Role of Gut Microbiota in Early Infant Development

REVIEW
Role of Gut Microbiota in Early Infant Development
R Wall1,2,3, R.P Ross1,2, C.A Ryan4, S Hussey4, B Murphy4, G.F Fitzgerald1,3
and C Stanton1,2
1Alimentary Pharmabiotic Centre (APC), Co. Cork, Ireland. 2Teagasc, Moorepark Food Research
Centre, Fermoy, Co. Cork, Ireland. 3University College Cork, National University of Ireland, Ireland.
4Department of Paediatrics and Child Health, University College Cork, Ireland.
Abstract: Early colonization of the infant gastrointestinal tract is crucial for the overall health of the infant, and establishment
and maintenance of non-pathogenic intestinal microbiota may reduce several neonatal infl ammatory conditions. Much effort
has therefore been devoted to manipulation of the composition of the microbiota through 1) the role of early infant nutrition,
particularly breast milk, and supplementation of infant formula with prebiotics that positively infl uence the enteric microbiota
by selectively promoting growth of benefi cial bacteria and 2) oral administration of probiotic bacteria which when administered
in adequate amounts confer a health benefi t on the host. While the complex microbiota of the adult is diffi cult to change in
the long-term, there is greater impact of the diet on infant microbiota as this is not as stable as in adults. Decreasing excessive
use of antibiotics and increasing the use of pre- and probiotics have shown to be benefi cial in the prevention of several
important infant diseases such as necrotizing enterocolitis and atopic eczema as well as improvement of short and long-term
health. This review addresses how the composition of the gut microbiota becomes established in early life, its relevance to
infant health, and dietary means by which it can be manipulated.
Keywords: infant, gut microbiota, colonization, infant health, probiotics, prebiotics
Introduction
The neonatal period is crucial for intestinal colonization, and the processes involved in the establishment
of microbial populations are complex and involve both microbial succession as well as interactions
between the infant and the microbes in the different regions of the gut.
However, there are confl icting reports in the literature regarding the composition of the neonatal
gastrointestinal microbiota and the factors that shape it. The gastrointestinal tract (GIT) of the fetus is
sterile but becomes rapidly colonized in the early days of life, infl uenced by factors such as the mode
of delivery, the maternal microbiota, milk source and the surrounding environment.1–5 Changes in the
colonization pattern occur up to two years of age, when the microbiota stabilizes and resembles that of
adulthood. When established, the adult gut contains trillions of microbes with a collective genome that
outnumbers the human genome by up to 1000-fold.6 Emerging evidence points to a dynamic and
generally favorable, symbiotic relationship between humans and their enteric microbiota. The diverse
bacterial species within this ecosystem each contain a battery of enzymes capable of performing a
myriad of different functions, ranging from transformation of substances present in the gut (to less or
more toxic compounds), the production of antimicrobial substances active against pathogenic bacteria
and stimulation of the immune system.7,8 Moreover, it has been demonstrated that some commensals
within the enteric microbiota are able to produce a range of bioactive fatty acids and metabolites such
as conjugated linoleic acid (CLA), short chain fatty acids (SCFA) and gamma-amino butyric acid
(GABA) which have shown great potential in the treatment of lifestyle diseases including cancer, obesity
and cardiovascular disease.9–13 While species of bacteria are found in the acidic conditions of the
stomach, the bacterial density progressively increases distally in the intestine.14 Anaerobic and aerobic
genera of bacteria inhabit the GIT,14,15 though the majority are strict anaerobes16 with Bifi dobacterium,
Clostridium, Bacteroides, Lactobacillus and Eubacterium being among the most commonly found
enteric bacteria.15,16
Since colonization with a non-pathogenic microbiota is essential to infant health and probably also
has an effect on overall health status in later life, it is important to understand how the composition of
Correspondence: Dr. Catherine Stanton, Teagasc Moorepark, Biotechnology Centre, Fermoy, Co. Cork, Ireland.
Tel: 00353 (0) 2542222; Fax: 00353 (0) 2542340; Email: catherine.stanton@teagasc.ie
Copyright in this article, its metadata, and any supplementary data is held by its author or authors. It is published under the
Creative Commons Attribution By licence. For further information go to: http://creativecommons.org/licenses/by/3.0/.
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Wall et al
this gut microbial ecosystem is established. delay in intestinal colonization following Caesarean
Moreover, given the importance of the establishment section on the development of the gut-associated
of a healthy GIT in early life, different strategies immune system. However, the balance between
have evolved to manipulate the microbiota Bifi dobacterium and Clostridium species is reported
particularly by using prebiotic supplementation to affect immuno-physiological development, with
and probiotic administration.17,18
a heightened risk for disease associated with fewer
bifi dobacteria and more clostridia.27,28
The composition of the enteric microbiota of
The Development of the Gut
infants is strongly infl uenced by diet. Several
Microbiota in the Infant
studies have reported that bifi dobacteria and other
The predominant sources of microbes for the initial lactic acid bacteria (LAB) dominate the microbiota
colonization of the GIT following birth are the of breast-fed infants, while formula-feeding
maternal microbiota, especially during vaginal generally results in a more diverse microbial
delivery, and the infant’s diet (breast versus for-
population, including bifi dobacteria, Bacteroides,
mula feeding). Other factors that infl uence the clostridia and streptococci and higher numbers of
composition of the enteric microbiota of infants facultative anaerobic bacteria, such as staphylococci,
are the environment during birth, gestational age, streptococci and Enterobacteriaceae.1–3,29,30 How-
hygiene measures and antibiotic treatment.3 ever, some recent studies have demonstrated that
Microbes have also been detected in amniotic fl uid bifi dobacteria only occur in a small fraction of breast-
and placenta from mothers and in the umbilical fed infants or are not numerically dominant4,31 and
cord blood of healthy neonates,19 suggesting that that coagulase-negative staphylococci are the pre-
these bacteria may also be part of the fi rst coloniz-
dominant species in breast-fed infants.32 In other
ers in the GIT of the newborn.
studies, different species of bifi dobacteria have
Mode of delivery is a key factor that shapes the been shown to appear as early as four days of age
developing infant microbiota3–5 and in this respect, in full-term breast-fed infants, and become the
infants delivered by Caesarean section have been predominant microorganism by day six,33–35
reported to harbor an enteric microbiota that differs exceeding enterobacteria by a ratio of 1000:1.36
from vaginally delivered infants, both in the timing Furthermore, breast-fed infants generally harbor
of colonization and in composition.3–5,20,21 Vaginally fewer species that are liable to be pathogenic, such
born infants are initially colonized by fecal and as E. coli, C. diffi cile and species of the B. fragilis-
vaginal bacteria from the mother,21–24 whereas group.3 While formula-fed infants are also known
infants born via Caesarean section are exposed to harbor bifi dobacteria in the GIT, the numbers
initially to bacteria originating from the hospital are reported to be lower than in breast-fed infants
environment and health-care workers.23,21,25 It has of the same age,37 in some studies as low as one-
been reported that approximately one quarter of tenth of that encountered in breast-fed infants.36,38
infants acquire vaginal lactobacilli from their moth-
Moreover, the incidence of C. diffi cile is reportedly
ers at birth.24 The microbiota of infants born by higher in formula-fed infants compared with
Caesarean section is characterized by lower num-
breast-fed infants.38–40
bers of strict anaerobes such as Bacteroides fragilis
The dominance of bifi dobacteria in breast-fed
and bifi dobacteria compared to vaginally delivered infants is attributable to the composition of human
infants.3,20,21,26 The colonization of these infants is milk, which is rich in bifi dogenic factors, such as
also often delayed, and it may take up to one month oligosaccarides (i.e. lacto-N-tetraose and lacto-N-
before similar numbers of bacteria are present neotetraose).41 Oligosaccharides are carbohydrates
compared with vaginally delivered infants.21 More-
made up of three to nine monosaccharide units42 and
over, the prevalence and numbers of Clostridium are quantitatively the third component of human
diffi cile and Escherichia coli are generally higher milk, after lactose and lipids. A peculiar characteristic
in infants born by Caesarean section.3 Compared of oligosaccharides is that their monosaccharides
with vaginally born infants, the median counts of are bound by specifi c bonds which are resistant to
B. fragilis group bacteria and C. diffi cile were human intestinal digestive enzymes and therefore
shown to be ∼100-fold lower and ∼100-fold higher, act as substrates for fermentation in the distal gut,
respectively, for infants born via Caesarean where they promote the growth of bifi dobacteria,
section.3 It is diffi cult to assess the infl uence of the i.e. natural prebiotics.43 Oligosaccharide concentration
46
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Role of gut microbiota in early infant development
of human milk differs at different stage of lactation, development of the immune system in infants.66,67
with the highest concentration found in early Moro et al.67 demonstrated a benefi cial effect of
lactation. For example, on day four of lactation, prebiotics on the development of atopic dermatitis
human milk contained 2 g/100 ml oligosaccharides, in a high-risk population of infants. Following
which declined 20% and 40% by 30 and 120 days supplementation of infant formula with 0.8 g/100 ml
of lactation, respectively.44 Breast milk is also a GOS/FOS (90% GOS and 10% FOS) for six
source of bacteria and contains up to 109 microbes/L months, the numbers of infants that developed
in healthy mothers.45 The most frequently encountered atopic dermatitis was only 9.8%, compared with
bacterial groups include staphylococci, streptococci, 23.1% of infants in the control group. In addition,
corynebacteria, lactobacilli, micrococci, propioni-
infants receiving the prebiotic supplement harbored
bacteria and bifi dobacteria. These bacteria originate higher numbers of fecal bifi dobacteria compared
from the nipple and surrounding skin as well as the with the control group.67
milk ducts in the breast.46,47 Moreover, it has been
The developmental aspect of the intestinal
demonstrated that human breast milk is a signifi cant bacterial colonization of preterm infants (infants
source of lactobacilli and bifi dobacteria for the infant born before 37 weeks of gestation) is reported to
GIT.48–50 Human breast milk is the preferred choice differ from that of full-term infants. Colonization
for infant nutrition51 and numerous benefi cial effects of benefi cial bacteria such as lactobacilli and bifi -
of breast milk have been demonstrated for both term dobacteria is often delayed in preterm infants and
and preterm infants, including neurobehavioral and these are only found in low numbers during the fi rst
cognitive development52–56 and decreased rates of few weeks of life, whereas colonization of poten-
infection.57–59
tially pathogenic bacteria such as E. coli, clostridia
In contrast to human milk, oligosaccharides are and staphylococci occurs such that these are found
virtually absent from bovine milk and thus, cows in high numbers.68–71 Schwiertz et al.72 studied the
milk-based infant formula. This has led to modifi -
establishment of the enteric microbiota in the fi rst
cation of infant formula using different oligosac-
few weeks of life of preterm infants by analyzing
charides (prebiotics) in order to improve the gut the 16S rRNA diversity in fecal samples using
microbiota composition, to more closely resemble PCR-denaturing gradient gel electrophoresis (PCR-
that obtained via breast-feeding. Prebiotics are DGGE). Twenty nine preterm infants, hospitalized
defi ned as “selectively fermented ingredients that in a neonatal intensive care unit and fi fteen breast-
allow specifi c changes, both in the composition fed, full-term infants were included in the study.
and/or activity in the gastrointestinal microbiota E. coli, Enterococcus sp. and Klebsiella pneumoniae
and that confer benefi ts on host well-being and were most commonly found in the fecal samples
health.”60 Thus, the role of prebiotics is to of all preterm infants, whereas for breast-fed full-
selectively stimulate the growth and/or activity of term infants, bifi dobacteria comprised the majority
bifi dobacteria and lactobacilli in the GIT. However, of the species present. Furthermore, in contrast to
for a food ingredient to be classifi ed as prebiotic, preterm infants, the genetic profi les were more
it must neither be hydrolyzed nor absorbed in the diverse in fecal samples of full-term infants,
GIT, be a selective substrate for one or a few indicative of a higher diversity of the bacterial com-
benefi cial bacteria in the colon and consequently munity. The profi les of the preterm infants became
be able to alter the enteric microbiota towards a more similar to each other over four weeks (the
healthier composition.17 Oligosaccharides that similarity values increased from 0% to 80% in
have been used as prebiotics in infant formula the preterm infants compared to 18.1% to 57.4%
include fructo-oligosaccharides (FOS), inulin, in the full-term infants), indicating that all preterm
gluco-oligosaccharides, galacto-oligosaccharides infants harbored a similar bacterial composition,
(GOS), isomalto-oligosaccharides and xylo-
regardless of birth weight, feeding regime, and
oligosaccharides.61 Indeed, numerous studies have antibiotic therapy.72 A Japanese study reported that
demonstrated that ingestion of infant formula gut colonization in breast-fed preterm infants was
containing prebiotics results in increased numbers characterized by high initial numbers of enterobac-
of bifi dobacteria and lactobacilli, over formula teria and streptococci, while bifi dobacteria appeared
without prebiotics, and also decreased numbers of late, at 11 days of age, and became predominant
E. coli, enterococci and clostridia.62–65 Moreover, only at 19 days of age, in contrast to full-term
prebiotics have been demonstrated to alter the infants who were colonized at four days of age.70
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Wall et al
As preterm infants often require intensive care Table 1. Bacteria within different regions of the adult
treatment with an increased risk of serious human GIT.80
infections, insight in the development of the Predominant genera of bacteria (colony forming
intestinal colonization of these infants is important, units/mL or/g)
especially since it is hypothesized that an inappro-
Stomach and
Jejunum and
Colon
priate colonization of the premature intestine may duodenum
ileum
play a role in the development of necrotizing
enterocolitis (NEC).73 Since preterm infants gener-
101–103
104–108
1010–1012
ally experience intensive care treatment and are Lactobacilli
Lactobacilli
Bacteroides
often treated with broad spectrum antibiotics in the Streptococci
Enterobacteria
Bifi dobacteria
Yeast
Streptococci
Streptococci
fi rst days of life, this could infl uence intestinal
Bacteroides
Fusobacteria
colonization. Antibiotic administration results in
Bifi dobacteria
Enterobacteria
suppression of all anaerobic bacteria, with the
Fusobacteria
Clostridia
exception of clostridia, which remain at detectable
Veilonella
levels, and increased numbers of Klebsiella,
Lactobacilli
Proteus
Enterobacter, Citrobacter and Pseudomonas.74,75
Staphylococci
Lactobacilli and bifi dobacteria are generally absent
Pseudomonas
in the intestine of antibiotic-treated infants.3,71,75–77
Yeast
Moreover, nursing of preterm infants in closed
Protozoa
incubators and reduced exposure to maternal
microbiota may affect the development and the
diversity of their intestinal microbiota.
small intestine (ileum) accommodates a more diverse
Overview of the Adult Human
and dense microbiota (108 bacteria/g or mL content).
Gut Microbiota
The bacterial species found in the distal small intes-
tine include an increasing proportion of anaerobic
Once established, the human GIT is home to 100,000 species such as, Bacteroides sp., Bifi dobacterium sp.,
billion (1014) bacteria, comprising over 1000 differ-
Enterobacteriaceae, Enterococcus sp., Streptococcus
ent species.14 Since bacteria encounter a variety of sp., and Lactobacillus sp.78 The large intestine is a
environmental conditions within the different areas cardinal site of microbial colonization by large
of the GIT, it is not surprising that their distribution numbers of bacteria (1011–1012 bacteria/g or mL
throughout the intestine varies in both concentration content) and is characterized by slow turnover, low
and population diversity (Table 1). Factors such as redox potential and relatively high SCFA concentra-
pH, peristalsis, redox potential, bacterial adhesion, tions.78 The high numbers of microbes in the colon
mucin secretion, nutrient availability, diet and bacte-
is refl ected in the large proportion of fecal mass that
rial antagonism are all believed to infl uence coloni-
consists of bacteria, i.e. around 60% of fecal solids.81
zation patterns.78
The quantitatively predominant bacteria in the
The small intestine is interposed between the human colon are members of the genus Bacteroides,
sparsely populated stomach and the densely Bifidobacterium, Eubacteria, Clostridium,
colonized bacterial microbiota of the colon. A limited Lactobacillus and gram-positive cocci.82,83 Every
number of ingested bacteria survive transit through individual has several hundreds of microbial species,
the acidic conditions of the stomach and reach the with a particular combination of predominant species
small intestine in viable form. The lumen of the small that is distinct from other individuals.84 In contrast
intestine is characterized by a pH ∼7, the presence to the infant microbiota which is variable and
of bile salts and pancreatic secretions, which contain dynamic in its composition over time,85 the GIT of an
digestive enzymes that are themselves bactericidal, adult appears to have a microbial imprint that remains
and is subjected to frequent peristaltic transit stable on a time-scale of months.86,87
waves.79 Thus, the numbers of bacteria in the
proximal intestine (duodenum) remain relatively low
(104–106 bacteria/g or mL content).80 Acid-tolerant Functions of the Enteric Microbiota
lactobacilli, streptococci and enterococci predominate Several hundred grams of bacteria living within
in the upper small intestine. In contrast, the distal the colonic lumen affect host homeostasis.
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Role of gut microbiota in early infant development
Some of these bacteria are potential pathogens metabolic effi ciency, and differences in microbial
and can be a source of infection and infl ammation composition between individuals might regulate
under some circumstances, while the majority energy storage and predispose to obesity.100,101
co-exist with the host and may contribute to Moreover, the enteric microbiota is a metabolically
health benefits. Examples of potentially patho-
active partner in host defense that infl uences the
genic bacteria are staphylococci, clostridia, normal structural and functional development of
enterobacteria, enterococci, streptococci and the mucosal immune system. Establishment of a
Bacteroides.88,89 In contrast, Lactobacillus and normal microbiota provides the host with a sub-
Bifidobacterium species are considered among stantial antigen challenge, with a strong stimulatory
the beneficial bacteria of the GIT.61,90 Enteric effect for maturation of the gut associated lymphoid
bacteria confer many benefits to intestinal tissue (GALT) and mucosal immunity.102,103 The
physiology including structural, protective and fact that approximately 80% of all immunologi-
metabolic functions.7 Much of our understanding cally active cells of the body are located in the
of the molecular mechanisms that can explain GALT is an affirmation of the importance of
the host-bacterial mutualism comes from studies microbe-gut immune system interactions.104
of Bacteroides thetaiotaomicron, a prominent Indeed, studies have shown that germ-free mice
member of the intestinal microbiota of humans have an under-developed sparse mucosal immune
that modulates a number of essential host system, with small Peyer’s patches without
functions.91
germinal centers and small T cell zones. Further-
Along the epithelium, enteric bacteria complement more, their lamina propria contains essentially no
the natural defense barrier against exogenous immunoglobulin A (IgA), plasma cells or CD4
microbes, thereby preventing invasion by patho-
cells, and intraepithelial lymphocytes are also rare
gens. Several mechanisms have been proposed for compared with conventional animals.92,105 However,
this barrier effect including displacement, reconstitution of germ-free mice with an intestinal
competition for nutrients and epithelial binding microbiota leads to a rapid expansion of the
sites, and production of antimicrobial factors such immune system.106 Intestinal bacteria are not
as lactic acid and bacteriocins.92,93 The microbiota uniform in their ability to drive mucosal infl am-
is not metabolically inert, having a metabolic matory responses. Some species such as Bacteroides
activity akin to that of a virtual, or hidden, inner vulgatus are proinfl ammatory,107 while other spe-
organ.15,94 Gene diversity in this microbial cies such as bifi dobacteria and lactobacilli lack
community provides various enzymes and infl ammatory capacity.15,108 The ability of immu-
biochemical pathways that are distinct from the nosensory cells, such as enterocytes, M cells, and
constitutive resources of the host. For example, dendritic cells to discriminate pathogenic bacteria
SCFA such as acetate, butyrate and propionate are from commensal bacteria is mediated in part, by
produced following fermentation of non-digestible two major host pattern recognition receptor (PRR)
prebiotic substances by certain anaerobic bacteria.17,82,95 systems—the family of Toll-like receptors (TLRs)
SCFA in general enhance the growth of lactobacilli and the nucleotide-binding oligomerization
and bifi dobacteria and play a central role in the domain/caspase recruitment domain isoforms
physiology and metabolism of the colon.95 In (NOD/CARD).109 These PRRs have a fundamental
addition, some of the SCFAs produced have been role in immune-cell activation in response to
demonstrated to reduce the risk of developing specifi c microbial-associated molecular patterns
diseases, such as colon cancer and infl ammatory such as lipopolysaccharide (LPS), lipotechoic acid,
bowel disease (IBD).11,96 Resident bacteria can also peptidoglycan and fl agellin. Many PRR ligands
metabolize dietary carcinogens, synthesize are expressed by commensal bacteria, nonetheless
vitamins such as biotin, folate and vitamin K, and the healthy gut does not evoke inflammatory
assist in the absorption of calcium, magnesium and responses to these bacteria. Conversely, some
iron.82,97–99 Overall, the benefi ts of this complex commensal bacteria such as bifi dobacteria and
metabolic activity are recovery of metabolic energy lactobacilli exert protective effects by attenuating
and absorbable substrates for the host, and supply proinfl ammatory responses induced by different
of energy and nutritive compounds for bacterial pathogens.108,110 Recent evidence is also emerging
growth and proliferation. It has also been proposed to show that certain enteric bacterial components
that the gut microbiota of individuals has a specifi c can ameliorate radiation induced mucosal injury.111,112
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Wall et al
Thus, it is possible that the composition of the including decreased frequency of infections,
enteric microbiota infl uences individual variations reduction in the severity and length of the diarrhea
in immunity.
episode, decreased shedding of rotavirus and pro-
motion of systemic and local immune responses.116,120
Evidence for Probiotic Treatment
For example, L. rhamnosus GG has repeatedly been
shown to reduce the duration of infant diarrhea by
in the Management of Common
about 50%,121 while Saavedra et al.119 reported that
Infant Diseases Associated with
administration of Bifidobacterium bifidum and
the Gut Microbiota
Streptococcus thermophilus to infants reduced the
Probiotics are defi ned as “live microorganisms incidence of diarrhea four-fold compared with
which, when administered in adequate amounts, unsupplemented controls. Moreover, Correa et al.122
confer a health benefi t on the host.”113 The bacteria demonstrated that supplementation with Bifi dobac-
most commonly used as probiotics belong to terium lactis and S. thermophilus to infants resulted
the genera Lactobacillus and Bifidobacterium. in a 50% reduction of antibiotic-associated diarrhea
Manipulation of the microbiota using probiotics in compared with controls.
infants has shown promising results in the prevention
NEC is the most common serious, acquired
and treatment of diseases such as diarrhea, allergy gastrointestinal disease in the preterm infant, which
and NEC (Fig. 1).114–118 The precise mechanisms is characterized by impaired mucosal barrier func-
behind these health-promoting effects are not fully tion and increased gut permeability. Although
understood, but include normalization of microbiota, many variables are associated with NEC, only
reduction in intestinal permeability, increase in prematurity has been consistently identifi ed in
mucosal barrier function, protection against invasion case-controlled studies.123 In infants weighing less
by pathogens, production of benefi cial metabolites than 1,500 g at birth, there is a 10% incidence of
and anti microbial substances and stimulation of NEC, with mortality rates ranging from 25% to
immunity117 (Fig. 1).
30%.124 Several bacterial species have been
By far the best-studied clinical outcome with the associated with NEC, including members of
use of probiotic bacteria in children has been that Enterobacteriaceae, Clostridia, and coagulase-
of treatment of acute infantile diarrhea.117 Acute negative staphylococci.125–127 A number of reports
diarrhea is a serious cause of infant morbidity and suggest that probiotics may play a role in the
mortality caused by a range of different factors. control or prevention of NEC in preterm infants.
Bacterial infections caused by Shigella, Salmonella A recent Cochrane review by Alfaleh and Bassler128
and Campylobacter, viral gastrointestinal infections compared the effi cacy and safety of prophylactic
(mainly rotavirus) and antibiotic treatment have all enteral probiotic administration versus placebo or
been associated with acute diarrhea in infants.119 no treatment in the prevention of severe NEC in
Oral administration of probiotics have shown preterm infants. Nine eligible trials randomizing
benefi ts in infantile diarrhea in a number of studies, 1,425 infants were included. However, included
Mechanisms
Clinical Benefits
Ratio of bifidobacteria &
lactobacilli to pathogens
Balanced intestinal microbiota
Increased mucin production
Duration of acute diarrhoea
Enhanced gut permeability
T
Incidence of acute diarrhoea
Modulation of gut immune
response
Severity and incidence of atopic
GAL
– Humoral immunity (IgA
diseases
Gut Lumen
Gut Mucosa
and other antibodies)
PROBIOTICS
Antibiotic associated diarrhoea
Modulation of Th1/Th2
–
response towards antigen
Severity and incidence of NEC
tolerance
Figure 1. Summary of reported mechanisms and related clinical benefi ts of probiotics in pediatrics.117
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Role of gut microbiota in early infant development
trials were highly variable with regard to enrolment in earlier recovery than standard treatment after
criteria (i.e. birth weight, and gestational age), two months. Similar fi ndings were reported for
baseline risk of NEC in the control groups, timing, Lactobacillus fermentum VRI-003, which led to
dose, formulation of the probiotics used and an improvement in the extent and severity of atopic
feeding regimes. It was concluded that enteral eczema, when administered to infants for eight
supplementation of probiotics can reduce the risk weeks.139 In addition to treatment of allergy, it has
of severe NEC and mortality in preterm infants.128 been reported that probiotics can also reduce the
Moreover, Lin et al.129 reported that probi-
risk for developing the disease. In this respect, one
otic administration reduced the incidence of of the earliest studies was performed with a non-
NEC by 50% when L. acidophilus and B. infan-
pathogenic E. coli strain which was administered
tis were administered to infants weighing 1,500 to term and preterm infants. At 10 and 20 years of
g. Bin-Nun et al.130 demonstrated that administra-
follow-up, subjects treated with the E. coli strain
tion of a probiotic mixture (B. infantis, S. ther-
during infancy experienced signifi cantly fewer
mophilus and B. bifidus) to infants weighing allergic diseases than untreated controls.140 This
1,500 g reduced the incidence of NEC by about study demonstrated that it is possible to direct the
25%. Possible mechanisms by which probiotics immune system towards tolerance in infants in
may protect against onset of NEC include preven-
which the immune system is still immature.
tion of bacterial migration across the mucosa,
competitive exclusion of pathogenic bacteria and
enhancement of immune responses.128,131,132
Conclusions
Research to date supports the importance of the The role of the enteric microbiota is undoubtedly
early human intestinal microbiota on the develop-
an important factor governing infant health and
ment of allergic diseases such as atopic eczema, probably has an effect on overall health status in
asthma and food allergy. Bacterial colonization of later life. Indeed, the ‘fetal programming hypothesis’
the GIT after birth is essential to redress the bal-
as proposed by Barker, suggests that disturbed
ance of the skewed T-helper-cell type 2 immune intrauterine growth has a negative infl uence on the
response present in the newborn infant. This development of the cardiovascular system and
normal interaction between infant and microbes favors the occurrence of hypertension, insulin
is thought to be compromised in the Western resistance, hypercholesterolemia, and hyperuricemia
world, with a reduction in bifi dobacteria and an in adult life.141 Thus, infl uencing the composition
increase in clostridial species, particularly in for-
of the gut microbiota in early life may impact on
mula-fed infants.133 Differences in intestinal tendency towards the development of certain
microbiota have been described between healthy diseases in later life. Several factors may promote
children and those exhibiting allergic dis-
a greater microbial diversity in infants, such as
eases.134,135 In a prospective study, children who breast milk feeding, vaginal delivery and avoiding
later developed allergic sensitization to common antibiotics, which could contribute to enhanced
allergens were shown to have lower numbers of infant health. Moreover, the use of pre- and probi-
fecal bifi dobacteria and increased numbers of clos-
otics may play an important role in preventative
tridia from the fi rst weeks of life.27 Bifi dobacteria health and in the management of specifi c conditions
have been associated with a lower risk of in infants by increasing the numbers of lactobacilli
atopy.27,135,136 Sudo et al.137 reported that oral tol-
and bifi dobacteria in the intestine. Groups who
erance was achieved in germ-free mice only if the may benefit from such interventions include
intestinal microbiota was reconstituted with bifi -
formula-fed infants, infants born by Caesarean
dobacteria during the infant period. Components section, premature infants, and infants treated with
of the potentially pathogenic microbiota such as antibiotics. However, current evidence justifying
LPS have been reported to be involved in the such interventions is limited and adequately
development of atopic eczema.27,138 Probiotics powered studies addressing these issues are keenly
have been reported to help prevent and/or manage awaited. In particular, further large randomized
atopic diseases and allergies in infants. Isolauri controlled trials are required to investigate the
et al.114 demonstrated that supplementation of infants potential benefi ts and safety profi le of probiotic
with atopic eczema with Bifi dobacterium animalis supplementation in extremely low birth weight
subsp. lactis Bb12 or L. rhamnosus GG resulted infants (ELBW) for the prevention of NEC.
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Acknowledgements
20. Bennet R, Nord CE. Development of the fecal anaerobic microfl ora
The authors are supported, in part, by Science
after caesarean section and treatment with antibiotics in newborn
infants. Infection. 1987;15:332–336.
Foundation Ireland, The European Union (Project 21. Grönlund MM, Lehtonen OP, Eerola E, et al. Fecal microfl ora in healthy
KBBE-2007-2-2-06), the Irish ministry for Food
infants born by different methods of delivery: permanent changes in
and Agriculture, the Higher Education Authority
intestinal fl ora after caesarean delivery. J Pediatr Gastroenterol Nutr.
1999;28:19–25.
and the Health Research Board of Ireland and the 22. Mandar R, Mikelsaar M. Transmission of mother’s microfl ora to the
Irish Government under the National Development
newborn at birth. Biol Neonate. 1996;69:30–35.
Plan 2000–2006. Rebecca Wall is a student funded 23. Bezirtzoglou E. The intestinal microfl ora during the fi rst weeks of life.
Anaerobe. 1997;3:173–177.
by the Alimentary Pharmabiotic Centre (APC).
24. Matsumiya Y, Kato N, Watanabe K, et al. Molecular epidemiological
study of vertical transmission of vaginal Lactobacillus species from
mothers to newborn infants in Japanese, by arbitrarily primed
Disclosure
polymerase chain reaction. J Infect Chemother. 2002;8(1):43–49.
The authors report no confl icts of interest.
25. Mackie RI, Sghir A, Gaskins HR. Developmental microbial ecol-
ogy of the neonatal gastrointestinal tract. Am J Clin Nutr. 1999;69:
1035S–1045S.
26. Torun MM, Baher H, Gur E, et al. Anaerobic fecal fl ora in healthy
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