,
2015. 459 full-text articles were analyzed by two of the authors. A
descriptive and explanatory qualitative approach was chosen for the
content analysis.
Mechanisms of Action
Indirect effects of prebiotics arise through
stimulation of health-promoting microbial taxa, such as
Bifidobacterium and Bacteroides [12-14], which block
intestinal pathogens, improve intestinal barrier function and
orchestrate immune pathways. There is even some evidence of gut
microbiota influencing brain function over microbiota-gut-brain axis
[15].
Direct effects are due to the action of SCFAs. They
are largely produced in colon where they act locally; however, some of
them reach high concentration in the bloodstream carrying them across
the body and allowing them to interact in extra-intestinal reactions
[16]. The main SCFAs formed are acetate, propionate and butyrate. Their
primary task is the energy supply for intestinal epithelial cells,
though they also play a role in gene expression, gut motility and
barrier function, metabolite absorption, lipid metabolism, appetite
control, insulin resistance, gut-liver axis regulation, and regulation
of the immune system, resulting in prevention of infection, diarrhea,
constipation and allergies [17].
Clinical Uses in Children
Infantile Colic
In a randomized non-blinded trial, published almost
ten years ago, 96 formula-fed infants under 4 months of age with colic
received a partially hydrolyzed whey protein formula containing FOS and
GOS. They experienced a greater reduction of crying episodes after 7 and
14 days compared with those assigned to a standard formula and
simethicone [18]. However, whether the effect is due to partially
hydrolysed protein, the prebiotics, or both, is not clear. Pärtty, et
al [19]. studied preterm infants randomized to receive a mixture of
GOS and polydextrose (1:1), probiotics or placebo during first 2 months
of life, and followed-up for 1 year. In both pre- and probiotic groups,
significantly less frequent crying was observed compared with the
placebo group (19% vs. 19% vs. 47%, respectively; P
= 0.02) . On the other hand, a systematic review and meta-analysis
including 12 prebiotic studies found no impact of prebiotics on the
incidence of colic, regurgitation, crying, restlessness or vomiting
[20]. Nonetheless, adding prebiotics to infant formula for full-term
infants was reviewed. Although, further confirmatory studies are needed,
no adverse effects of prebiotics were found during this review.
Constipation
Majority of clinical studies concerning the effects
of supplementation of infant formulas with prebiotics confirmed increase
in frequency of defecation and/or softer consistency of stools, similar
to that of breast-fed infants [21-31]. Current analysis of stool
characteristics of infants receiving short-chain GOS (scGOS) and
long-chain FOS (lcFOS) in ratio 9:1 showed that effects on stool
consistency were more often found to be significant than effects on
stool frequency [32]. Bongers, et al. [33] published the only
therapeutic randomized controlled trial (RCT) using prebiotic formula
for functional constipation in 2007. The consumption of a high
concentration sn-2 palmitic acid, scGOS/lcFOS 8g/l and partially
hydrolyzed whey protein formula resulted in a strong tendency of softer
stools in constipated infants, but not in a difference in defecation
frequency. In a randomized, double-blind, prospective study [25], it was
shown that prebiotics can soften stools and increase stool frequency
even in toddlers [25].
A more recent study, [34] indicated a significant
rush of motilin following prebiotic supplementation. Motilin being a
peptide, produced by endocrine M cells, largely presents especially in
duodenum and jejunum. Its essential role is to clean undigested food
from the gut by controlling inter-digestive migrating contractions [34].
All together suggesting an association with improved gastric emptying,
better tolerance to food and improved digestion in general [35].
Changes in defecation patterns in pediatric
population due to prebiotic supplementation mostly result in improvement
of abdominal comfort and reduction of prevalence of functional
constipation. Since constipation affects one third of children usually
before the age of five [36-38] but often persists beyond puberty, these
observations are relevant for preventive or curative treatment of this
very common functional disorder [39]. Yet, to establish specific doses
in avoiding diarrhea, more studies are awaited.
Absorption of minerals
Acidic environment in colon increases solubility of
certain minerals [40]. Bioavailability of calcium when consuming
prebiotic ingredients has been well-studied. Animal studies verified the
positive correlation; efficiency in humans is nevertheless not
consistent. Abrams, et al. [41] found significantly enhanced
calcium absorption and bone mineralization in adolescents after
receiving inulin-type fructans daily for a year. On the contrary, no
significant effect of prebiotics was observed on calcium absorption or
other markers of bone mineralisation in infants [42]. Recent
observations show that prebiotic oligosaccharides enhance iron
absorption in deficient rats [43]. Clearly, further human trials are
needed, but this seems to be encouraging information, given the
prevalence of iron-deficiency in children.
Weight-gain
At the Summer Meeting of the Nutrition Society in
2010, it was announced that an overview of studies investigating effects
of oral SCFA on appetite regulation did not reveal a positive
connection. The experts concluded that sensory characteristics are those
influencing our choice of which food we eat and the quantity of it
rather than a physiological effect of SCFA [44]. In children, especially
in the first months of life when milk is the basic nutrition, there are
some encouraging results. For instance, Mugambi, et al. [20]
conducted a meta-analysis that summarized positive context of prebiotics
in infant formulas and increased weight gain; there was no impact on
length or head circumference gain. Whether this is the result of
intensified energy harvests by intestinal bacteria and/or increased
absorption by enterocytes is not yet clear. It is very likely that the
outcome is dose-dependent [14]. Interestingly, these results are to some
extent antagonistic with the inverse correlation between fibre intake
and obesity known in adults as well as in adolescents [22,45,46]. In
fact, dietary fibre reduces the risk of childhood obesity by up to 21%
[47]. Furthermore, Dasopoulou, et al. [35] found that
supplementation of infant formula with scGOS/lcFOS resulted in
significantly lower mean cholesterol values compared with preterm
neonates fed with standard formula.
Diarrhea
An open-label RCT published six years ago [48],
included more than 300 healthy infants, age 1-2 months. The group
receiving a GOS/FOS mix had a significantly lower number of
gastrointestinal infections and antibiotic use per year [48]. Still,
when Duggan, et al. [49] studied a group of 282 infants 6-12
months of age, there was no difference in diarrheal prevalence or the
mean duration of diarrhea between those receiving an infant cereal
enriched with oligofructose with and without prebiotics [49].
Destruction of microbial population in GIT has the
power to start the so called antibiotic-associated diarrhea. Preventive
intervention by giving prebiotics after or along with antibiotic
treatment has so far not been properly evaluated. A RCT published in
2006 by Brunser, et al. [50] showed no significant difference in
the frequency of antibiotic-induced diarrhea between two groups, aged
1-2 years. The first group received inulin and oligofructose (total of
4.5 g/L) containing milk formula for 3 weeks after they had ended
amoxicillin therapy for respiratory infection. The second group received
prebiotic-free milk formula [50]. Another trial was organized by the
ESPGHAN Working Group on Pro- and Pre-biotics. In this multi-centre
trial, children with oral and/or intravenous antibiotic therapy covering
common infections were treated with inulin and FOS in age-dependent
doses (max 5g/day) for as long as they were taking antimicrobial drugs.
These children were below 11 years old and tolerated the mixture well;
nonetheless, it had no effect regarding antibiotic-associated diarrhea.
The study was stopped before time because of slow recruitment and the
working group concluded that overall prevalence of diarrhea was not high
and caution must be taken when judging the results. However, there is a
need for further research with different prebiotics [51].
Administration of prebiotic compounds via oral
rehydration solution (ORS) is under investigation. A decade ago,
Hoekstra, et al. [52] also completed a multi-centre European
double-blind randomized placebo controlled study on behalf of the
ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology,
and Nutrition) Working Group on intestinal infection. The subject was
ORS containing a mixture of prebiotics (soy polysaccharides 25%,
alpha-cellulose 9%, gum arabic 19%, FOS 18.5%, inulin 21.5%, resistant
starch 7%) in the acute diarrhea treatment. Children aged 1 month to 3
years with acute diarrhea resulting in mild-to-moderate dehydration were
given either supplemented or non-supplemented ORS [52]. There was no
significant difference between participants of the two groups in mean
48-h stool quantity, duration of symptoms and hospitalization [52]. No
significant influence on clinical course of acute gastroenteritis was
also reported by Israeli analysts. A mixture of 80% lcFOS/scGOS and 20%
AOS in a three 2-g sachets per day significantly increased stool
consistency (P=0.048) but not total of daily stools number (P=0.66)
in 9- to 24-month-old children [53]. A recent randomized controlled
trial in Italian children showed significant efficiency when FOS and
xylo-oligosaccharides – both 0.35 g/L were consumed along with hypotonic
ORS. Children aged 3 months to 3 years in prebiotic group drunk more ORS
in the first 24 hours (P<0.001), diarrhea was over after 72 hours
in a greater percentage (P=0.01) and their parents missed fewer
working days compared to placebo "team" of parents (P<0.001)
[54]. An older double- blind, placebo controlled RCT including boys from
Bangladesh enrolled a group of 150 male children, aged 4 to 18 months
that looked for medical help because of watery non-cholera diarrhea of
less than 48 hours of duration. Adding partially hydrolyzed guar gum to
oral rehydration solution resulted in important reduction of total
extent of acute gastroenteritis [55].
Respiratory infections
It would be simple, safe and economical if prebiotics
would help to prevent respiratory infections. There are some supportive
results revealed by Luoto and colleagues in a recent RCT. Ninety-four
preterm infants were randomized to receive PDX/GOS 1:1 (600mg/24h day 1
to 30, 1200 mg/24h day 31 to 60), probiotic (Lactobacillus rhamnosus
GG (LGG); 1×10
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