Desarrollo de Inmunidad y Microbiota - Collado 2018
Desarrollo de Inmunidad y Microbiota - Collado 2018
Desarrollo de Inmunidad y Microbiota - Collado 2018
sciences
Review
Gut Microbiota and Mucosal Immunity in the Neonate
Majda Dzidic 1,2,† , Alba Boix-Amorós 1,2,† ID
, Marta Selma-Royo 1,† , Alex Mira 2, * and
Maria Carmen Collado 1, * ID
1 Department of Biotechnology, Institute of Agrochemistry and Food Technology-Spanish National Research
Council (IATA-CSIC), 46980 Valencia, Spain; majda.dzidic@iata.csic.es (M.D.); albaboix@iata.csic.es (A.B.-A.);
mselma@iata.csic.es (M.S.-R.)
2 Department of Health and Genomics. Center for Advanced Research in Public Health, FISABIO Foundation,
46020 Valencia, Spain
* Correspondence: mira_ale@gva.es (A.M.); mcolam@iata.csic.es (M.C.C.);
Tel.: +34-961-925-925 (A.M.); +34-963-900-022 (M.C.C.)
† These authors contributed equally in this paper.
Received: 8 June 2018; Accepted: 12 July 2018; Published: 17 July 2018
Abstract: Gut microbiota colonization is a complex, dynamic, and step-wise process that is in
constant development during the first years of life. This microbial settlement occurs in parallel with
the maturation of the immune system, and alterations during this period, due to environmental and
host factors, are considered to be potential determinants of health-outcomes later in life. Given that
host–microbe interactions are mediated by the immune system response, it is important to understand
the close relationship between immunity and the microbiota during birth, lactation, and early infancy.
This work summarizes the evidence to date on early gut microbiota colonization, and how it influences
the maturation of the infant immune system and health during the first 1000 days of life. This review
will also address the influence of perinatal antibiotic intake and the importance of delivery mode and
breastfeeding for an appropriate development of gut immunity.
1. Introduction
Epidemiological studies highlight the relevance of the period from conception to early life in
the physiological and structural patterns of infant development, affecting their potential “health
programming”. The fetus adapts to the intrauterine environment, being able to alter its metabolism in
response to external stimuli. The physiological and metabolic adaptations that the fetus undergoes in
response to those stimuli could produce permanent changes in the host, which may lead to a higher
risk of developing diseases and/or disorders, such as obesity, allergies, diabetes, or cardiovascular
diseases, in adult life [1].
The first 1000 days after conception (including the pregnancy period and the first two years of
life), which are considered a “window of opportunity”, are crucial for the development and health of
the future adult, as well as key to the establishment of the intestinal microbiota and immune system
maturation. The physiological and immune development of the infant and the establishment of their
microbiota occur in parallel throughout this short space of time. This microbiota plays a central role in
health, intervening in key host metabolic and immunological functions.
DEFINITIONS
Microbiota: the microbial community in a specific niche/environment.
Microbiome: the total genomic repertoire of a microbial community (microbiota).
with term deliveries and higher birth weight [34]. Indeed, the microbiota could have an impact on the
risk for preterm delivery, as periodontal treatment during pregnancy reduced the rate of premature
birth from 10% to 1.8% [35]. Many studies have focused on the role of the maternal vaginal [36] and
oral microbiota [37], or even the placental microbiota, in preterm delivery [38,39]. However, these
studies do not adress the possible immune mechanisms involved in premature delivery, which could
be mediated by pro-inflammatory molecules from a microbial source or by direct exposure to microbial
antigens due to bacterial translocation from bleeding gingiva, triggering an autoimmune response that
could lead to a premature delivery. Nevertheless, it is still under debate whether the microbes could
really reach the gestational cavity and, if so, whether they may have any beneficial effects for pregnancy
outcomes and future health status for neonates. Indeed, most of these studies have been performed
using culture-independent techniques of which the results are commonly affected by contamination.
However, a few studies have isolated cultivable obligated anaerobes from meconium samples [17],
which are unlikely to be a contamination during delivery. Furthermore, metabolically active bacteria
in the meconium have also been shown by RNA sequencing analysis [40]. Despite these recent results,
more studies about the presence of bacteria in the meconium, placenta and amniotic fluid are needed
in order to confirm the hypothesis of the in utero colonization.
3. Perinatal Factors Influencing Infant Microbiota Development and Immune System Maturation
Neonatal colonization is a fragile, dynamic, and step-wise process and may be affected by several
maternal and neonatal factors (Figure 1). It has been reported that the effect of perinatal factors,
including the mode of delivery, breastfeeding, and antibiotics use early in life, could influence the
microbiota composition during a short period of time [41–46]. For instance, Lactobacillus, Bifidobacterium,
Bacteroides, Clostridium, and Streptococcus, which are commonly influenced by the above-mentioned
factors, have been shown to affect the regulatory T cells activity in mice models and cell cultures [47,48].
Thus, the studies considering the effect of specific bacteria on naïve T cells differentiation [41,49] or
the influence of bacterial antigens in the T helper cells (Th) activity [50] have become crucial to assess
the impact of those factors in the neonate microbiota. Although, the alterations of the microbiota due
to perinatal and postnatal factors appear not to be maintained after neonates acquire an adult-type
microbiota, at around 3–5 years of age, these coordinated events could have long-lasting effects on
how the microbial community would influence the host immune responses [51].
location, diet, and lifestyle upon studying the microbiota composition, because the effect observed by
a specific factor could vary depending on the country where the study has been performed.
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in the colon [84,85]. Antibiotics also affected diversity, motility,
and toll-like receptor (TLR) expression in mice colons [86]. Furthermore, antibiotics treatment can
modify the homeostasis between bacterial, fungal, and viral microbiota components (50). For example,
antibiotics can cause the overgrowth of fungal species, particularly Candida albicans, with the induction
1. Introduction
of mast cells and inflammatory interleukin (IL) expression, such as IL-5 or IL-13 [87].
Immune stem cell- migration Increased Tregs levels --> limited T cell and
and expansion antibody production
Th2
Th1/Th2
Th1 balance
antigens (including polysaccharide A and LPS) and short-chain fatty acids would be key inthe specific
microbial species colonization and its influence on driving normal immune mucosal and systemic
maturation [89,91]. It is believed that the pioneer microbiota, consisting of Firmicutes, Bacteroidetes,
Enterobacteriaceae, Veillonella, and especially Bifidobacterium [91–94], is responsible for the initial
education of the evolving immune system, as it provides a favorable environment for further microbial
settlement, including the production of an anaerobic milieu, specific compounds, and protection
from the systemic immune system [92]. The early intestinal microbiota is characterized by low
diversity and a relative dominance of the phyla Proteobacteria and Actinobacteria. Subsequently, the
microbiota becomes more diverse, thus resembling an adult composition by 2–5 years of age [18].
However, the microbial community development and species interactions seem to be influenced by
the order and timing of species immigration to the host tissue [51]. For instance, changes in the
gut microbiota during the first months of life, such as shifting from facultative anaerobes to strict
lactic acid-producing anaerobes, might partially be a consequence of the infant’s history exposure
and the patterns of colonization from their mother [62,95]. These events suggest that a priority effect
of microbial colonization may have long-lasting consequences during the early stages of the gut
microbiota development, although the importance for the host health remains unexplored [51].
The settlement of bacteria on the surface of the gut can protect against pathogen penetration
in a process known as ‘colonization resistance’, which is of great importance for the prevention
of pathogen-induced gastrointestinal inflammation [96]. Commensal bacteria have been shown to
control potential pathogen infections by competition for nutrients, adhesion sites, pH, receptors, and
production of specific metabolites and antimicrobial peptides [97] by creating a hostile environment for
pathogen survival and establishment (for instance, lactobacilli is able to reduce local pH and produce
some anti-pathogenic compounds in the vagina).
of host–commensal microorganism interactions, which are essential for tolerant immune cells of
the gut, limiting the steady-state inflammation, as well as directing appropriate immune responses
against pathogens and commensal bacteria [101,102]. IEC-derived IL-25 cytokine, thymic stromal
lymphopoietin, or retinoic acid together with transforming growth factor-β are important for the
priming of adaptive immune cell responses and homeostasis, as well as for the regulation of innate
effector responses [101].
have innate-like recognition characteristics that may assist the adaptation to a broad range of the
microbiota and their antigens/metabolites encountered at the mucosal surface of the gut [122].
Interestingly, the pattern of bacterial recognition by IgA in infant feces has been shown to be
aberrant during the first months of life in children that develop allergies or asthma years later. From an
applied point of view, this suggests that the IgA coating pattern with bacteria can be used as an early
diagnostic marker of allergy risk [123].
Figure 2. Selected microbial and immunological factors in breast milk (BM). sIg: secretory immunoglobulin,
IL: interleukin,
Figure TGF:microbial
2. Selected transforming
andgrowth factor, LPS: factors
immunological lipopolysaccharide.
in breast milk (BM). sIg: secretory
immunoglobulin, IL: interleukin, TGF: transforming growth factor, LPS: lipopolysaccharide.
6.1. Breast Milk Microbiota
6.1. Breast Milk Microbiota
Staphylococcus, Streptococcus, and Propionibacterium are universally predominant in BM [149], and
typical probiotic genera, such as Bifidobacterium and Lactobacillus [150–153], are commonly detected
Staphylococcus, Streptococcus, and Propionibacterium are universally predominant in BM [149], and
and isolated from BM. Other lactic acid bacteria, such as Lactococcus, Weisella and Enterococcus, as well
typical probiotic genera, such as Bifidobacterium and Lactobacillus [150–153], are commonly detected
as typical oral inhabitants, such as Veillonella and Prevotella, and skin bacteria, such as Propionibacterium,
and isolated from BM. Other lactic acid bacteria, such as Lactococcus, Weisella and Enterococcus, as well
Corynebacterium, and so on, are frequently detected in BM samples [154–156].
as typical oral inhabitants, such as Veillonella and Prevotella, and skin bacteria, such as
In addition, shared species between maternal feces, BM, and infant feces have been identified [157].
Propionibacterium, Corynebacterium, and so on, are frequently detected in BM samples [154–156].
Although information about the function of BM bacteria is scarce, several roles have been associated
In addition, shared species between maternal feces, BM, and infant feces have been identified
with them, including seeding colonizers to the infant microbiota, facilitating infant digestion,
[157]. Although information about the function of BM bacteria is scarce, several roles have been
offering protection by competing with pathogens, and improving intestinal barrier functions by
associated with them, including seeding colonizers to the infant microbiota, facilitating infant
enhancing mucine production and reducing intestinal permeability [141]. Breast milk microbiota and
digestion, offering protection by competing with pathogens, and improving intestinal barrier
other milk molecular components likely help to educate the infant’s immune system. It promotes
functions by enhancing mucine production and reducing intestinal permeability [141]. Breast milk
an adequate intestinal immune homeostasis that initially influences a shift from an intrauterine
microbiota and other milk molecular components likely help to educate the infant’s immune system.
Th2 predominant to a Th1/Th2 balanced response and a stimulation of T-regulatory cells by BM-specific
It promotes an adequate intestinal immune homeostasis that initially influences a shift from an
microorganisms [158]. Furthermore, some strains isolated from BM have shown an ability to modulate
intrauterine Th2 predominant to a Th1/Th2 balanced response and a stimulation of T-regulatory cells
both natural and acquired immunity [152,153]. Recently, several yeasts and other fungi have been
by BM-specific microorganisms [158]. Furthermore, some strains isolated from BM have shown an
detected in BM samples from healthy mothers, including Malassezia, Candida, Saccharomyces, and
ability to modulate both natural and acquired immunity [152,153]. Recently, several yeasts and other
Rhodotorula, among others. This finding suggests that BM could be not only participating in shaping the
fungi have been detected in BM samples from healthy mothers, including Malassezia, Candida,
infant microbiome, but also the infant mycobiome [159]. Future research is needed to fully understand
Saccharomyces, and Rhodotorula, among others. This finding suggests that BM could be not only
the role of BM microbiota in the infant, but the increasing evidence reinforces its importance on infants’
participating in shaping the infant microbiome, but also the infant mycobiome [159]. Future research
protection and training of the immune system during the first months of life.
is needed to fully understand the role of BM microbiota in the infant, but the increasing evidence
reinforces
6.2. Humanits importance on infants’ protection and training of the immune system during the first
Milk Oligosaccharides
months of life.
One of the major protective roles of BM resides on human milk oligosaccharides (HMOs), which
6.2. Human Milkcarbohydrates
are complex present in high concentrations in milk (5–20 g/L) [160]. Human milk
Oligosaccharides
oligosaccharides are responsible for promoting the growth of beneficial commensal bacteria, such as
One of the major protective roles of BM resides on human milk oligosaccharides (HMOs), which
Bifidobacterium and Lactobacillus, which is reflected in differences observed in the intestinal microbiota of
are complex carbohydrates present in high concentrations in milk (5–20 g/L) [160]. Human milk
breast-fed and formula-fed infants [148,161]. Human milk oligosaccharides are essentially indigestible
oligosaccharides are responsible for promoting the growth of beneficial commensal bacteria, such as
by the human gut and reach the colon where they serve as substrate for fermentation to bacteria, such
Bifidobacterium and Lactobacillus, which is reflected in differences observed in the intestinal microbiota
as bifidobacteria and lactobacilli and also Bacteroides and Staphylococcus, playing an important role in
of breast-fed and formula-fed infants [148,161]. Human milk oligosaccharides are essentially
shaping the infant microbiome [150,151]. This fermentation results in sub-products, such as lactate
indigestible by the human gut and reach the colon where they serve as substrate for fermentation to
and Short-chain fatty acids (SCFAs), including acetate and butyrate, and other metabolites. SCFAs also
bacteria, such as bifidobacteria and lactobacilli and also Bacteroides and Staphylococcus, playing an
important role in shaping the infant microbiome [150,151]. This fermentation results in sub-products,
Med. Sci. 2018, 6, 56 10 of 23
represent the main energy source for colonocytes and provide important immune protective functions.
For example, acetate stimulates the proliferation of Treg cells in the lamina propria, regulating intestinal
homeostasis [162], and several immunological functions for butyrate have been reported, many of
them associated with potent regulatory effects on gene expression [163]. Importantly, specific HMOs
can act as homologous to infant gut cell receptors, inhibiting the binding of pathogens to the intestinal
epithelium and therefore offering protection against infections [160,164].
6.5. Cytokines
Breast milk contains several cytokines at physiologically relevant concentrations, including
Interleukin (IL)-1β, IL-6, IL-8, and IL-10, especially in colostrum, which regulate and modulate
the immune system and inflammatory responses [182]. Interleukin 10, a key immunoregulatory
and anti-inflammatory cytokine, has been shown to inhibit blood lymphocyte proliferation [182].
Mutations in the encoding genes of the IL-10 receptor have been observed in infants developing
early-onset colitis, resulting in hyperinflammation of the intestine [183]. Similarly, mice with
a disrupted IL-10 gene spontaneously developed enterocolitis after weaning, and the condition
was associated with unpaired cytokine production by CD4+ Th1-like T cells, as well as activated
macrophages [184]. Intestinal inflammation could be prevented by parenteral administration of the
IL-10, thus suggesting a crucial role of BM IL-10 on the infant intestinal homeostasis and prevention
of exacerbated response to foreign antigens. Transforming growth factor (TGF-β) is associated with
the regulation of T-cell activation, but it also affects B cells, natural killer (NK) cells, macrophages,
and dendritic cells [180]. TGF-β can reduce inflammation by decreasing pro-inflammatory cytokines
production while favoring IgA production, thus increasing intestinal immunity [180]. Infants fed with
BM containing high concentrations of TGF-β, have been associated with lower risk of developing
atopic diseases and wheezing [185,186].
7. Concluding Remarks
The maturation of the immune system is accomplished through bidirectional interactions where
the gut microbiota directs the development of the immune system, while the host immune system
shapes the establishment of the gut microbiota. Even though current studies are attempting to associate
specific microbes to unique immunological states, it is worth remembering that the microbiome is
a highly dynamic, diversified, and complex human organ, where all the composing microbes are
expressing a vast number of potential ligands and metabolites. Under normal homeostatic conditions,
both inflammatory and regulatory features are highly balanced, thus leading to the establishment of
stable tissue immunity and limited inflammation. Hence, upon alterations within the microbiota that
may cause an inflammatory state, it is unlikely that the outcome observed is due to a single microbial
product, but rather a result from a shifted balance state of an entire community.
Several prenatal and perinatal factors, including the mode of delivery, antibiotics consumption,
diet, and other environmental factors, may influence the microbial colonization of the infant and
in turn its immune system maturation. Here, breast milk plays an essential role, guiding a normal
microbiome development in the infant through transference of prebiotic compounds that support
the colonization of beneficial bacteria and antimicrobial components that protect the infant against
infections. Breast milk microbiota should also be considered as an important source of microorganisms
to the infant microbiomes and as part of microbial tolerance and immune training in the child.
In addition, BM contains several bioactive and immunomodulatory compounds, which together
with immune cells and microorganisms support the infant’s protection when its immune system is
still immature (Figure 3). Most of the existing literature is focused on the role of bacteria, but more
studies need to elucidate the importance of archaea, fungi, and non-pathogenic viruses that also may
be important for early gut immunity maturation. Finally, the molecular mechanisms involved in the
interactions between early life microbiota and the immune system are still to be clarified.
Med. Sci. 2018, 6, 56 13 of 23
Figure 3. Key factors influencing microbiota development and maturation of the immune system in early life. BM: breast milk; and HMO: human milk oligosaccharides.
Med. Sci. 2018, 6, 56 14 of 23
Funding: The authors would like to acknowledge the European Research Council (ERC) under the European
Union’s Horizon 2020 Research and Innovation Programme (ERC Starting Grant, project no. 639226) and the grants
AGL2015-707487-P and BIO2015-68711-R from the Spanish Ministerio de Economía, Industria y Competitividad
(MINECO). MSR would like to acknowledge the support from the Ayudas para la Contratación de Personal
Investigador en Formación (ACIF) program of Generalitat Valenciana with the European Social Fund (ESF).
Conflicts of Interest: The authors declare no conflict of interest.
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