Antenatal Microbiome

Biology Review Series

Antenatal Microbiome Potential Contributor to Fetal Programming and Establishment of the Microbiome in Offspring Michelle L. Wright ▼ Angela R. Starkweather

Background: Endogenous and exogenous exposures during fetal development have potential to impact birth and health outcomes of offspring. Accumulating evidence suggests exposures may alter the antenatal microbiome and subsequently alter the microbiome and health of offspring. Objectives: The purpose of this integrative review is to summarize and critically evaluate the current state of knowledge regarding the assessment of the antenatal microbiome on the health of human offspring. The article provides a brief summary of the known factors affecting the human microbiome and studies that assessed relationships between the antenatal microbiome and health outcomes of the offspring. Methods: An integrative review was conducted to examine human research studies that focused on the antenatal microbiome and the health of the offspring using the electronic databases PubMed/MEDLINE and CINAHL from 2004 to the present. Results: In addition to the known individual factors that are associated with establishment of the microbiome, the results of the integrative review suggest that medications (including antibiotics) and comorbidities (including infectious diseases, diet, socioeconomic status, and exposure to pollutants) should also be measured. Discussion: The composition of the antenatal microbiome at various time points and body sites may be important mediators of short- and long-term health outcomes in offspring. In order to advance our understanding of the role of the antenatal microbiome on health and disease risk of the offspring, it will be important to further elucidate the composition of a healthy microbiome and specific mechanisms that contribute to altered health in later life. Key Words: antenatal  microbiome  microbiota  neonate Nursing Research, Month 2015, Vol 00, No 0, 00–00

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etal development is a period of unparalleled cellular proliferation, tissue formation, and organ construction within the confines of the womb—a human incubator that surrounds the fetus with amniotic fluid and provides nourishment for growth and protection of vulnerable tissues (Agin, 2009). Although historically the womb and fetus have been considered sterile until birth or rupture of the amniotic sac, recent evidence shows that the womb is host to a diversity of microorganisms that closely resemble the mother’s oral microbial community (Aagaard et al., 2014; DiGiulio et al., 2008). In addition, nutrient exchange that occurs through active and passive transport from the mother’s circulation to the placenta—an organ that acts as a selective maternal–fetal barrier—can also include toxins and microbes that can gain direct entry into fetal circulation. Thus, microbes from the placenta, amniotic fluid, and umbilical cord Michelle L. Wright, PhD, RN, is Postdoctoral Nurse Scholar, Virginia Commonwealth University School of Nursing, Richmond. Angela R. Starkweather, PhD, ACNP-BC, CNRN, is Associate Professor and Chair, Department of Adult Health and Nursing Systems, Virginia Commonwealth University School of Nursing, Richmond.

DOI: 10.1097/NNR.0000000000000101 Nursing Research

blood provide a diverse array of exposures to the developing fetus. For this reason, evaluation of the antenatal microbiome (microbial composition at multiple sites during pregnancy) may provide insight into the developmental origins of disease that have not been identified. The purposes of this article are to (a) briefly introduce the microbiome, the antenatal microbiome, and the microbiome and fetal programming; (b) present findings from an integrative review designed to summarize and critically evaluate the current state of knowledge regarding the antenatal microbiome and the health of human offspring; and (c) discuss findings in light of implications for nursing science.

The Microbiome The microbiome (the community of microorganisms, including bacteria, fungi, and viruses, which reside upon and within the human body) has gained attention as an important modulator of health and disease (Moloney, Desbonnet, Clarke, Dinan, & Cryan, 2014). Researchers have characterized a unique “core” microbiome inhabiting the skin, mouth, gut, urogenital tract, and vagina of adults (The Human Microbiome Project Consortium, www.nursingresearchonline.com

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2012), and many associations have been established between microbiota dysbiosis and chronic diseases, such as obesity (Turnbaugh et al., 2009), diabetes (Larsen et al., 2010), and metabolic syndrome (Zhang et al., 2010). Increasingly, investigations are designed to study the microbial composition in relation to specific body sites (e.g., vagina, placenta, gut, skin) because different conditions (e.g., moisture, pH) at each site are ideal for the proliferation of specific types of microbes and may be referred to as microbiota (Cox, Cookson, & Moffatt, 2013). However, there has been less attention given to evaluating the influence of the antenatal microbiome—the plethora of maternal and fetal microbial communities during pregnancy—on the short- and long-term health of the offspring.

Microbes from the placenta, amniotic fluid, and umbilical cord blood provide a diverse array of exposures to the developing fetus Antenatal Microbiome Several emerging areas of investigation concerning the antenatal microbiome support the notion that interactions occur among the maternal microbiome (particularly the womb) and fetus throughout pregnancy. However, precise classifications of dysbiosis—an unhealthy change in microbial composition—by bacterial species, composition, or amount and mechanisms by which dysbiosis leads to altered health outcomes remain enigmatic. Recent advances in the detection of microbes have resulted in support against the longstanding dogma that the fetus develops in a sterile environment (Aagaard et al., 2014; Ardissone et al., 2014; Funkhouser & Bordenstein, 2013). Microbes that gain access to the fetus in utero are primarily thought to be detrimental, for example, TORCH infections (Toxoplasma gondii, other agents like Treponema pallidum, rubella virus, cytomegalovirus, and herpes simplex virus), because of their teratogenic effects. Others have argued that additional pathogens should also be considered related to pregnancy because of their potential for altering short- and long-term outcomes in exposed offspring (Newton, 1999; Waldorf & McAdams, 2013). The 2013 review by Waldorf and McAdams (2013) thoroughly delineates fetal outcomes associated with known pathogens, including fetal death, spontaneous abortion, and residual morbidity in offspring. Given the number of known pathogens that cross the placenta and alter fetal outcomes (at least 22), it is likely that nonpathogenic microbes also cross the placental barrier. Several recent studies have characterized the vaginal microbiome in women with full-term, uncomplicated pregnancy as having low diversity and high stability of a dominant species, Lactobacillus (Aagaard et al., 2012; Walther-António et al., 2014). While Lactobacillus crispatus promotes stability of the

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normal vaginal microbiota during pregnancy, Lactobacillus gasseri and/or Lactobacillus iners predispose to the occurrence of abnormal vaginal microbiota (Verstraelen et al., 2009). The impact of abnormal vaginal microbiota on the developing fetus remains unknown. However, evidence suggests that dysbiosis of the vaginal microbiota is associated with adverse pregnancy outcomes and that varied species and compositions of bacteria are present in women that experience preterm labor (Bujold et al., 2008; DiGiulio et al., 2010; Nelson et al., 2009). The type and timing of antimicrobial treatment used to correct vaginal dysbiosis may also be significantly related to birth outcomes. For example, when metronidazole was solely used in the second trimester of pregnancy—as opposed to clindamycin—metronidazole was associated with a greater risk of preterm delivery in high-risk populations (Morency & Bujold, 2007). It has been reported that preterm infants develop an alternate gut microbiome phenotype characterized by a dominance of Proteobacteria and lack of Bifidobacterium and Lactobacillus, which are two of the main bacterial genera in healthy-term infants (Barrett et al., 2013). This finding may have implications for the developing gut microbiome, as infants who are exclusively breastfed show an enrichment of Bifidobacterium, which aids in the utilization of oligosaccharides found in human milk (Costello, Stagaman, Dethlefsen, Bohannan, & Relman, 2012). Microbiome exposures at birth have also been linked with health outcomes—infants who are delivered by caesarean section instead of vaginally are more likely to have asthma, allergies, and diabetes later in life (Cho & Norman, 2013; Romero & Korzeniewski, 2013). Differences in the composition of microbiota have also been identified between infants born at home versus in the hospital, underscoring that the environment contributes to the initial colonization of the infant (Penders et al., 2006). Other investigators have used an epidemiological approach to evaluate the relationship between maternal stress, smoking, and antibiotic exposure on specific disease outcomes, such as celiac disease in the infant, but have not conclusively determined that such relationships exist (Mårild, Ludvigsson, Sanz, & Ludvigsson, 2014). However, epidemiological studies that are focused on a single type of exposure may fail to identify the influence of synergistic exposures and the associated mechanisms that contribute to future altered health outcomes. Collectively, these findings suggest that there are maternal and fetal microbiome interactions that may affect fetal programming—the epigenetically regulated responses that allow an organism to adapt to environmental signals. Figure 1 summarizes a conceptual model that could be used to test hypotheses regarding the relationships between environmental exposures, maternal and fetal epigenome signatures, and microbiome composition. We propose that maternal antenatal environmental exposures, epigenome signature, and microbiome compositions contribute to birth outcomes and the initial programming (epigenome signature and microbiome) of the offspring. Throughout life,

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FIGURE 1. Influences of antenatal environment and microbiome on health outcomes. Single-headed arrows indicate a direct influence of a measured variable on another variable (e.g., environmental exposures may alter the individual’s epigenome signature), and double-headed arrows indicate covariance known to exist between variables (i.e., difference of the epigenome signature may be associated with different microbiome composition, but the direction of influence is uncertain).

the offspring’s health will continue be influenced by their own environmental exposures, epigenome signature, and microbiome composition. To date, most microbiome studies have been retrospective and/or lack the longitudinal data necessary to make inferences that changes in microbial composition cause disease or to fully decipher the complex relationship among environment, microbiome composition, and health status (Tyler, Smith, & Silverberg, 2014). Although we are far from understanding the precise mechanisms by which these interactions influence health, there is reason to believe that there is a certain degree of plasticity involved in fetal programming that may prove amenable to therapeutic strategies particularly related to environmental influences.

Microbiome and Fetal Programming Fetal (or prenatal) programming is the influence of endogenous and exogenous exposures during development of the embryo and fetus that impact local fetal cellular environments resulting in changes in the phenotype (Agin, 2009). These changes can potentially impact the construction and function of tissues and organs, including systems that affect behavior, neuroendocrine and immune responses, and metabolic homeostasis, resulting in short- and/or long-term alterations in health. Studies that have evaluated folic acid supplementation during pregnancy have established that nutrition can have a dramatic impact on inheritance not by changing the DNA sequence of a gene or via single nucleotide polymorphisms but by changing the methylation pattern of that gene (Waterland & Jirtle, 2003). The concept of fetal programming and the developmental origins of health and disease arose from studies that followed pregnant mothers and infants who survived the Dutch “Hunger Winter.” David Barker first identified an association with nutrient deprivation of the mother during pregnancy with the development of cardiovascular

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disease of the offspring who endured undernutrition in utero (Barker, 1995). Subsequently, scientists have also identified other alterations in future health outcomes in offspring exposed to famine in utero, including obesity (Ravelli, van Der Meulen, Osmond, Barker, & Bleker, 1999), perception of health (Roseboom et al., 2003), and clotting factors (Roseboom et al., 2000). Other exposures in utero have also been associated with altered health outcomes offspring, such as type 2 diabetes (Simeoni & Barker, 2009) and alteration in the epigenome signatures in offspring with unknown consequences (Dolinoy, Huang, & Jirtle, 2007; Loke et al., 2013; Pilsner et al., 2009; Vidal et al., 2013). In addition to the influence of nutrients and diet on fetal health, the microbiome—particularly the gut microbiome of the mother and/or fetus—can contribute to variation in health outcomes. For example, there has also been a significant amount of work investigating the transmission of the human immunodeficiency virus (HIV) from mother to child that is beyond the scope of this review. However, it should be noted that some infants are indeed infected with HIV in utero (Dickover et al., 1994), indicating that HIV virus is also capable of crossing the placental barrier. Furthermore, infants born to HIV-infected mothers who are not infected in utero or during delivery develop different T-cell profiles than children born to uninfected mothers (Lamers et al., 1994), suggesting that maternal infections may contribute to fetal programming even without direct microbial exposure. Furthermore, several microbes can produce substances that are used in various biological pathways involving human health. For example, certain bacterial microorganisms, such as Lactobacillus species, are able to convert nitrate to nitric oxide, a potent regulator of the nervous and immune systems. Bacteria can also generate neurotransmitters and neuromodulators—Lactobacillus species and Bifidobacterium species are known to produce GABA, whereas Bacillus species and Saccharomyces species produce noradrenalin (Cryan & Dinan, 2012). The precise interactions between the maternal and fetal microbiome and the mechanisms that lead to variation in health outcomes have yet to be characterized. However, accumulating evidence suggests that the antenatal microbiome is an important mediator of health outcomes of the offspring and that certain exposures during pregnancy can alter the microbiome and potentially increase vulnerability to the risk of chronic disease.

Integrative Review In order to advance understanding of the influence of the antenatal microbiome on health of the offspring, an integrative review was conducted. Research of microbial communities related to human health has largely increased in recent years because of the improved technology used to identify microbiomes via sequencing methods. Previous culture-based methods were limited because microbial species could only be studied if they could be grown in the laboratory. Currently, sequence-based

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technologies capitalize on the fact that a small subunit of bacterial ribosomal RNA is highly variable but highly conserved between species and can be used for identification purposes. Table 1 summarizes some terms frequently used in the microbiome literature. Several reviews of microbiome methods have been published and are available for a more detailed description of sequencing methodology (Cox et al., 2013; Sherman, Minnerly, Curtiss, Rangwala, & Kelley, 2014; Tyler et al., 2014). The aims of this integrative review were to summarize and critically evaluate the current state of knowledge regarding the assessment of the antenatal microbiome on the health of human offspring.

METHODS An integrative review was conducted to examine human research studies that focused on the relationship between the antenatal (maternal and fetal) microbiome on health outcomes of the offspring. The search of the electronic databases PubMed/ MEDLINE and CINAHL from 2004 to the present used key words “microbiome,” “microbiota,” “antenatal period,” “pregnancy,” “offspring,” and “birth outcomes.” Manual searches were also completed using references from previously published studies and literature reviews. Articles that were retrieved via these multiple search methods (n = 254) were reviewed for duplication and for whether they met the following inclusion criteria: (a) research studies that involved human participants with a primary aim of assessing the relationship between the human microbiome during pregnancy and health outcomes of the offspring; (b) studies that reported clear methodologies for measuring the microbiome; and (c) studies written in English within the last 10 years (see Figure 2 for process of the literature selection). A total of 20 articles met the inclusion criteria and are included in this review (Tables 2–4).

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whereas meconium with more lactic acid was associated with respiratory problems in infants. Hu et al. (2013) reported that the most robust predictor of the infant gut microbiome was maternal diabetes status. Pozo-Rubio et al. (2013) found no significant differences in the gut microbiome of infants who had a first-degree relative with celiac disease compared to those who did not; however, infants who were exposed to antibiotics had altered microbiome composition of the gut. These studies suggest that some maternal comorbidities may alter the gut microbiome of the fetus and infant, potentially conferring risk of chronic disease in later life. More data on the specific diagnoses, severity of disease, and treatments used will be necessary to fully understand the influence on health outcomes of the offspring.

Diet Most studies (10/13) to date have evaluated probiotic therapy during the antenatal, prenatal, or postnatal period on health outcomes, ranging from weight/obesity to allergies/eczema. One study set out to determine if fetal ingestion of amniotic fluid resulted in intestinal colonization that would result in inflammation and preterm birth but did not asses long-term health implications for the offspring or diet of the mother per se (Ardissone et al., 2014). Several studies only evaluated the fecal composition of the infant with maternal exposure to probiotics—of these, several did not find any significant changes in the infant fecal microbiome, whereas others did. However, in one of the studies, the administration of probiotics during pregnancy was associated with altered gene expression associated with inflammatory responsiveness in both the placenta and neonatal gut (Rautava, Collado, Salminen, & Isolauri, 2012). The variation in probiotic composition, length, and dose of probiotic therapy make any generalization of the findings very difficult.

DISCUSSION

RESULTS Medications Including Antibiotic Exposures The four studies identified in the literature review were focused on the effect of medications (mostly antibiotics) on the microbiome of premature infants in all of the studies. The studies indicate that premature neonates exposed to antibiotic therapy were more likely to have less diverse gut microbiome composition and a higher risk of infection and mechanical ventilation (Madan et al., 2012; Milisavljevic et al., 2013; Moles et al., 2013; Stewart et al., 2013). No additional studies were identified that assessed medication exposure during pregnancy on the microbiome or health of the fetus later in life.

Comorbidities There were three publications that focused on maternal comorbidities, meconium/fecal microbiome, and infant health outcomes. Gosalbes et al. (2013) found that the gut microbiome of infants was less diverse in mothers with atopic eczema,

The discussion centers on the major findings of the integrative review relative to other microbiome research as well as considerations for future research. Overall, sample sizes for the studies were small (6–160 participants, with one study enrolling 1,223 pregnant women), observational (seven studies) or randomized control trials involving probiotics (10 studies) and contained variable results (12 studies identified significant differences and eight did not).

Medications This review did not find any publications evaluating maternal medication exposures on the health of the offspring beyond those that assessed for the relationship between antibiotic exposure and risk to premature infants. Considering 94% of women will take at least one medication during pregnancy and 50% will take four or more medications, investigation of the impact of medication should be a high research priority (Mitchell et al., 2011). Of the studies that have investigated the short-term

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TABLE 1. Terms Used in Studies of the Microbiome During Pregnancy Term 16S rRNA

Amplicon Antenatal Dysbiosis Enterotype (vagitype, etc.) cluster

Epigenetics Epigenome

Epigenome signature Exposure, endogenous Exposure, exogenous Fetal programming FISH

Mediator (biological)

Metagenomics

Microbiome

Microbiota

Modulation (biological) Plasticity PCR

Pyrosequencing

qPCR Symbiosis T-RFLP

Definition Subunit of ribosomal RNA that is highly conserved between bacterial species; the nine (V1–V9) highly variable regions within the subunit can be used for identification Multiple copies of specific segment of RNA or DNA sequence; can be made during PCR reactions During pregnancy, from conception to birth Unhealthy change in microbial composition (e.g., Clostridium difficile infection) Grouping of communities of microbes based on the predominant taxa; e.g., enterotypes categorize gut bacteria which tend to be dominated by Bacteroides, Provetella or Ruminococcus; whereas vagitypes tend to cluster by Lactobacillus crispatus, Lactobacillus iners etc. Study of changes in gene expression that occur without changes in the DNA sequence Chemical compounds that are not part of the DNA but modify the genome and may alter gene expression; these modifications are maintained during cell division (e.g., DNA methylation adds a methyl group to the 5’ position of the cytosine ring and is associated with gene silencing) Chemical modifications to DNA that do not change the sequence, are specific to an individual, and may be stable in that individual over time Contact or influence from a source that originates within an individual (e.g., cortisol, estrogen) Contact or influence from a source that originates outside of an individual (e.g., smog, sunlight) Theory that posits maternal exposures during pregnancy influence offspring development and risk for disease later in life (e.g., cardiovascular disease) A small portion of DNA is fluorescently labeled and linked to DNA of interest to determine the presence or absence of that specific sequence; in microbiome studies, specific microbes Factor that can enhance and activate other functions, may be a coactivator, or may be involved with biological signaling; does not always need to be present for a reaction to occur Study of genetic material extracted directly from an environmental sample (e.g., vaginal swab); all genetic material is sequenced; may be referred to as shotgun sequencing Community of microorganisms (bacteria, fungi, viruses) that reside upon and within the human body; usually refers to the collective genomes in a specific environment Community of microorganisms that reside in a certain location or region, usually specifically referring to the actual microorganisms; this term is also used interchangeably with microbiome Changes in cellular function and/or morphology in response to changes in environment Change of phenotype (observed characteristic) in response to environmental exposures, with the ability to change or be molded Thermal cycling method used to generate multiple copies of a specific DNA sequence that can be used for various laboratory processes, such as cloning for sequencing of the DNA DNA sequencing method that determines the nucleotide (A/T/C/G) by detecting how much light is emitted by pyrophosphate release when a single-strand DNA template is being constructed; 454 pyrosequencing uses parallel processing to determine many sequences at once Measurement of the amount of targeted DNA generated during PCR by detecting the amount of fluorescence Two or more organisms living together in close association; interactions can be long term Method used to identify microbes that labels the restriction site closed to the end of the PCR product; only the terminal fragments (the labeled portions at the end of the product) are sequenced

Note. FISH = fluorescence in situ hybridization; PCR = polymerase chain reaction; qPCR = quantitative polymerase chain reaction; T-RFLP = terminal restriction fragment length polymorphism.

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FIGURE 2. Literature review process.

implications on the microbiome of the offspring, most have focused on the infant gut microbiome via meconium sampling. Given the study of the microbiome is in its infancy, it may be important to study the impact of the medication on other microbiome sites, because there remains much uncertainty in how different microbiome subcommunities interact with the human system to contribute to or serve as a biomarker for health outcomes. The studies currently presented in the literature have identified that medications will indeed have an impact on microbial compositions (Table 2). However, longitudinal studies with much larger sample sizes are needed to gain insights into interactions between multiple medications and other environmental factors that may influence microbial composition. Considering that the largest sample size we identified in the literature was 55, none of them have enough participants to accurately assess multiple outcomes or variables and, therefore, lack sufficient power to make a conclusive observation of association. Collectively, the studies to date support the need to assess medication exposures during pregnancy and the potential influence on the fetal microbiome when evaluating the relationship between microbiome alterations and health outcomes of the offspring.

Comorbidities Maternal comorbidities appear to have a significant impact on the antenatal microbiome and may confer disease risk to the fetus by presenting the same antecedents or conditions of the

disease etiology (Table 3). All three studies that assessed the fetal microbiota in relation to preexisting maternal comorbidities found significant differences based on maternal health status. However, the sample sizes were small (20–55 infants), and the study evaluating infants with a first-degree relative with celiac disease did not have a control group (Pozo-Rubio et al., 2013). To date, a number of health conditions have been associated with variations in microbiome composition in other populations, including psoriasis (Gao, Tseng, Strober, Pei, & Blaser, 2008), gastrointestinal ailments (Garrett et al., 2010; Krisanaprakornkit et al., 2000; Tana et al., 2010), asthma (Chen & Blaser, 2007), cardiovascular disease (Wang et al., 2011), type 2 diabetes (Larsen et al., 2010), and obesity (Turnbaugh et al., 2009). It is likely that the microbial composition of the mother is shared with and influences the development of the offspring’s microbiome composition, and the composition of her microbiota is likely associated with her own health status (Funkhouser & Bordenstein, 2013; Song, Dominguez-Bello, & Knight, 2013). This sharing of microbial communities can result in the offspring developing similar comorbidities that may be modulated by the microbes that colonize them. For example, in animal models when otherwise healthy mice are given a fecal transplant containing feces from overweight mice, they become obese (Turnbaugh et al., 2009). The complexity of determining which compositions may be harmful or beneficial is vast, and because we do not fully understand the interrelationships between

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Prospective

Prospective

Milisavljevic et al. (2013)

Moles et al. (2013)

a

14

Premature infants Exposed to antibiotics Premature infantsb Exposed to antibiotics 27

12

6

N

VLBW neonates NICU setting

Premature neonates Exposed to antibiotics

Population

Analysis

Results

Meconium Feces Parallel 454 pyrosequencing

• Meconium: not sterile • Meconium: less diverse from birth in infants who developed late-onset sepsis GI aspirates qPRC • Ureaplasma were dominant in the first week of life • Staphylococci were the predominant bacteria overall • By age 4 weeks, Gram (−) bacteria increased to account for 50% of the total organisms • No effect of antibiotic exposure Meconium 16S rRNA amplicons • Serratia were associated with sepsis, higher degree of gut Feces immaturity, and mechanical ventilation Meconium 454 Pyrosequencing • Twins shared similar gut microbiome development Feces • Antibiotic exposure and feeding were significant determinants of gut microbiome composition

Site(s)/ sample(s)

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EEFc

Pozo-Rubio et al. (2013)

55

23

20

N

Feces

Meconium Feces

Meconium

Sample(s)

qPCR

16S rRNA PCR amplicons

High-throughput pyrosequencing: 16S rRNA gene

Analysis

• Two meconium microbiota types • First type: less diverse, dominated by enteric bacteria, associated with maternal atopic eczema • Second type: dominated by lactic acid-producing bacteria, associated with infant mucous congestion during first year of life • Mode of delivery: not associated with meconium microbiota diversity • Maternal diabetes status: associated with microbiota composition • Infant antibiotic intake: associated with lower counts of Bifidobacterium longum • Infant antibiotic intake: associated with higher counts of Bacteroides fragilis group

Results

Note. EEF = early environmental factors; PCR = polymerase chain reaction; PGM = personal genome machine; qPRC = quantitative polymerase chain reaction; rRNA = ribosomal ribonucleic acid. aMaternal. bCoded as no diabetes, pre/gestational diabetes, type 2 diabetes. cFactors included type of delivery, maternal antibiotics during pregnancy or labor, milk-feeding practices, early infant infections and rotavirus immunization, and allergy within the first 18 months of life. dFirst-degree relative.

Infants

Diabetesa,b

Hu et al. (2013)

Term infants

Population

Atopic disease

a

Comorbidity

Gosalbes et al. (2013)

Study

TABLE 3. Observational Studies of Maternal/Family Comorbidities and Gut Microbiota of Newborns or Infants

Note. GI = gastrointestinal; qPRC = quantitative polymerase chain reaction; VLBW = very low birth weight. a24–27 weeks gestation at birth. bTwelve twin pairs and one triplet set.

Stewart et al. (2013) Longitudinal Twin cohorts

Prospective Longitudinal

Design

Madan et al. (2012)

Study

TABLE 2. Studies of Medication Exposure (Including Antibiotics) and Neonatal Gastric Aspirates or Meconium

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Design

Populationa

Feces (mother) At 38 weeks gestation Feces (infant) At 7, 14, 28, 84 days Mother–infant dyads (Mother: 1223 Feces (infant) At birth probiotics 2–4 weeks prior and 2 years to delivery)

Mother–infant dyads (Mother: probiotic before delivery)

RCTd

RCTb

RCTb

Comparativee Healthy pregnant women (probiotic VSL#3 during antenatal weeks 33–37)

Urwin et al. (2014)

Rinne et al. (2006)

Salvini et al. (2011)

Vitali et al. (2012)

Infants of hepatitis C virusinfected mothers (Infant: formula with probiotics) Cabrera-Rubio Observational Lactating women (3 postnatal time points) et al. (2012) Longitudinal

Kukkonen et al. RCTb (2007)

Mother–infant dyads (Mother: probiotic supplementation with LGG during late prenatal period) Mother–infant dyads (Mother: 2–150 g portions of salmon/week)

RCTb

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Vagina

Feces (infant) At birth; At 3, 6, 12 months Breast milk

Feces (infant)

Feces (infant) At 1 week

Results

• Degree of weight gain influenced maternal fecal microbiota • Mode of infant feeding influenced infant fecal microbiota

• Eczema significantly lower with intervention during the first 3 months of life • IL-5 production was decreased with intervention • Incidence of eczema was similar after 3 months • Probiotic supplementation had a bifidogenic effect on maternal gut microbiota that was not transferred to neonates and had no effect on infant immunity • Administration of LGG to mothers during late pregnancy had no effects on fecal samples

qPCR

(continues)

• Probiotic treatment showed no effect on incidence of all allergic disease by age 2 years • Probiotic treatment significantly prevented eczema, especially atopic eczema FISH • Stools, vomits, crying were comparable between groups • At 2 years, less lactobacilli/enterococci and clostridia in feces in the probiotic group Culture • Prebiotic supplementation resulted in more fecal bifidobacteria and lactobacilli throughout first year of life. Pyrosequencing • Milk from obese mothers tended to contain a qPCR different and less diverse bacterial community • Elective and nonelective cesarean delivery contained a different bacterial community than those who delivered by vaginal birth qPCR • Probiotic appeared to counteract the decrease of Bifidobacterium and the increase of Atopbium in control women during late pregnancy along with decrease in IL-4 and IL-10

FISH

T-RFLP

FISH qPCR

T-RFLP qPCR

16S rRNA • GA: largest effect on microbial community Ion Torrent PGM structure • Mode of delivery: also had an effect qPCR • Clear association: mother and infant gut colonization by Bifidobacteria • Maternal probiotic treatment effect was minor

Analysis

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18

20

132

123

98

Feces (mother) Feces (infant)

Ismail et al. (2012)

48

Mother–infant dyads (Mother: probiotic 25 weeks gestation until delivery)

Pilot RCTb

Shadid et al. (2007)

Feces (mother) At 1 month postpartum Feces (infant) At 1 and 6 months Feces (mother) Feces (infant)

Mother–infant dyadsc (Mother: 156 probiotics) (Infants: probiotics for first 12 months of life)

80

Meconium

Site(s)/sample(s)

RCTb

Mother–infant dyads (Mother: probiotics 2 months prior to delivery, 2 months during breastfeeding)

52

N

Niers et al. (2009)

(2011)

AQ1 Grönlund et al. RCTb

Ardissone et al. Observational Infants 23–41 weeks GA (Fetus: (2014) ingestion of amniotic fluid)

Study

TABLE 4. Studies of Diet and Antenatal Microbiota

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29 Maternal-infant dyads (Mother: probiotics 2 weeks before delivery) RCTb Rautava et al. (2012)

RCT Lahtinen et al. (2009)

Antenatal Microbiome and Offspring Microbiome

Note. Studies ordered by site/sample: meconium, feces (mother and infant), feces (infant), breast milk, vagina (mother), multiple sites/samples. FISH = fluorescence in situ hydbridization; GA = gestational age; LGG = Lactobacillus rhamnosus GG; PGM = personal genome machine; RCT = randomized controlled trial; TLR = Toll-like receptor; T-RFLP = terminal restriction fragment length polymorphism. aTreatment is given parenthetically for RCTs and comparative studies; comparisons were placebos or usual diet. b Double-blind, placebo-controlled. cInfants were at high risk of allergic disease. dSingle-blind, controlled. eTreatment assigned by availability to consume product.

• Probiotics altered expression of TLR-related genes in the placenta and neonatal gut

• Probiotics associated with higher prevalence of species belonging to Bifidobacterium longum group and development of healthy infant-type microbiota

Feces (mother) At T-RFLP qPCR enrollment At birth Vaginal swabs (mother) At 38 weeks gestation Feces (infant) At 3, 7, 28, 90, 180 days Breast milk At 7, 28 days Amniotic fluid qPCR Placenta Meconium 122 Mother–infant dyads from 36 weeks of gestation until delivery or placebo

Site(s)/sample(s) N

b

Populationa Design Study

TABLE 4. Studies of Diet and Antenatal Microbiota, Continued

Analysis

Results

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microbiome communities and human health, purposely disrupting this balance without knowing the long-term implications could be potentially devastating for future generations. Stress (Cryan & Dinan, 2012), socioeconomic status (Ding & Schloss, 2014), and environmental exposures (Lozupone, Stombaugh, Gordon, Jansson, & Knight, 2012) are all known to contribute to microbiome variability and possible dysbiosis in humans. However, these factors were not considered in the research studies of the antenatal microbiome reviewed. For example, Ding and Schloss (2014) found that women with a bachelor’s degree or higher were more likely to have a vaginal microbiome associated with high levels of Lactobacillus. In their data set, they did not have the capability to determine which confounding factors associated with advanced education may be contributing to the altered compositions in vaginal microbiomes. One possible explanation is women of different socioeconomic status may have different environmental exposures that alter the microbiome, such as different diets or types of stress. Until additional studies are completed that assess various environmental and socioeconomic variables, it is difficult to hypothesize which factors may contribute synergistically. Multiple reviews have identified altered microbiome compositions in patients with disease associated with stress (Cryan & Dinan, 2012; Stilling, Dinan, & Cryan, 2014; Wang & Kasper, 2014), although little is known on how the stress of a normal or complicated pregnancy contributes to variations in the antenatal microbiome. In one study investigating heritability of microbes, monozygotic and dizygotic twins appear to have equal similarities in gut microbiome compositions, indicating that a shared environment may be a stronger predictor of microbiome composition than genetic composition (Turnbaugh et al., 2009). Additional twin studies incorporating the use of meticulous biobehavioral measures may help determine how different shared environmental factors associated with different socioeconomic status are linked with various microbial niche communities.

Diet Although there is very little information regarding how the maternal diet contributes to the antenatal microbiome, we identified multiple studies that have examined the use of probiotics in pregnant women. Several of the probiotic studies identified by this review found that factors, other than probiotics, were associated with changes in the infant gut microbiota (CabreraRubio et al., 2012; Grönlund, Grześkowiak, Isolauri, & Salminen, 2011; Urwin et al., 2014) or that probiotics had no influence on the infant (Grönlund et al., 2011; Ismail et al., 2012; Kukkonen et al., 2007; Shadid et al., 2007). The remaining studies identified some significant difference in microbiota compositions (Lahtinen et al., 2009; Rinne, Kalliomäki, Salminen, & Isolauriet, 2006; Salvini et al., 2011), alterations in gene expression associated with immune function (Rautava et al., 2012), or a decrease in reported eczema up to 3 months of age that did not persist (Niers et al., 2009). The lack of consistency between studies

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suggests that multiple factors—not just the bacteria administered in the probiotics—contribute to the development of the microbiota composition in neonates and contribute to immune system development. For example, Wu et al. (2011) found that the long-term composition of gut microbiota is clustered by diet and that alterations in diet can significantly change microbial composition within 24 hours, although not enough to change the overall enterotype cluster of the individual. Furthermore, even though communities of microbes in the gut are highly variable between individuals, the functions different microbes carry out in different individuals are the same (Lozupone et al., 2012). Because we do not fully understand how multiple variables work in concert to support certain compositions of bacteria, it may be premature to try to alter them by adding or removing specific types of bacteria and may explain the variability in results of the probiotic studies. However, it is important to note that, when the initial bacterial composition in the gut within an animal model is purposely changed, it is associated with alteration in immune programming and inflammatory response later in life (Olszak et al., 2012). Given intervention studies have already been done, this area of exploration may benefit from longitudinal designs in women with and without probiotic exposure—with examination of the maternal and fetal microbiome and health outcomes over time. Future studies evaluating the actual diets of women, without a probiotic intervention, may be beneficial for improving our understanding of how the microbiome interacts with the host diet and how it contributes to the antenatal microbiome and microbiome of the offspring. In addition, consideration of the chemicals and microbes in the food supply consumed by pregnant women and the influence on the antenatal microbiome and health outcomes of the offspring should be included in future research.

Antenatal Microbiome and Offspring Health Few studies have assessed for the actual presence of bacteria in utero during healthy pregnancy. The probiotic study by Rautava et al. (2012) assessed for the presence of bacteria in placentas and amniotic fluids of women treated with probiotics during pregnancy and found bacterial DNA present in all placentas and 43% of amniotic fluid obtained during cesarean section. They also found that, when bacteria were present in the amniotic fluid, gene expression related to immune function was altered in the fetal gut. Furthermore, bacteria have been identified in meconium and umbilical cord blood of infants delivered via cesarean section, indicating that there is some passage of bacteria from mother to infant in utero, and it is unknown if these bacteria have any correlation to future health outcomes in the offspring (Gosalbes et al., 2013; Jiménez et al., 2005). The following discussion will include justification for further investigation of the factors affecting the antenatal microbiome and evaluating relationships to the health outcomes of the offspring. Our understanding of the relationship between mother, offspring, and microbiome development may benefit by closer

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examination of the fetal compartment for microbes and plausible explanations for how it evolves. For example, dendritic cells may be involved in the process of introducing commensal bacteria to the fetus. Dendritic cells can pick up and hold bacteria and/or antigens from the intestines for a number of days and pull them into the lymphatic system (Macpherson & Uhr, 2004; Rescigno et al., 2001). Mesenteric lymph nodes in pregnant mice are 60% more likely to harbor bacteria than nonpregnant mice (Perez et al., 2007). Commensal bacteria and antigens that are in the lymphatic system may travel to the lymphatic system of the uterus. Lymphatic vessels have been identified in all regions of the placenta, including the area adjacent to the amniotic membrane, and it has been suggested that the abundance of dendritic cells at the maternal–fetal lymphatic interface may exist to present fetal antigens to the mother (Red-Horse, 2008). However, perhaps the converse is true and the dendritic cells are presenting antigens, including microbial antigens, to the fetus to which it will be exposed after birth (i.e., the initial programming of the fetal immune system). Investigations on the mechanisms of maternal transmission of microbes to the fetus and the influence on the health of the offspring are clearly warranted. In addition, the mechanisms by which pathogens and nonpathogenic microbes influence health outcomes in later life are yet to be elucidated. It is possible that specific microbes differentially contribute to multiple mechanisms or disease pathways, which further add to the complexity of microbiome research. For example, the microbiome subcommunities appear to be unique to each individual, although the overall functional characteristics of microbiome communities are essentially the same (Ding & Schloss, 2014). This means that similar to redundancy seen when multiple DNA codons encode for the same amino acid, multiple species of bacteria can carry out the same functional roles related to microbiome composition. Until the baseline functional qualities of the microbiome are established, it may be difficult to determine which pathways are affected by alterations in composition. Previous studies in animal models and humans suggest that epigenome—specifically DNA methylation (Kellermayer et al., 2011; Olszak et al., 2012)—and hypothalamic–pituitary–adrenocortical axis alterations (Clarke et al., 2013; Diaz Heijtz et al., 2011; Gareau et al., 2011) may be associated with microbiome composition and changes (Figure 1).

Implications for Nursing Research Advancements in understanding the unique contributions of the microbiome in health and disease provides new avenues to pursue in nursing research, particularly as it related to modulating health risks throughout the lifespan. As a discipline grounded in health promotion and disease prevention, nursing research offers a distinct lens from which to study the impact of the microbiome on person–health–environment interactions. At this stage of the science, many studies have focused on

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TABLE 5. Current National Institute of Nursing Research Antenatal Microbiome-Related Projects Project

Title

PI

R01 NR014792 A multi-omics approach toward deciphering the influence of the microbiome on preterm birth K23 NR014674 Early life experience imprints gut microbiome in preterm infants R01 NR014800 Biobehavioral determinants of the microbiome and preterm birth in Black women R01 NR014784 Revealing the role of the cervico-vaginal microbiome in spontaneous preterm birth

Aagaard-Tillery, Kjerstie Cong, Xiaomei Sophia Corwin, Elizabeth Elovitz, Michal A.

Note. PI = principal investigator.

describing the composition of microbiota and detecting dysbiosis that may be associated with disease. However, accumulating evidence on the influence of the maternal microbiome on the epigenome of the developing infant suggests that it may play a significant role in fetal programming and the development of disease later in life. Although empirical evidence is needed to establish precise cause–effect relationships, the potential to mitigate disease risk by enhancing symbiotic conditions during development and in later life has many implications for nursing research. Investigations focused on characterizing symbiosis and dysbiosis at various sites of the body will be a prerequisite for the development of assessment and monitoring technologies that can be used in practice. Research to understand the interplay between the microbiome, epigenome, and disease will inform nursing interventions that utilize microbiome modification strategies. Studies described in this review point to a wide range of environmental exposures that can alter an individual’s microbiome composition, including medications and diet. Given that the microbiome is modifiable, there is great potential to develop nursing interventions geared toward

enhancing the protective capacity of the microbiome in states of health and prevent disease across the lifespan. Because of the general sparsity of data in this area, there has been support from federal research agencies to improve our understanding of how the antenatal microbiome contributes to health outcomes. There are currently 34 studies funded by the National Institutes of Health listed in the National Institutes of Health RePORTer system (http://projectreporter.nih .gov/reporter.cfm) when “microbiome” and “pregnancy” are used as search terms. Of the 34 studies, four studies have been (Table 5) funded by the National Institute of Nursing Research, and multiple institutes continue to issue grant funding for this area of research (Table 6). Conducting interdisciplinary, clinically relevant research investigating the antenatal microbiome mirrors the National Institute of Nursing Research’s mission to incorporate new biological and behavioral science technologies into nursing science to promote and improve health. Enhancing our understanding of how the antenatal microbiome contributes to health outcomes in the offspring of pregnant women will provide a foundation for future development of preventative interventions

TABLE 6. Antenatal Microbiome-Related Funding Opportunities at the National Institutes of Health RFA/PA

Institute Mechanism

PA-15-100

NINR

R01

PAR-14-264a NICHD

R01

PAR-13-389a NICHD

R01

PA-15-126 PA-15-124 PA-15-125 PA-15-135

Jointb

NIDCR

R01 R03 R21 R01

Call Maternal Nutrition and Pre-pregnancy Obesity: Effects on Mothers, Infants and Children Global “Omics” Approaches Targeting Adverse Pregnancy and Neonatal Outcomes Utilizing Existing Cohorts Discovery of Molecular Targets for Pregnancy-Related/ Induced Diseases and Development of Therapeutics to Prevent/Treat These Diseases Early-Life Factors and Cancer Development Later in Life

Expiration 05/08/2018 10/08/2016

05/08/2017

01/08/2018

Advancing Mechanistic Probiotic/Prebiotic and Human 05/08/2018 Microbiome Research

Note. NCI = National Cancer Institute; NICHD = National Institute of Child Health and Human Development; NIDCR = National Institute of Dental and Craniofacial Research; NIEHS = National Institute of Environmental Health Sciences; NINR = National Institute of Nursing Research; PA = Program Announcement. aProgram Announcement with special receipt, referral, and/or review considerations. bNCI, NICHD, and NIEHS.

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Antenatal Microbiome and Offspring Microbiome

and policy to protect the health of future generations. Investigations into this area of inquiry will likely require an innovative approach to protect the health of both mother and offspring. For example, observational studies investigating several simultaneous influences (e.g., stress, medications, microbiome, genetic sequence) with bioinformatics support to identify factors associated with disease risk may be preferred over intervention studies.

Conclusions A deeper understanding of the influence of the antenatal microbiome on the health of the offspring may provide new insight on the origins of chronic disease as well as inform practice and healthcare decision-making. As shown in this review of the literature, multiple factors (maternal transmission of microbes, comorbidities, and diet) have been shown to be associated with alterations in the fetal environment during pregnancy with documented changes in fetal microbiome composition and disease risk in the offspring. Less attention has been focused on investigating the influence of medication exposures (including antibiotics) on the antenatal microbiome and the long-term implications on health outcomes of the offspring. Other areas that warrant further research were identified in the literature review. In particular, investigations that provide data on the antenatal microbiome composition over the course of pregnancy and incorporate mechanisms of fetal programming (epigenomics) have potential to greatly advance this area of research. Accepted for publication March 30, 2015. The authors have no conflicts of interest to report. Corresponding author: Michelle L. Wright, PhD, RN, Virginia Commonwealth University School of Nursing, 1100 East Leigh Street, P.O. Box 980567, Richmond, VA 23298-0567 (e-mail: [email protected]).

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