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Médecine et maladies infectieuses (2014) 1–8

General review

Probiotics, gut microbiota and health

Probiotiques, microbiote intestinal et santé
M.-J. Butel
Écosystème intestinal, probiotiques, antibiotiques (EA 4065), université Paris Descartes, PRES Sorbonne Paris Cité, 4, avenue de l’Observatoire, 75006 Paris,
France
Received 5 September 2013; received in revised form 21 October 2013; accepted 21 October 2013
Available online 28 November 2013

Abstract
The human gut is a huge complex ecosystem where microbiota, nutrients, and host cells interact extensively, a process crucial for the gut
homeostasis and host development with a real partnership. The various bacterial communities that make up the gut microbiota have many functions
including metabolic, barrier effect, and trophic functions. Hence, any dysbiosis could have negative consequences in terms of health and many
diseases have been associated to impairment of the gut microbiota. These close relationships between gut microbiota, health, and disease, have
led to great interest in using probiotics (i.e. live micro-organisms), or prebiotics (i.e. non-digestible substrates) to positively modulate the gut
microbiota to prevent or treat some diseases. This review focuses on probiotics, their mechanisms of action, safety, and major health benefits.
Health benefits remain to be proven in some indications, and further studies on the best strain(s), dose, and algorithm of administration to be used
are needed. Nevertheless, probiotic administration seems to have a great potential in terms of health that justifies more research.
© 2013 Elsevier Masson SAS. All rights reserved.

Keywords: Microbiota; Probiotics; CIBD; Allergy

Résumé
Le tube digestif est un écosystème extrêmement complexe où microbiote, nutriments et cellules de l’hôte sont en contact permanents. De plus
en plus de travaux montrent les interactions entre ce microbiote commensal et l’organisme humain, faisant du microbiote un véritable partenaire,
partenariat qui débute dès la naissance. Ce microbiote très complexe a de nombreuses fonctions dont les principales sont des fonctions métaboliques,
des fonctions de barrière et des fonctions trophiques. Tout déséquilibre bactérien ou dysbiose peut donc conduire au développement de pathologies,
et de nombreuses pathologies ont été associées à des dysbioses. Cette relation microbiote-santé a développé l’intérêt de moduler ce microbiote par
le biais de l’administration de bactéries vivantes, appelées probiotiques, ou de substrats indigestibles – les prébiotiques – dans un but de prévention
voire de guérison de certaines pathologies. Cette revue fait le point sur les probiotiques, leurs mécanismes d’action, les risques liés à leur utilisation
et leur intérêt dans les principales indications. Dans certaines indications les preuves de leurs effets bénéfiques sont encore à faire, avec en particulier
le choix de la ou des souche(s) idéale(s), de la dose, et de l’algorithme d’administration. Cependant, leur potentiel santé est indéniable, justifiant
la poursuite des études à leur sujet.
© 2013 Elsevier Masson SAS. Tous droits réservés.

Mots clés : Microbiote ; Probiotiques ; MICI ; Allergie

1. The gut microbiota, a partnership with the host bacteria could produce toxins and/or invade the gut mucosa,
and/or translocate and disseminate, causing systemic infections.
The human gut is an extremely complex ecosystem where Nevertheless, no attention was paid to most gut bacteria whose
microbiota, nutrients, and host cells interact extensively. role and relationship with the host’s health remained unknown
These micro-organism/host relationships were for a long time for a long time. Currently, more and more authors have reported
considered only from a pathogenic point of view, because some the beneficial interactions between this commensal microbiota
and the human body, pointing to the microbiota as a true partner,
the partnership beginning at birth. This very complex micro-
E-mail address: [email protected] biota is acknowledged as an active element of gut physiology,

0399-077X/$ – see front matter © 2013 Elsevier Masson SAS. All rights reserved.
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2 M.-J. Butel / Médecine et maladies infectieuses (2014) 1–8

with many functions the main of which are: metabolic, barrier in vitro studieş in animal models and clinical trials have proven
effect, and trophic functions. Any bacterial unbalance, called the potential of these probiotics for many diseases.
dysbiosis, may cause diseases, and several diseases have been
associated to dysbiosis. Even if it is not always easy to determine 3. Which probiotics?
whether microbiota modifications are a cause or a consequence
The work group of WHO and FAO (Food and Agriculture
of the disease, the relationship between microbiota and diseases
Organization) experts who defined probiotics, also worked on
has been suggested by many authors. This microbiota-health
the characteristics of a bacterial strain to be considered as a
relationship has raised interest in positively modulating this
probiotic [1,2]. First, the strain must reach its site of action,
microbiota through administration of live bacteria (probiotics),
usually the gut, and thus survive to physiological stress met
or non-digestible substrates (prebiotics) for the prevention or
during its ingestion: acid stomach and gut pH, presence of bil-
even cure of some diseases. The aim of this review was to make
iary salts. Then, it must have proved its beneficial effect for the
an update on probiotic use, their mechanisms of action and their
host. Its ingestion must not present any risk for the host. Fur-
contribution; since even though their effectiveness is sometimes
thermore, it must maintain its characteristics and remain stable
questioned, their healthcare potential is interesting.
during the manufacturing process and its conservation in the
matrix in which it was incorporated.
2. Probiotics, microbiota modulators, a story that began
The most frequently used bacterial genera are lactic bacte-
a long time ago
ria, mainly the Lactobacillus and Bifidobacterium genera. Other
genera are also used such as the Enterococcus, Streptococcus,
Probiotics are currently defined as “live micro-organisms,
Leuconostoc genera, etc. Most of these micro-organisms come
which when consumed in adequate amounts, confer a health
from fermented dairy products such as kefir, Maasai milk, or
effect on the host” [1,2]. The era of probiotics really began with
Kurut. These fermented milks are an important source because
Elie Metchnikoff who correlated at the beginning of the 20th
they can contain several species of lactic bacteria, as demon-
century the longevity of Bulgarians to their high consumption of
strated by the authors of a recent study on koumiss samples
fermented milk. At the same time, a French pediatrician, Henry
(fermented Yak milk) coming from various regions of China
Tissier, observed that infants presenting with diarrhea had few
where strains of lactobacilli belonging to 11 different species
Y shaped Gram-positive bacteria in their stools, whereas these
have been identified. Lactic bacteria having been isolated from
“bifid” bacteria were dominant in the stools of healthy infants.
human milk [3] and fermented food, studies were made on iso-
He even suggested, in a report to the Biology Society, to make
lates from these sources, especially on lactobacilli. For example,
children presenting with diarrhea drink “1 to 2 Bordeaux glasses
feeding with infantile formula milk containing the Lactobacil-
of a pure culture of Bac. acidiparalactici, or even better of a sym-
lus fermentum CECT5716 strain isolated from human milk
biosis of this species with Bac. bifidus, so as to accelerate the
decreased the incidence of gastro-intestinal and upper respira-
building up of a preventing flora”. This principle of beneficial
tory tract infections in 6 months old children [4]. Another source
bacteria is in fact very ancient, several publications mentioning
of these micro-organisms is the intestinal tract, in which the
the use of fermented milk to treat gastroenteritis. In the Genghis
Bfidobacterium and Lactobacillus genera belong respectively
Khan era, during the 12th century, fermented milk was consid-
to the dominant and sub-dominant microbiota. Some probio-
ered as source of strength and health, and Mongolian women
tic strains were isolated from the stools of healthy children or
sprayed horses and riders with it to protect them during battles!
adults. Strains with probiotic properties were also isolated from
Metchnikoff’s observation on the benefit for health of fermented
the digestive tract of animals (bees, fish, shrimps, etc.) but also
milk and its active ingredient, bacteria, led him to suggest that
from non-fermented food such as meat, sausage, or vegetables
maybe “all microbes were not dangerous for health” and that
(fruits, olives, etc.).
it could be beneficial to replace the “putrid flora” by enriching
Probiotics may belong to other bacterial genera not included
the normal flora with bacteria able to ferment glucose, weakly
in lactic bacteria, such as Escherichia coli or Propionibac-
proteolytic, such as lactic bacteria. This concept of beneficial
terium. These latter genera are nevertheless less frequently used
bacteria was forgotten during the era of antibiotics and vacci-
and present a higher potential risk of adverse effects, as pro-
nation, but studies on the commensal microbiota have renewed
biotics belonging to Enterococcus genus. Indeed, these live
interest for their contribution.
bacteria can translocate and cause systemic infections in the
The word probiotic was first used by Lilly and Stillwell
host, even if the case is rare [5]. These bacterial genera can
in 1965, as opposed to the word antibiotic, to qualify “a
also be vectors of antibiotic resistance. These aspects will be
microbial substance able to stimulate the growth of another
developed in the paragraph dealing with the safety of probio-
micro-organism”. Then, the notion of microbial origin was
tics. Besides bacteria, the yeast Saccharomyces boulardii has
introduced, redefining probiotics as “living micro-organisms
also been used for several decades, because of its probiotic
with beneficial effects on the host, by modifying the equi-
properties.
librium of its gut microbiota”. The notion of interaction on
the microbiota is no longer part of the definition; probiotics 4. How do probiotics act?
may act through other mechanisms and are defined as “live
micro-organisms, which when consumed in adequate amounts, The mechanisms of action of probiotics are not always
confer a health effect on the host” [1,2]. The results of numerous well understood, which is one of the problems considered by
 M.-J. Butel / Médecine et maladies infectieuses (2014) 1–8 3

the European Food Safety Authority (EFSA), which recently Probiotic strains can also have beneficial effects directly by
refused the health claims of marketed probiotics, because of the providing enzymes such as beta-galactosidase or other enzymes
lack of sufficient proof. Furthermore, the authors of some clini- improving the digestive symptoms of patients.
cal trials did not associate an analysis of the microbiota with the Probiotic bacteria can act, whatever their mode of action, via:
observation of an expected clinical effect, thus not allowing any
analysis of the potential effect of the probiotic on the gut micro- • their structures such as DNA (especially by the CpG motifs),
bial balance. The mechanisms of action of probiotics are hence peptidoglycan, LPS, flagellin;
mainly documented through in vitro or animal model studies • and/or their metabolites (especially short-chain fatty acids).
with the consequent limitations to extrapolate these results to
man.
Their action may be direct, related to their digestive col-
The mode of action of probiotics may firstly be related to the
onization, or indirect because these strains will modulate the
modulation of the host’s microbiota. One of the first suggested
microbiota, by increasing the inoculum of bacteria with benefi-
modes of action is the “barrier” effect, also called resistance to
cial effects.
the colonization, exerted against pathogenic bacteria preventing
or limiting their colonization. The bacterial inhibition may be
due to the production of broad-spectrum inhibition bacteriocins, 5. Safety of probiotics
to metabolites such as short-chain fatty acids inducing a decrease
of the pH little favorable for bacterial growth, or to biosurfactants The probiotic effect is strain dependent, hence it must be per-
with an antimicrobial activity. This barrier effect can also act via fectly identified (phenotypic and genotypic identification) and
various mechanisms: competition for binding sites, inhibition of characterized. The strain must remain stable during the manu-
adhesion. facturing process and conservation before use. It must of course
The second mode of action concerns the improvement of be free of any pathogenicity.
the barrier function of the gut mucosa. This barrier function Probiotics, especially bifidobacteria and even more lacto-
is related to the quality of tight junctions between intestinal bacilli, have a long history of safety with their use in fermented
epithelial cells. Other elements also participate in this barrier food and milk. Furthermore, these bacteria, and here again espe-
function such as Paneth cells by producing antimicrobial pep- cially lactobacilli, are frequently encountered in nature: plants,
tides (defensins, lysozyme), and mucus cells, mucus acting as animals, and in humans for whom they belong to the commensal
a protective layer preventing any direct contact with bacteria microbiota. Lactobacilli, bifidobacteria, lactococci, and yeasts
of the intestinal lumen. Probiotics can thus act at the level of are classified in the category of organisms Generally Regarded
signaling pathways leading to the increase of the mucus layer As Safe (GRAS). Nevertheless, a few cases of infections have
or to the production of defensins, as well as on proteins of been reported, but mostly in immunocompromised patients [8].
tight junctions by improving their physiological barrier func- Not all the probiotics used belong to this GRAS category; this is
tion. the case for enterobacteria or enterococci some strains of which
The third mode of action is modulation of the immune are used for their probiotic properties [9].
system. More than 70% of immune cells are located at the There are different types of theoretical risks related to the use
gut level, especially in the small bowel, making up the gut of probiotics. Firstly, probiotics may be responsible for infec-
associated lymphoid tissue (GALT). Peyer patches, particu- tions due to a translocation, defined as the passage from the
lar sites featuring a follicular center and covered by M cells digestive tract to extra-intestinal sites, first step leading to infec-
associated to the epithelium, are a real portal of entry for anti- tion. Few authors have analyzed this risk. In fact, they have
gens. Activation of the immune response requires recognizing usually focused on the effect of probiotic strains on the translo-
specific receptors of innate immunity cells (epithelial cells, den- cation of pathogenic bacteria for a protective effect, some strains
dritic cells, and macrophages). These receptors called pattern having the capacity to decrease or increase the translocation of
recognition receptors (PRR) include mostly Toll like recep- gut bacteria. Probiotic strains have been implicated in infec-
tors (TLRs) and nucleotide binding oligomerization domain tions, but only in rare cases. Thus bacteremia, endocarditis, or
agents (NODs). They are recognized by some structural com- abscesses have been reported when using the Lactobacillus GG
ponents repeated at the surface of micro-organisms called strain [10]. These infections occurred only in patients presenting
microbial associated molecular patterns (MAMPs) which inter- with risk factors such as a short bowel or harboring a central
act with the gut epithelium and stimulate the cells of the venous catheter. The safety of probiotic strains was also demon-
gut immune system at the lamina propria level [6]. The strated indirectly via a lactobacilli bacteremia surveillance study
consequences are activation of regulatory T cells and differen- in Finland without any variation in the prevalence of infections
tiation of T helper lymphocytes (Th) inducing the production between 1990 and 2000, whereas during the same period the
of pro- or anti-inflammatory cytokines. Bacteria with pro- consumption of Lactobacillus GG increased from 1L to 6L per
biotic potential, especially lactic bacteria may have different capita [11]. Cases of fungemia with the probiotic yeast Saccha-
effects, depending on the cytokine profile [7]. The effects romyces boulardii have been reported [12]. These rare cases of
may be local and limited to stimulation of gut immunity fungemia, considering the extremely frequent use of this pro-
(stimulation of secretory IgA production for example) or sys- biotic, may be attributed to a translocation from the digestive
temic. site in patients presenting with severe diseases; but they can
4 M.-J. Butel / Médecine et maladies infectieuses (2014) 1–8

also be a consequence of catheter colonization when opening conducted, but too many with an insufficient number of patients
the probiotic pack [13]. included, or with an inadequate protocol to support the effect of
Other negative effects of probiotics could be related to the probiotics. Furthermore, the use of various strains, different from
production of metabolites with a toxic potential. One of the pos- one study to the next, make it difficult to compile the results of all
sible risks concerns the production of D-lactate during bacterial the studies. Nevertheless, a number of strains or strain mixtures
fermentation responsible for lactic acidosis. In children pre- are becoming increasingly popular and used in many indications
senting with a short bowel syndrome, a microbiota abnormally with encouraging results. The targeted diseases were primarily
rich in lactobacilli or the administration of probiotic lactobacilli diarrhea, inflammatory bowel diseases (IBD), and allergy, before
strains have been associated to acidosis, resulting in hyperven- extending the indications to other diseases when studies proved
tilation or encephalopathy. Nevertheless, no lactic acidosis has their relationship with the microbiota.
ever been reported in healthy children [14].
One of the indications for probiotic strains is their 6.1. Probiotics and infectious diarrhea
immunomodulating potential which may have a protective effect
against allergy. These effects are strain-specific. The use of pro- One of the first recommendations for probiotic use was the
biotic strains may theoretically have a deleterious effect on the treatment and/or the prevention of diarrhea. The authors of a
immune response. Up to now, this type of adverse has rarely recent meta-analysis of 63 clinical trials reported a significant
been assessed, and never reported. benefit of probiotics for acute diarrhea, with a shortened duration
Another important risk is the transfer of genes of resistance to of 1 day for diarrhea lasting more than 4 days, and a decreased
antibiotics in the host’s digestive tract, among probiotic strains number of stools [20]. Nevertheless, the effects are quite variable
and the host’s commensal bacteria. Digestive tract bacteria are an from a study to the next. One of the reasons may be that the
important reservoir of resistance genes, either because of resis- specific effect of a given strain on a given enteropathogen, make
tant bacteria selected during antibiotic treatments, or acquired comparison between studies difficult. The authors of another
by direct or indirect contact with other carriers or with food recent meta-analysis took into account the effects of probiotics
[15]. Gene transfers may occur within this intestinal micro- in adults and in children, and noted the absence of effect for
biota, supported by the great number and diversity of bacteria diarrhea in adults [21]. In children, probiotics once again had
there. These exchanges have been demonstrated indirectly by the for effect to decrease the duration of diarrhea and the fever, but
homology of resistance gene sequences among various micro- no effect on the duration of hospitalization and on the number
organisms. Resistance plasmids, such as genes erm and tet de stools [21], and a limited effect in cases of persistent diarrhea
present in the genome of commensal bacteria, have also been [22]. One of the most interesting effects was the decrease of
found in a number of probiotic strains belonging to the Lac- nosocomial rotavirus diarrhea. In this indication, the probiotic
tobacillus and Bifidobacterium genera [16,17]. Thus, probiotic Lactobacillus GG, especially in 3 randomized controlled trials
strains may be vectors of resistance genes, acting as donor or having included more than 1,000 children, induced a significant
recipient. Transfer of these resistance genes have been demon- decrease of rotavirus diarrhea [23].
strated from commensal bacteria to probiotics and conversely Another indication for probiotics is diarrhea associated to
from probiotic strains to commensal strains in vivo in animal antibiotic intake, most often due to Clostridium difficile, the col-
models [18,19]. Despite the low frequency of the latter transfers onization of which being promoted by the dysbiosis induced by
when they were demonstrated experimentally, this possibility antibiotic treatments. The usual regimen is administration of
has resulted in recommending the use of probiotic strains free metronidazole or vancomycin per os but recurrence is frequent,
of acquired and potentially transferable resistance genes [2]. related partly to the resistance of C. difficile spores to antibiotics.
This raises the problem of using probiotic strains belonging to Administration of probiotics clearly allows rebuilding a “bar-
genera or species naturally carrying factors of virulence and/or rier microbiota”. The results of many meta-analyses and reviews
resistance to antibiotics such as enterococci or E. coli. Neverthe- suggest their effectiveness when administrated with antibiotics.
less, their use in human or animal medicine has up to now never Once again, the benefits are related to the strain used [24]. The
been associated to infectious issues [9]. Genomic analyses of most effective species or strains seem to be Bifidobacterium
enterococci strains used as probiotics have proven the absence lactis, Lactobacillus GG, as well as the yeast Saccharomyces
of virulence factors in these strains. Nevertheless, the risk of boulardii. The latest meta-analysis from the Cochrane Library
transferring genes via these strains justifies recommendations demonstrates effectiveness for the prevention of C. difficile diar-
concerning a thorough genomic analysis of these strains as well rhea but not for the decrease of their incidence [25]. Nevertheless
as assessing their capacity for gene exchange. the meta-analysis results were to be taken cautiously because of
an insufficient number of cases, requiring new trials. Further-
6. Probiotics today in human medicine more, these complementary trials are necessary to assess each
strain as well as optimal doses and duration.
Despite the fact that the EFSA recently refused health claims
for all probiotics marketed in in Europe due to insufficient proof, 6.2. Probiotics and IBD
the effectiveness of probiotics was demonstrated for of the a
number of diseases. Various reasons may account for the insuf- IBD (Crohn’s disease, and ulcerative colitis) are chronic dis-
ficient proof mentioned by the EFSA: many clinical studies were eases of unknown etiology the incidence of which has been
 M.-J. Butel / Médecine et maladies infectieuses (2014) 1–8 5

increasing for a few decades in developed countries. Patients 6.4. Probiotics and allergy
present with ulcerations of the small bowel or colon mucosa,
alternating periods of activity with periods of remission. Some The increase of allergy in the industrialized countries was
authors have reported, besides genetic predisposition, dysbiosis explained by the hygiene theory associating modifications of
and decrease of microbial diversity in patients presenting with intestinal microbiota implantation related to improved hygiene
IBD, but the causal link remains to be determined [26]. This conditions in perinatology and antibiotic therapy in the early
possible relationship between microbiota and mucosal inflam- childhood, to inadequate immune system maturation [39]. This
mation has raised a growing interest for probiotics use in IBD, theory was supported by epidemiological studies demonstrating
as a complement to usual treatment, to decrease the recurrence; differences of microbiota between allergic and non-allergic chil-
but the effectiveness of probiotics has not been proved. The dren [40]. The use of probiotics allowing an adequate stimulation
clinical trials were mostly conducted with the aim to induce of the immune system is once again attractive, despite the discor-
remission or prolong it [27]. The results were rather disap- dances in study results for the relationship between microbiota et
pointing for Crohn’s disease, and did not allow recommending allergy. Many authors of clinical trials have reported promising
probiotics in this indication [28,29]. Nevertheless, some posi- results [40]. Unfortunately, contradictory results among stud-
tive effects observed with either Escherichia coli Nissle 1917 ies do not currently allow recommending probiotic use in the
or Saccharomyces boulardii led to investigating this approach prevention of allergy [40]. Several points may explain the intra
through larger studies. The conclusions were almost identical study variations:
for ulcerative colitis; a few authors have reported either a pro-
longation of remission as effective as with the usual treatment, • the type of population studied in terms of age, type of allergic
or a decrease of clinical signs, suggesting the contribution of disease, disease stage, number of patients included, genetic
probiotics but mostly for inducing remission [27]. The effects background, environment;
of probiotics seemed more significant for pouchitis with even • the probiotic(s) tested in terms of bacterial species, mixture
some recommendations for their use to decrease recurrence [30]. of strains use, doses administrated, administration algorithm,
Thus, even if it is difficult to currently recommend probiotics for with a consequent great heterogeneousness among studies
the management of IBD, this approach is of interest but requires [41].
further studies [31], including investigation of the relationships
between microbiota and diseases, some low levels of some bac- Nevertheless, the results of some studies clearly prove the
terial species having recently been associated to active periods effectiveness of probiotics for the prevention of some allergic
of IBD such as Faecalibacterium praustnizii [32]. diseases, most frequently in high risk families, justifying further
experimental research and clinical trials, focusing on the selec-
6.3. Probiotics and irritable bowel syndrome tion of the strain(s) to be used and the time of administration
[40,42].
The irritable bowel syndrome or functional colopathy is
an intestinal disorder characterized by abdominal pain and a 6.5. Probiotics and Helicobacter pylori
chronic disorder of the intestinal transit such as diarrhea and/or
constipation. The etiology of this disease, very frequent and Some authors have reported the potential contribution of pro-
disturbing for the patient, remains badly documented making biotics for diseases due to Helicobacter pylori, such as gastric
management difficult. Several factors have been implicated in ulcers and some gastric cancers. But the results of clinical trials
the occurrence of this syndrome such as stress, low-grade inflam- in humans, with various strains, various doses, and a small num-
mation of the intestinal mucosa, abnormal colic motility, and ber of included patients, are not significant enough at this time
gastro-intestinal infectious diseases. Furthermore, the current to recommend using probiotics in the management of H. pylori
data seems to prove a relationship with dysbiosis, even if no bac- infection [43], even if the results of some trials are promising,
terial marker has been demonstrated yet [33]. This has opened such as those dealing with the yeast S. boulardii as an adjuvant
the way to probiotic use for functional colopathy [34,35]. Some treatment of the usual triple antibiotic combination [44].
authors of meta-analyses of case controlled clinical trials have
demonstrated the potential contribution of probiotics in this indi- 6.6. Probiotics for obesity and diabetes
cation [36,37]. Nevertheless, some differences in effectiveness
have been observed depending on the strains and doses admin- The authors of some studies in mice then in humans have
istrated, and on the experimental protocol. Furthermore, the reported a relationship between microbiota and obesity [45] as
placebo effect is known to be beneficial in this disease, and the well as one with type 2 diabetes [46]. One of the explanations
better results come from the smallest studies. This would tend to is related to the colic fermentation of food not digested by the
over estimate the beneficial effect of probiotics, allowing use of microbiota in the small bowel, which induced the production of
this treatment only in 2nd intention in recommendations for the metabolites such as short-chain fatty acids which are absorbed
management of this type of functional colopathy [38]. Never- by the mucosa, thus allowing recovering energy [47,48]. Cur-
theless, probiotics are an interesting alternative treatment, even rently, the authors of interventional studies have not proved any
if complementary clinical trials are needed; bifidobacteria or a beneficial effect of probiotics on the BMI, maybe because no
mix of strains seem to be the most effective [35,36]. genera and/or species could be associated to the pathological
6 M.-J. Butel / Médecine et maladies infectieuses (2014) 1–8

state [47,48]. Nevertheless, some clear results such as the ones delivered by C section to children delivered normally, with a
reported by Qin et al., proving that fecal metagenomic markers potential impact on health [53]. For example, the dysbiosis
differentiated obese from non obese patients more easily than induced by a high hygiene level in developed countries has
markers of the human genome, are reasons to continue working been associated to an increased incidence of allergies in these
on microbiota modulation in the management of these diseases countries [54], for C section delivery and very premature birth
[46]. to an increased risk of being allergic [55] or obese [56], and for
very premature birth to an increased risk of being allergic [57].
6.7. Other indications Other diseases have been associated to an alteration of early
colonization such as IBD [58], autism [59], or type 1 diabetes
Other indications have been suggested but with, currently, [60].
an insufficient level of proof. Some relationships have been Many clinical trials focusing on an early probiotic supple-
found among dysbiosis, dysfunctions and/or alterations of the mentation in full-term neonates have been conducted. The
metagenome, and diseases supporting a probiotic approach [49]. European Society of Pediatric Gastroenterology, Hepatology,
The gut microbiota, via the production of toxic metabolites, was and Nutrition (ESPGHAN) recently published a review of these
implicated in the genesis of GI cancers, and some bacterial gen- trials [61]. The authors did not conclude on any significant
era, such as lactobacilli, have shown protective effects against clinical benefit of early supplementation, which is why it is
cancerogenesis [50]. It is thus justified to believe that manip- not currently recommended. Nevertheless, some authors have
ulation of the microbiota may have beneficial effects at least reported beneficial effects such as the decrease of GI infections, a
in the prevention of some GI cancers. There is evidently more decreased use of antibiotics, and a weaker incidence of diarrhea.
data from animal models. In this case also, the effects depend The prevention of allergy seems to be an interesting indication
on the probiotic strains administrated and seem more effective for children at high risk of allergy [62], even if this effect was
for prevention. There is much less data in human models, partly not reported in every study. The Cochrane Library published a
because large cohorts are needed and for a long-term follow-up. meta-analysis and concluded on the potential interest of probio-
Using probiotic strains genetically modified for the production tic use in the prevention of allergy [63]. Furthermore, the authors
of anti-proliferative or pro-apoptotic factors could be very help- of a study tested the effectiveness of probiotic supplementation
ful. Elena Serban, in an excellent and very recent review, made for the prevention of obesity, and reported a trend of body mass
a very complete update of breakthroughs in this domain [50]. index (BMI) decrease at 4 years of age [64].
The authors of some studies have suggested a contribution Currently, the most evident contribution of early probio-
of probiotics in the prevention of upper respiratory tract infec- tic administration for very premature neonates is to decrease
tions. The Cochrane Library recently published a meta-analysis the incidence of necrotizing enterocolitis (NEC), the first GI
including the results of 10 randomized controlled clinical trials. emergency in premature neonates born before 33 weeks of ges-
The administration of probiotics, mostly lactobacilli and bifi- tation. Indeed, the microbiota establishment is quite disrupted
dobacteria, was beneficial with a decreased number of the upper in these neonates who are more often delivered by C-section
respiratory tract infections [51]. Nevertheless, the level of evi- and frequently receive broad-spectrum antibiotics [53]. This
dence for the use of probiotics in this indication remains low very abnormal microbiota, with especially a very prolonged
because of the great heterogeneousness among studies, espe- delay before colonization by bifidobacteria, is a risk factor for
cially for their main objective, and for some types of infections NEC. The authors of some clinical trials have reported the
because of the small number of patients included. Once again, decreased incidence and severity of NEC in premature babies
some complementary trials must be made before recommending having been supplemented with one or several probiotic strains.
probiotics in this indication [52]. The authors of all the reviews and meta-analyses concluded
on the contribution of this type of supplementation, but ques-
6.8. Probiotics in pediatrics tioned its effectiveness in neonates with a very low birth weight
(< 1,000 g) [65,66]. Nevertheless, despite this analysis [66], this
The colonization of neonates in the first weeks of life is a supplementation is still not routinely used by neonatologists,
crucial step for the implementation of its different functions: the maybe because of the lack of documentation on the mechanism
immune system is not mature at birth and the sequential col- of action, as well as because of the potential risk induced by this
onization of the digestive tract during the neonatal period has bacterial supplementation in a very premature neonate. Some
an impact on restoring of the Th1/Th2 balance. The neonate is studies are currently ongoing to determine the ideal probiotic,
born with a Th2 profile and a dysbiosis may prevent the switch the dose, and the optimal administration algorithm.
from Th2 to Th1, potentially affecting health, a Th2 orientation
being a risk factor for presenting with an allergic disease. This 7. Conclusion
concept is the basis for what was called the “hygiene theory”,
“the excess of hygiene” in developed countries, especially during It is currently acknowledged that the gut microbiota inter-
delivery, being responsible for a modification of the microbiota acts with human health and that its modulation by probiotics
implementation resulting in an inadequate maturation of the and/prebiotics is an interesting way to prevent some diseases.
immune system [39]. Such early dysbiosis may have a prolonged But the effectiveness has not been proven in too many indi-
impact for many months, as was proven by comparing children cations, limiting the current recommendations for probiotic use.
 M.-J. Butel / Médecine et maladies infectieuses (2014) 1–8 7

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