in animal models, concerns the role of maternal and fetal microbiota in the development and functions of the central nervous system (in particular on behavioral aspects). The third trimester of pregnancy, just when the maternal intestinal microbiota becomes more abundant, is also characterized by a greater passage of nutrients to the fetus and constitutes a sensitive phase for the processes of synaptogenesis, myelinization and development of some specific areas, such as the hypothalamus ^[112]^[113]^[114]. The maternal–fetal microbiota, at the center of metabolic processes, is likely to contribute to brain development through mechanisms that are still poorly understood: microbiota-derived metabolites can constitute a substrate for neuronal development, stimulate energy production and induce remodeling and receptor activation ^[114].

Early childhood disturbances of the developing gut microbiota can impact neurodevelopment and lead to negative mental health outcomes throughout life ^[115]^[116]^[117]^[118]^[119]^[120]^[121]^[122]. In addition, some psychiatric diseases of children and adults have been associated with the exposure, during fetal life, to unfavorable factors such as hypoxia and reoxygenation. In response to altered oxygen concentrations, the placenta seems to releases certain substances that damage developing neurons ^[123]^[124]^[125]^[126]. Thus, brain damage can occur not only due to a lower oxygen supply than required, but also due to the accumulation in the fetal circulation of reactive products, released from the placenta, that negatively affect the vascularization and metabolism of the brain ^[127].

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