Review
The Bacterial Microbiome and
Virome Milestones of Infant Development
1 1 2,
Efrem S. Lim, David Wang, and Lori R. Holtz *
The human gut harbors a complex community of bacteria, viruses, fungi,
Trends
protists, and other microorganisms (collectively termed the microbiome) that
The gut bacterial microbiome and vir-
impact health and disease. Emerging studies indicate that the gut bacterial ome affect healthy infant development.
microbiome and virome play an important role in healthy infant development. In
In contrast to the adult's gut bacterial
turn, the composition of the microbiome during development can be influenced
microbiome and virome, those in the
by factors such as dietary, environmental, and maternal conditions. As such, the infant are dynamic.
microbiome trajectory during early infancy could be predictors of healthy devel-
Transkingdom interactions between
opment. Conversely, adverse early events in life may have consequences later in
viruses and bacteria influence the
life. This review focuses on our understanding of the bacterial microbiome and health and disease of the host.
virome during early development, conditions that might influence these pro-
Infant gut bacterial colonization is cor-
cesses, and their long-term implications for infant health.
related with a contraction in the bacter-
iophage community.
Microbial Communities of the Infant Gut
While microbes are historically viewed as potential pathogens, we now appreciate their
beneficial role in health, immune function, and metabolism. The gut harbors the highest
density microbial community within the human body. This gut microbiome (see Glossary)
encompasses the diverse community of eukaryotic viruses and bacteriophages (virome),
bacteria (bacterial microbiome), and other microorganisms. An emerging concept from
recent studies is that these microbial communities are important for healthy infant develop-
ment. The developmental trajectory includes milestones such as the choreographed coloni-
zation of bacterial populations, dynamic alterations in the virome, and transkingdom
interactions between members of the two communities. Alterations in the bacterial micro-
biome and virome early in life are significant because they could set the stage for the infant's
future health and disease risk. Thus, early infancy may present a unique opportunity to
leverage the bacterial microbiome and virome to intervene and influence immune develop-
ment and disease outcomes.
1
The aim of this review is to summarize current understanding of the early development of the Departments of Molecular
human gut bacterial microbiome and virome in terms of the dynamic nature of this progression Microbiology and Pathology and
Immunology, Washington University
and the factors that influence its trajectory. We discuss the potential interactions between
School of Medicine, St Louis, MO,
members of these two kingdoms and how perturbations of the infant gut bacterial microbiome USA
2
and virome may set the stage for disease later in life. Division of Gastroenterology,
Hepatology, and Nutrition, Department
of Pediatrics, Washington University
Development of the Gut Bacterial Microbiome School of Medicine, St Louis, MO,
Multiple factors influence the composition of the bacterial microbiome (Figure 1, Key Figure). USA
Many variables early in life, including mode of delivery, infant diet, use of antibiotics, the physical
environment surrounding the infant, host genetics, and perhaps even the in utero environment,
*Correspondence:
fl
in uence this complex process. [email protected] (L.R. Holtz).
Trends in Microbiology, October 2016, Vol. 24, No. 10 http://dx.doi.org/10.1016/j.tim.2016.06.001 801
© 2016 Elsevier Ltd. All rights reserved.
Womb Exposure Glossary
Traditionally the womb has been considered a sterile sanctuary for the developing fetus.
Bacterial microbiome: community
However, recently this dogma has been questioned by numerous observations, raising the of bacteria that share an ecological
space.
possibility that the infant gut is colonized before birth. Specifically, bacteria have been detected in
Microbiome: community of
full-term placentas using culture-based methods [1] and they have been visualized in the
microorganisms, including bacteria,
placental basal plate from healthy pregnancies [2]. Bacterial sequences have been detected viruses, fungi, protists, and other
in the placenta [3], amniotic fluid [4], cord blood [5], and meconium [6]. Aagaard et al. found that microorganisms, within an ecological
space.
the placental bacterial microbiome resembled the oral bacterial microbiome [3]. Interestingly, the
Virome: community of eukaryotic
connection between these two microbial communities has also been seen in murine systems.
viruses and bacteriophages that
Tail vein injection of Fusobacterium, an oral anaerobe, localizes to the placenta, but does not share an ecological space.
colonize other organs [7]. It is unclear from where the bacteria that comprise the pIacental
microbiome originate. One hypothesis suggests that the bacteria are spread hematogenously
either from the oral cavity or the gut to the placenta. In support of this model, labeled
Enterococcus fed to pregnant mice can be detected in the meconium of the pup [6]. It has
been noted that bacterial translocation from the gut to the blood is higher in pregnant mice than
in nonpregnant mice [8], which may permit seeding of the placenta. Alternatively, it has been
suggested that the nonpregnant uterus is colonized with microbes in the endometrial epithelium
as bacteria have been cultured from the endometrium and these could be the source of the
placental bacterial microbiome [9].
Bacteria have been isolated from the amniotic fluid of mothers with chorioamnionitis. Commonly
recovered bacteria include Ureaplasma, Mycoplasma, Fusobacterium, Streptococcus, Bacter-
oides, and Prevotella. Broad-range PCR assays have demonstrated the presence of Firmicutes,
Bacteroidetes, Actinobacteria, Proteobacteria, and fusobacteria DNA in amniotic fluid [4]. The
relative abundances of specific bacterial taxa in amniotic fluid differs between preterm labor with
Key Figure
Influences on the Gut Microbiome during Infant Development
Influences on microbiome during infant development Mode of Gesta onal Diet Womb delivery age Gene cs Environment An bio cs
Microbiome
or Healthy Disease
development
Figure 1. The infant gut bacterial microbiome and virome can be influenced by various factors as shown. Notably, while
most studies have demonstrated their effects on modulation of the bacterial microbiome, further research is needed to
extend these findings to the virome (e.g., mode of delivery and gestational age). Collectively, alterations in the infant gut
bacterial microbiome and virome can lead towards a healthy development or disease.
802 Trends in Microbiology, October 2016, Vol. 24, No. 10
intact membranes versus preterm labor with ruptured membranes [4]. The role of bacteria in the
amniotic fluid from women with preterm delivery remains unknown.
Jimenez et al. collected cord blood from 20 healthy infants born via Cesarean section (C-section)
[5]. From 9 (45%) of these samples, they cultured and identified by 16S sequencing multiple taxa
of Gram-positive bacteria, including Enterococcus, Streptococcus, Staphylococcus, and
Propionibacterium.
Studies have also suggested that meconium is not sterile as once previously thought, supporting
the hypothesis that gut colonization occurs before birth. Jimenez et al. [5] showed, using culture,
that Staphylococcus and Enterococcus were the predominant bacteria in meconium. Subse-
quent 16S-based studies of meconium found that samples had low bacterial diversity and that
the microbiome is dominated by a few genera in a given individual [10]. Additionally, Ardissone
et al. [10] demonstrated that the bacterial microbiome in meconium most closely resembled that
of amniotic fluid.
Mode of Delivery
The mode of delivery (vaginal versus C-section) has a strong correlation with the bacterial
communities that first colonize the gut [11,12]. Infants born vaginally have gut bacterial micro-
biomes that resemble their mother's vaginal bacterial microbiome, which is dominated by
Lactobacillus [11]. By contrast, infants born by C-section have a gut microbiome most similar
to their mother's skin bacterial microbiome. Interestingly, this altered colonization pattern seen in
babies delivered via C-section persists to at least 1 year of age [12,13] and has been hypothe-
sized to be responsible for the increased risk of obesity [14] and asthma [15] seen in children
delivered by C-section. A pilot study to expose infants delivered by C-section to maternal vaginal
fluids [16] demonstrated that vaginal microbes could be partially restored at birth in C-section-
delivered babies. However, the long-term impact and possible benefits of this procedure as well
as potential risks (e.g., exposure to bacteria that may be harmful to the infant) have yet to be
defined [17].
Gestational Age
The gut bacterial microbiome also differs with gestational age. A longitudinal study of preterm
infants showed that the pace of the gut bacterial microbiome development was most strongly
driven by postconceptional age [18,19]. The importance of gestational age in the development of
the bacterial microbiome has also been seen in a longitudinal study of term and near-term infants
in Singapore [20]. Furthermore, a study of meconium showed that gestational age had the
greatest influence on the microbial community structure [10]. While factors such as delivery
mode and diet are influential on the term infant bacterial microbiome, these factors have less of
an influence on the gut bacterial microbiome in preterm infants, which is most affected by gestational age [18,21].
Diet
Another strong influence on the development of the gut bacterial microbiome is the infant
diet (breast milk vs. formula). Infants that are breastfed typically have a microbiome domi-
nated by bifidobacteria and lactobacilli while formula-fed babies have a more diverse
community and increased abundance of Escherichia coli, Clostridium, and Bacteroides
[12,22]. Identical bacterial strains have been isolated from mother's breast milk and infant's
stool, suggesting an important role of breast milk in gut bacterial colonization [23]. As the
infant's diet is diversified and solid foods are introduced, there is an increase in Bacter-
oidetes, presumably to facilitate nutrient utilization [24]. Additionally, weaning from breastmilk
leads to large shifts in the infant's bacterial gut microbiome towards a more adult-like
composition [12].
Trends in Microbiology, October 2016, Vol. 24, No. 10 803
Environment
Other environmental factors, such as family contacts, geographical location, and dust, are
thought to have an influence on the development of the bacterial microbiome. Members of the
same household have bacterial microbiomes that are more similar than individuals that do not
reside together [25]. Additionally, longitudinal studies of fraternal twins demonstrated the
coincidental appearance of specific bacteria [26]. Interestingly, firstborn children have a less
diverse and less rich bacterial microbiome than children with older siblings, suggesting that
there is transfer of bacteria from close contact with the older sibling and/or that parental hygiene
practices are different as more children are born into the family [27]. The bacterial microbiome
also differs between infants living in different geographical locations [25,28–30]. These geo-
graphical variations may be secondary to differences in diet, hygiene, sanitation, other envi-
ronmental exposures, or host genetics. Additionally, the immediate environment has an effect
on the infant's bacterial microbiome. Konya et al. [31] showed an association between the
bacteria found in house dust and in the infant. Due to the finding that infants born via C-section
acquire a skin-like bacterial microbiome at birth, Shin et al. [32] recently examined the dust
found in the operating room at the time of C-section and found that the dust contains deposits
of human skin bacteria. The role of this possible environmental exposure on the infant still needs
to be further explored.
Host Genetics
The role of host genetics in shaping the infant bacterial microbiome is poorly understood. The
most informative studies come from those focused on twins. 16S sequencing of relatively small
numbers of twins and their parents did not show any significant differences in bacterial diversity
between monozygotic and dizygotic twins [25,33]. These studies did, however, show that
members of the same family were more similar than unrelated individuals (Figure 2). Under-
standing the role of host genetics on the bacterial microbiome is complicated by the fact that it is
influenced by other factors such as diet, maternal factors, and environment. It has been argued
that, in order to find human genomic loci that are responsible for microbial abundances, studies
must include very large cohorts to overcome the variation that is caused by nongenetic factors
[34]. Recently, a large study of 416 adult twin pairs did identify bacterial taxa whose abundances
are influenced by host genetics [35].
Infant Adult Low High Low High Bacterial diversity Interindividual bacterial varia on Bacterial microbiome stability Interindividual virome varia on Co-twin virome varia on Bacteriophage diversity
Bacteriophage stability
Figure 2. Comparisons of the Human Gut Bacterial Microbiome and Virome between Infants and Adults.
Depicted are the microbiome traits (as relatively low or high) of an infant (less than 1 year old) compared to those of an adult
(greater than 18 years old).
804 Trends in Microbiology, October 2016, Vol. 24, No. 10
Antibiotics
The adult bacterial microbiome is thought to be rather resilient to disruption by antibiotics [36] in
that abrupt changes occur, but the bacterial microbiome eventually recovers. By contrast, the
developing infant bacterial microbiome can be significantly altered by antibiotic use and may fail
to recover fully [37]. This ecological disruption may facilitate colonization by enteric pathogens
[38]. Antibiotic use during pregnancy and breastfeeding might also affect the infant's gut
bacterial microbiome [30]. Nobel et al. [39] used a mouse model to mimic pediatric antibiotic
use and saw changes in the gut microbes that lasted for several months and the mice had
changes in their body composition, hepatic gene expression, and metabolic hormone levels.
These findings support the concept that antibiotics affect the gut bacterial microbiome, and this
disruption may have long-term metabolic effects.
Development of the Gut Virome
In contrast to the bacterial microbiome, much less is known about the gut virome (in adults or
infants), the factors that influence its composition, and from where it arises (Figure 1). While many
studies using traditional culture or PCR assays have established the sporadic presence of
specific eukaryotic viruses in the infant gut, to date there have been only a limited number of
unbiased, metagenomic studies of the gut virome. Collectively, they demonstrate that diverse
bacteriophages are present in the infant gut and that eukaryotic viruses can be sporadically
found in the infant gut [40,41].
Womb
There are many pathogenic eukaryotic viruses, such as HIV, influenza, rubella, varicella, cyto-
megalovirus (CMV), and human papilloma virus, that can be transmitted transplacentally or
vaginally to the newborn. The clinical manifestations of these infections vary depending on the
viral agent and the gestational age at exposure but may range from miscarriage to asymptomatic
infection. Recently, Zika virus has been detected in the amniotic fluid of pregnant women whose
fetuses were diagnosed with congenital microcephaly [42]. Various eukaryotic viruses, including
adenovirus, CMV, herpes simplex virus, enterovirus, Epstein–Barr virus, respiratory syncytial
virus, and human parvovirus B19, have been detected by targeted PCR in amniotic fluid
obtained via amniocentesis for genetic screening [43,44]. These studies suggest that eukaryotic
viruses can be detected in amniotic fluid without obvious immediate clinical implications for the
infant. Notably, to date, there have been no metagenomic studies defining the in utero virome of
healthy pregnancies. It will be important to characterize the in utero virome and understand its
role in the health of the developing fetus.
Diet
Although it is established that diet has an impact on the gut bacterial microbiome, the role of diet
on the gut virome is not well understood. To investigate this, Minot et al. [45] studied the human
gut virome of six healthy adults over an 8-day period during a dietary intervention in which two
subjects received a high-fat/low-fiber diet, three subjects received a low-fat/high-fiber diet, and
one subject received an ad lib diet. Each individual contained a unique virome that was globally
stable over the 8 days. However, viromes of individuals on the same diet were more similar at the
end of the dietary intervention than they were before the intervention. It is unlikely that phage
populations are predominantly acquired as transients in food because individuals eating the
same food did not have identical viromes. Whether the changes in phage abundance are a result
of changes in abundance of their bacterial hosts or are driven by an independent mechanism
needs to be further evaluated.
Environment
In comparison to the bacterial microbiome, not much is known about what environmental factors
influence the human gut virome. One study has compared the eukaryotic virome in stools of
Trends in Microbiology, October 2016, Vol. 24, No. 10 805
87 children with diarrhea collected from two different locations–Melbourne, Australia and the
Northern Territory, Australia–characterized by distinct environments (a westernized urban set-
ting versus remote communities across a large geographic area) [46]. Diarrhea samples from the
Northern Territory contained more viral families per sample than did diarrhea samples from
Melbourne. Additionally, the families Adenoviridae, Picornaviridae, and Reoviridae were more
common in Northern Territory samples than in those collected in Melbourne. It is possible that
environmental factors such as diet, living conditions, water quality, hygiene and/or socioeco-
nomic status drive the composition of the gut virome. Future studies are needed to determine the
impact of these environmental factors on the gut virome.
Interindividual Variability
While it is recognized that there is high interindividual variability in the gut virome [40,41,45,47–
49], studies of twin pairs have uncovered a unique setting where interindividual virome variability
is limited. During infancy, the gut viromes are more similar between infant twin pairs as compared
to nonrelated infants [40,41]. This is consistent with studies showing frequent transmission of
vaccine-strain rotavirus from a vaccinated infant to their unvaccinated co-twin [50], suggesting
that close contact could be a driver of virome sharing. Gut viromes of infant co-twins were
distinguishable from those of their mother or their older non-twin sibling [40], further arguing that
age-dependent factors are determinants of viral community composition. However, the degree
of genetic influence on the infant virome is largely unknown. In this regard, comparisons between
genetically identical monozygotic twins and dizygotic twins would be particularly informative in
attributing the influence of host genetics on the virome. Interestingly, in infant twin pairs that were
discordant for severe acute malnutrition where one co-twin develops disease and the other co-
twin is healthy, the infant co-twins still had highly similar viromes [40]. Unlike infant twins, adult
twin pairs harbored gut viromes that substantially differed from those of their co-twins or mother
[47]. It is plausible that environmental factors (such as diet, geography, and exposure) may have
greater influence on virome variability with increasing age. Taken together, these studies indicate
that there is high interindividual variability in the virome throughout life, with the exception that
virome interindividual variability is less among infant co-twins.
Dynamic Bacterial Microbiome and Virome in Infancy
A striking hallmark of the infant gut bacterial microbiome and virome is its highly dynamic nature
during early development. This is in contrast to the gut bacterial microbiome and virome in
adults, which are largely stable and resilient to change [36,45,47].
The gut bacterial microbiome during early infancy is characterized by an expansion of, as well as
by sudden and profound shifts in, the community composition [12,18]. Soon after birth, the
bacterial microbiome rapidly switches from predominantly facultative anaerobic bacteria
towards a diverse community of anaerobes [12,24–26,41,51]. These compositional shifts
are mirrored during the early life of premature infants [18], indicating a fundamental progression
associated with natural colonization. The ecology of the bacterial microbiome increases in
richness and diversity towards an adult-like composition by 2–3 years after birth [24,25].
Recently, it has been shown that the Bacteroidetes phyla may even take up to 5 years to
stabilize [52]. Children with severe acute malnutrition have an immature gut bacterial microbiome
configuration compared to that of age-matched individuals, indicating that a delayed micro-
biome maturation has physiological implications [53,54]. Given the role of bacterial interactions in
host immunity and metabolism, it will be important to better understand the long-term impact of
alterations in the bacterial microbiome.
Likewise, the virome is highly dynamic during infant development. During the first months of life,
the early infant gut bacteriophage virome is composed primarily of a rich and diverse community
of bacteriophages, the majority of which derive from the Caudovirales order. The bacteriophage
806 Trends in Microbiology, October 2016, Vol. 24, No. 10
virome subsequently contracts (decreases in richness) and shifts towards a Microviridae-
dominated community over the first 2 years of life [40,41]. Moreover, the timeframe of this
transition approximately parallels the age at which the infant bacterial microbiome approaches a
composition similar to that found in adults [24,25]. While the overall dynamic changes in the
bacteriophage virome might be generalizable across infant development, it is possible that
the specific bacteriophage composition shifts could be heavily influenced by geography and
diet, as shown for their bacterial counterparts.
Enteric eukaryotic viruses, such as members of the Picornaviridae, Adenoviridae, Astroviridae,
Anelloviridae, Reoviridae and Caliciviridae families, have been frequently observed in infants.
However, they are more sporadically distributed over time, with generally limited persistence
during early development [41,55,56]. The epidemiology of eukaryotic viruses could be driven by
a combination of factors such as maternal antibodies, geography, and environmental factors
[46,57,58]. For example, the seasonality of influenza and parechovirus infections is well docu-
mented [59,60].
The dynamic nature of the microbiome during early infancy is significant for at least two reasons.
First, steps in the progression of the microbiome could represent important developmental
milestones that correlate with functional development of the host immune system and metabo-
lism. This parallels the motor, language, and emotional developmental milestones of infants.
Second, early infancy may present a unique opportunity in life where the microbiome is alterable.
One of the challenges with microbiome-based interventions is the resilience of the adult bacterial
microbiome to changes [12,36]. Recent studies indicate that the first 100 days of life is a unique
window where the gut microbiome is most influential on immune development and disease
outcome [61–63]. Collectively, this indicates the importance of the dynamic bacterial micro-
biome and virome during early infant development.
Interactions between the Virome and Bacterial Microbiome
One of the most significant findings that emerged from recent microbiome studies is that
transkingdom interactions between the viruses and bacteria can influence health and disease
of the host [64,65]. Intestinal antiviral immunity depends on Gram-negative bacterial signaling
[66], and conversely, enteric viral infection protects against intestinal damage and pathogenic
bacteria [67]. Gut bacterial microbiota can also enhance the replication of enteric viruses such as
poliovirus, mouse mammary tumor virus, mouse norovirus, reovirus, and rotavirus [67–72].
Bacteriophages may also alter the bacterial microbiome structure through predator–prey
relationships [49,73]. Bacteriophage predation has been observed in the infant gut between
bifidobacteria species and bifidoprophages [74]. While the classical predator–prey model
predicts that prey (bacteria) oscillations precede predator (bacteriophage) oscillations, bacteri-
ophage–bacteria interactions during early infant development begin with the opposite dynamics.
Early-life bacterial colonization is correlated with a contraction in the bacteriophage community
[41]. Notably, such reverse cycles are still consistent with predator–prey community dynamics
[75]. It is tempting to speculate that the reverse predator–prey dynamics suggests that bacter-
iophages serve a protective role in the vacant ecological niche of the neonatal gut at birth, by
selecting against aberrant bacterial colonization and choreographing the acquisition of beneficial
bacteria. Taken together, these studies indicate that transkingdom interplay between viruses
and bacteria adds a new layer of complexity to host-microbiome homeostasis.
Developing Bacterial Microbiome and Virome and Disease Associations
There is growing evidence that the initial bacterial microbiome and resulting immune program-
ming have a long-lasting effect on the risk for disease later in life. Here we highlight a few studies
that support the role of the early gut bacterial microbiome in outcomes such as immune function,
Trends in Microbiology, October 2016, Vol. 24, No. 10 807
including asthma and allergy, growth, including obesity and malnutrition, and neurodevelop- Outstanding Questions
fl
mental disorders such as autism-spectrum disorder. Do animal models accurately re ect
human infant bacterial microbiome
and virome development?
The development of atopic diseases is a complex interaction of host and environmental factors,
and our understanding of the importance of the gut bacterial microbiome in this process is
Is the infant gut virome vertically trans-
growing. A small study found that meconium dominated by lactic acid bacteria was associated ferred from the mother?
with asthma-related conditions in the infant [76]. Furthermore, Arrieta et al. [61] showed that
infants at risk for asthma had a transient bacterial microbiome shift driven by a decreased relative Do alterations in the infant gut virome
lead to disease later in life?
abundance of four bacterial genera during the first 100 days of life. The adult progeny of germ-
free mice inoculated with these four bacterial taxa had amelioration of their airway inflammation.
Can the infant bacterial microbiome be
Additionally, a longitudinal study of infants with allergic and nonallergic parents showed that
altered by bacteriophages as thera-
nonallergic children acquired lactobacilli more frequently early in life than did children with peutic treatments?
allergies, regardless of their parents allergy status [77].
What factors influence the develop-
ment of the infant virome (e.g., mode
Certainly the function and composition of the bacterial microbiome plays a role in the host's
of delivery, gestational age, etc.)?
ability to extract and use energy from their diet. Changes in the bacterial microbiome have been
associated with both extremes of growth, including obesity and malnutrition [53,78]. A longi-
tudinal study of term or near-term infants in Singapore showed that an earlier acquisition of an
anaerobic microbiome dominated by Bifidobacterium and Collinsella compared to Enterobac-
teriaceae and Streptococcus within the first 6 months of life was associated with normal
adiposity at 18 months of age [20]. Additionally, a study of children in Bangladesh demonstrated
that children with severe acute malnutrition had a relative microbiome immaturity when com-
pared to children with normal growth [54]. These findings were recently confirmed in a study of
Malawian children [79]. Furthermore, gnotobiotic mice that received stool transplanted from
undernourished children grew poorly compared to mice receiving a transplant from healthy
children [79]. These studies suggest that the nutritional status of children might be modifiable
through manipulation of the gut bacterial microbiome.
It is hypothesized that gut barrier integrity may be impaired when the gut bacterial microbiome is
disturbed and leaves the host vulnerable to diseases outside of the gastrointestinal tract such as
autism-spectrum disorder [80]. Another potential role for the bacterial microbiome in autism-
spectrum disorder is through neuroactive metabolites produced by the bacteria, which can
cross the blood–brain barrier [80]. Some studies have shown an abnormal composition of the
gut bacterial microbiome in children with autism-spectrum disorder while others have shown no
difference [81]. More research is needed to assess whether there is a role of the bacterial
microbiome in autism-spectrum disorders.
While we are now beginning to appreciate the role of the developing gut bacterial microbiome in
human health, how the developing infant gut virome influences later life is not well studied.
Recently, a study of twins–some of which were discordant for severe acute malnutrition–showed
that the DNA virome is perturbed in both the twin with malnutrition and the one with normal
growth [40]. This suggests that the virome is associated with, but not necessarily a cause of,
severe acute malnutrition. Certainly, future studies evaluating the role of the developing gut
virome on disease outcomes are needed.
Concluding Remarks
It is evident that the gut microbiome plays a major role not only in natural human developmental
but also in contributing to a variety of diseases. A challenge of future studies is to transition these
stark observations towards a mechanistic understanding through functional experiments such
as animal models that recapitulate aspects of early development [82] (see Outstanding Ques-
tions). Further, much less is known about the functions of or influences on the infant gut virome in
comparison to the bacterial microbiome. This is particularly evident in the gap of knowledge of
808 Trends in Microbiology, October 2016, Vol. 24, No. 10
mother–infant virome transmission. Nonetheless, it is clear that future studies of the infant virome
and bacterial microbiome have the potential to develop new therapeutic interventions [16].
Acknowledgments
We thank Dr Phillip Tarr for comments on the manuscript. LRH is supported by Children's Discovery Institute (MD-FR-2013-
292). ESL is an Eli & Edythe Broad Fellow of the Life Sciences Research Foundation.
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