Nutrients 15 00643 v2

nutrients
Review
Pathogen-Specific Benefits of Probiotic and Synbiotic Use in
Childhood Acute Gastroenteritis: An Updated Review of
the Literature
Maria Oana Săsăran 1 , Cristina Oana Mărginean 2, * , Heidrun Adumitrăchioaiei 3 and Lorena Elena Melit, 2
1 Department of Pediatrics III Faculty of Medicine in English, George Emil Palade University of Medicine,
Pharmacy, Science, and Technology of Târgu Mures, , Gheorghe Marinescu Street No 38,
540136 Târgu Mures, , Romania
2 Department of Pediatrics I, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of
Târgu Mures, , Gheorghe Marinescu Street No 38, 540136 Târgu Mures, , Romania
3 Doctoral School of Medicine, George Emil Palade University of Medicine, Pharmacy, Science, and Technology
of Târgu Mures, , Gheorghe Marinescu Street No 38, 540136 Târgu Mures, , Romania
* Correspondence: marginean.oana@gmail.com
Abstract: Probiotics represent viable microorganisms which are found within the normal gut micro-
biota, that exert strain-specific benefits in the management of several gastrointestinal disorders in
children, including acute gastroenteritis. This review aims to evaluate the pathogen-specific role of
probiotic supplementation in childhood diarrhea. A search of scientific databases was conducted
to identify studies which investigated efficacy of probiotics and synbiotics in influencing outcome
of acute gastroenteritis of known etiology. We identified 32 studies, most of which analyzed impact
of probiotic supplementation in rotavirus gastroenteritis, while a very limited number of these con-
ducted a separate analysis on bacterial diarrhea. Lactobacillus rhamnosus (L. rhamnosus), L. reuteri and
S. boulardii still remain the most researched strains, with a proven role in decreasing diarrhea and hos-
pitalization duration, especially in the setting of rotavirus infection. Combined products containing
Citation: Săsăran, M.O.; Mărginean,
at least one of the aforementioned strains also performed similarly and might also influence rotavirus
C.O.; Adumitrăchioaiei, H.; Melit, , fecal shedding. Rotavirus immunization status has also been proposed as a significant influencing
L.E. Pathogen-Specific Benefits of factor of probiotic use impact. The paucity of research focusing on bacterial etiologies, as well as of
Probiotic and Synbiotic Use in clinical trials conducted within ambulatory care units leaves room for further research on the matter,
Childhood Acute Gastroenteritis: An which needs to include larger cohort studies.
Updated Review of the Literature.
Nutrients 2023, 15, 643. https:// Keywords: probiotics; synbiotics; rotavirus infection; bacterial diarrhea; children
doi.org/10.3390/nu15030643
Academic Editors: Stefano

Guandalini and Ruggiero
Francavilla 1. Introduction
Probiotics have been defined as oral supplements which contain viable microorgan-
Received: 8 January 2023
isms, in the form of bacteria and yeasts similar to those found within the microbiota of
Revised: 24 January 2023
Accepted: 25 January 2023
the normal, healthy gut [1,2]. The first evidence available in the literature regarding their
Published: 27 January 2023
existence comes from Henry Tissier, who was the first person to remark on a poorer stool
bacterial culture in children infected with diarrhea, as well as in those fed with formula,
as opposed to healthy and breastfed infants [3,4]. Since the publication of these first data
in 1907, many studies have emerged, but their poor design and inadequate cultivation of
Copyright: © 2023 by the authors. bacteria in substrates other than human milk initially hindered the acquisition of reliable
Licensee MDPI, Basel, Switzerland. evidence. However, later research, and the ability to isolate and characterize specific bacte-
This article is an open access article rial cultures, showed the numerous health benefits of probiotics, which have been proven
distributed under the terms and to improve intestinal health, alleviate symptoms related to lactose intolerance and decrease
conditions of the Creative Commons the risk of developing disorders such as inflammatory bowel disease, infectious diarrhea
Attribution (CC BY) license (https:// or allergies [3,5]. Thus, their administration in adequate amounts can be beneficial for the
creativecommons.org/licenses/by/ host and their lack of side effects has encouraged their widespread use [6].
4.0/).
Nutrients 2023, 15, 643. https://doi.org/10.3390/nu15030643 https://www.mdpi.com/journal/nutrients

Nutrients 2023, 15, 643 2 of 18
Ensuring the equilibrium and integrity of intestinal microflora facilitates a functioning

intestinal mucosal defense system, which in turn will trigger an appropriate immune
response of the intestinal mucosa after exposure to non-self-antigens [7]. Probiotic products
can interfere with the ability of invasive species to interact with endothelial receptors,
can positively impact the integrity of enterocyte tight junctions, can stimulate local mucin
production (Lactobacillus species) or the production of lactic acid and hydrogen perox-
ide which lowers intraluminal pH [8,9]. Thus, probiotic strains not only create a hostile
environment for potential pathogens, but also enhance protection of the intestinal mu-
cosa from external aggression. Probiotic effects vary from one strain to the other. For
example, Saccharomyces boulardii (S. boulardii) is one of the protease-producing probiotics
which promote neutralization of toxins such as those produced by Escherichia coli (E. coli),
Clostridium difficile or Vibrio cholerae [10]. Lactobacilli species, on the other hand, produce
β-galactosidase, an enzyme with a proven role in preventing diarrhea and facilitating
lactose digestion [11].
As ongoing research provided insights into the role of probiotics in modulating mu-
cosal immune response and combating antigen invasion, multiple randomized controlled
trials assessed the role of probiotics in decreasing severity and duration of diarrhea-
related symptoms and results obtained have constituted the basis of meta-analysis pub-
lications [12–14]. Most of these published trials have included pediatric populations, as
diarrhea represents a major health burden at young ages, constituting one of the leading
causes of morbidity and mortality under the age of 5 years [15]. The strains which were
most frequently analyzed were Lactobacillus rhamnosus GG (L. rhamnosus GG) and S. boulardii,
which also constitute the two major probiotics universally recommended through con-
sensus statements, alongside with L. reuteri, in the management of acute gastroenteritis
in children for decreasing symptom intensity and duration [16]. European guidelines
sustain the use of L. rhamnosus GG and S. boulardii for 5–7 days, as adjuvant to oral re-
hydration solutions in childhood acute gastroenteritis, after consistent expert agreement,
whereas American guidelines sustain the use of probiotic preparations in both infectious
and antimicrobial-related diarrhea in children and adults, but only based on weak and
moderate evidence [16,17]. Moreover, an update on the treatment of childhood acute
gastroenteritis provided in 2020 by the Working Group on Probiotics and Prebiotics of the
European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)
also sustained the use of a combination between L. rhamnosus and L. reuteri and recom-
mended against the simultaneous use of L. helveticus and L. rhamnosus, as well as against
the use of Bacillus clausii (B. clausii) strains [18]. Thus, in spite of multiple probiotic strains
available on the market, only a few have demonstrated their superiority in decreasing
symptom intensity and duration of acute gastroenteritis compared to placebo and are as a
result recommended as adjuvant therapies.
The beneficial probiotic effects seem to be strain specific, not only in the setting
of acute gastroenteritis, but also in the prevention of antibiotic-associated diarrhea, the
management of infantile colic or the treatment of other digestive tract conditions, such as
Helicobacter pylori gastritis [19,20]. However, there are few reports available regarding the
pathogen-specific benefits of probiotic strains, with a particular focus given in recent years
to the outcome of probiotic supplementation upon the evolution and severity of diarrheic
episodes with known etiology [21,22].
This review aims to investigate the pathogen-specific role of probiotic and synbiotic
supplementation in pediatric acute gastroenteritis, in light of recent literature data.
2. Methods
We searched the Pubmed, Web of Science and Google Scholar databases for random-
ized controlled trials and pediatric population-based studies which have evaluated efficacy
of probiotics and synbiotics in influencing outcome of acute gastroenteritis. We only fo-
cused on those studies which included patients with a known infectious etiology of the
diarrheic disease or which had also performed a separate analysis on subgroups in which
Nutrients 2023, 15, 643 3 of 18
a certain viral or bacterial causative agent was identified or on those cohorts in which
rotavirus vaccination status was known. We refrained from reporting data provided by
publications limited to abstract formats or by in-extenso manuscripts written in a language
different from English. Search terms used included “probiotic” AND “diarrhea” AND
“child”, or “probiotic” AND “gastroenteritis” AND “child” or “probiotic” AND “rotavirus”
or “prebiotic” AND “diarrhea” AND “child”, or “prebiotic” AND “gastroenteritis” AND
“child” or “prebiotic” AND “rotavirus” or “synbiotic” AND “diarrhea” AND “child”, or
“synbiotic” AND “gastroenteritis” AND “child” or “synbiotic” AND “rotavirus”.
3. Results
We identified 32 studies which complied with our inclusion and exclusion criteria, as
summarized in Tables 1–4. Most of these studies assessed the influence of probiotics on
rotaviral diarrhea, whereas a very limited number of clinical trials evaluated the impact of
probiotics upon bacterial diarrhea-related symptoms and aftermath. The most intensely
researched probiotics on this subject still remain L. rhamnosus, L. reuteri and S. boulardii, but
a few others have also showed promising potential in combating the burden of rotaviral
or bacterial diarrhea-related hospitalizations and complications. In this paper, we will
provide a background on probiotics and synbiotic products and detail how these impact
the outcome of childhood acute gastroenteritis with an identified etiology.
3.1. Lactobacillus rhamnosus

L. rhamnosus has been proven to be one of the probiotics that can positively influence
hospital stay length, as well as diarrhea duration (Table 1) [23]. A European multicenter
trial, which randomized an impressive number of children aged 1 month to 3 years of age
demonstrated that a combination of oral rehydration and L. rhamnosus is superior to oral
rehydration alone in terms of reducing hospitalization duration and number of watery
stools after 3 days of diarrhea evolution. Recovery from watery stools was significantly
more rapid in those subjects whose stool samples were positive for rotavirus infection.
Bacterial etiologies were scarcely detected, not allowing for a convenient statistical analysis,
but no differences were reported in terms of diarrhea duration in these cases, independently
of the study group allotment [24]. Likewise, a randomized controlled trial conducted in
India highlighted the benefits of L. rhamnosus in decreasing diarrhea extent and timespan
of parenteral rehydration, but only in those subjects confirmed with rotavirus infection, as
opposed to other etiologies [25]. Similar results were reported by Guarino et al., with a
slightly more consistent reduction of diarrhea duration in children diagnosed with rotavirus,
as well as of fecal viral identification after 6 days of diarrhea onset [26]. Another study,
conducted in Taiwan, suggested that L. rhamnosus also aids in decreasing the extent of fecal
elimination of rotavirus, in a dose-dependent manner [27]. On the other hand, increase
in stool consistency and recovery from diarrheic stools took place after a shorter amount
of time with L. rhamnosus administration, but independently of the presence of rotavirus
fecal shredding, according to the study of Aggarwal et al. [28]. Moreover, a meta-analysis
reported a better performance of L. rhamnosus in children who had not received a vaccine
against rotavirus and a lack of significant difference in gastroenteritis outcome in those
who were immunized [29]. In terms of bacterial infections, data are scarce; one Indian
study in which a little over 60% of the stool cultures were negative, but which individually
assessed the role of L. rhamnosus in relation to each particular type of pathogen identified
in the stool samples, concluded that its efficacy is limited to reducing diarrhea duration
in Clostridium difficile positive patients. However, this conclusion is supported by a very
limited number of cases [23].
Two randomized clinical trials which analyzed the efficacy of a combined probiotic
strain containing L. rhamnosus and L. helveticus reported no virus-specific benefit over
placebo in terms of reducing viral load at 28 days post-enrollment, nor in decreasing inten-
sity of clinical symptoms. Both studies included children diagnosed with gastroenteritis of
viral etiologies (norovirus, rotavirus, adenovirus), as well as of bacterial etiologies [21,22].
Nutrients 2023, 15, 643 4 of 18
Still, a decrease in number of diarrhea episodes caused by adenovirus infection was noted
(Table 1) [22].
There are limited reports regarding the efficacy of L. rhamnosus in the absence of
hospitalization. An Indian study reported a significant reduction in diarrhea episodes
during a follow-up period of 4 weeks in recipients of L. rhamnosus diagnosed with rotavirus
gastroenteritis, as opposed to those with Crytosporidial diarrhea, in whom administration
of the same probiotic showed no benefit compared to placebo. L. rhamnosus also seemed
to augment specific IgG (and not IgA) production against rotavirus, but did not influence
antibody levels for Cryptosporidium species (Table 1) [30]. Another randomized controlled
trial, conducted in Uganda, highlighted the benefit of both L. rhamnosus and S. boulardi
in reducing diarrhea episodes only in outpatient settings in children with severe acute
malnutrition, and not in those who required hospitalizations. The study suggested that
both strains do not influence the outcome and evolution of severe gastroenteritis, but
provided no data regarding etiology of the diarrheic manifestations [31].
Table 1. Characteristics of clinical studies which assessed overall and pathogen specific impact of
L. rhamnosus supplementation in childhood diarrhea.
Type of Intervention
Reference (Author, Population and Study
Type of Study Main Outcome Pathogen Specific Benefits
Year) Group Assignment Intervention/Study Duration of
Control Group
Group Treatment/Dosage
• Rotavirus positive
patients: reduction in
duration of diarrhea,
in number of watery
stools starting from
287 children, with ages: Reduction in duration the 3rd day of
Guandalini et al., Double-blind
1 month–3 years
L. rhamnosus + ORS Dosage: 1010 CFU/ of diarrhea and treatment and in
147 in intervention ORS 250 mL 2×/days; hospitalization period hospitalization period
2000 [24] RCT
group up to 7 days in the intervention in the intervention
140 in placebo group group group
• Invasive
pathogens—no
significant differences
between intervention
and control group
Rotavirus positive patients:

No influence upon
significant reduction of
87 children with ages Three L. rhamnosus Dosage: duration of diarrhea, of
diarrhea duration, especially
Szymański et al., Double-blind 2 months–6 years strains. (573L/1, parenteral rehydration,
2006 [25] RCT 49 in intervention group 573L/2, 573L/3) +
ORS/IV rehydration 1.2 × 1010 CFU nor of weight gain
within the first 72 h of
2×/days, 5 days treatment; overall reduction in
44 in control group ORS/IV rehydration within the entire
duration of parenteral
intervention group
rehydration

slightly greater efficacy of L.
100 children with ages: Significant reduction in rhamnosus in reducing
Double-blind 3–36 months L. rhamnosus + oral Oral rehydration Dosage: 3 × 109 CFU in diarrhea duration in the diarrhea duration; significant
Guarino et al., 1997 [26] 200 mL milk or formula,
RCT 52 in intervention group rehydration therapy therapy intervention group reduction in viral excretion
48 in control group 2×/days, up to 5 days versus control group 6 days after the onset of
diarrhea in the
intervention group
• Significant
reduction in
fecal rotavirus
concentration
Dosage: in the
23 patients with ages: low-dose group— high-dose
9–72 months 2 × 108 L. rhamnosus + group after
low-dose group and
9 in the low-dose group, Simethicone 80 mg/day 3 days of The study included only
Fang et al., 2009 [28] RCT high-dose group—L. Simethicone 80 mg/day
8 in the high-dose high-dose group— treatment rotavirus positive patients
rhamnosus+ Simethicone
group, 6 in 6 × 108 L. rhamnosus + • No significant
control group Simethicone 80 mg/day, difference in
3 days fecal rotavirus
shedding in the
low-dose and
control group
after 3 days
Significant reduction in
200 children with ages: Significant reduction in
L. rhamnosus + Standard duration of diarrhea and in
6 months–5 years duration of diarrhea
Aggarwal et al., 2014 Open Label
100 in intervention
manage-ment (ORS/IV
Standard management Dosage: 1010 CFU once and in time to
time to improvement in stool
[28] RCT rehydration + zinc daily, 5 days consistency independently of
group improvement in stool
20 mg/day for 14 days) the presence/absence of
100 control group consistency
Rotavirus fecal antigen
235 children with ages: Dosage: 60 million cells

2–6 years dissolved in ORS twice Significant reduction in C. difficile positive patients:
Double-blind
Basu et al., 2007 [23] 117 in intervention L. rhamnosus + ORS ORS daily, at least duration of diarrhea Significant reduction in
RCT
group 7 days/until diarrhea and hospital stay duration of diarrhea
118 control group stopped
Nutrients 2023, 15, 643 5 of 18
Table 1. Cont.
Reference (Author, Population and Study
Type of Study Main Outcome Pathogen Specific Benefits
Year) Group Assignment Intervention/Study Duration of
Control Group
816 patients with ages: Dosage: 4 × 109 CFU L. No significant changes

L. rhamnosus RO011 + L. rhamnosus RO011 + L.
3–48 months in disease severity,
Freedman et al., Double-blind helveticus RO052 helveticus No significant reduction in
408 in intervention Standard therapy assessed using the
2020 [21,22] RCT (95:5 ratio) + standard RO052(95:5 ratio) + stool viral and bacterial load
group modified Vesicari
therapy standard therapy twice
408 control group score [32]
daily, 5 days
Dosage:
US Group—received
only L. rhamnosus— No significant reduction in
US Group—370 with L.
1010 CFU, twice daily, stool viral and bacterial load
1565 patients with ages: rhamnosus GG No significant changes
5 days Adenovirus positive patients:
Two 3–48 months Canadian Group—408 in disease severity,
Freedman et al., Canadian Group— significant decrease in number
Double-blind 778 in intervention L. rhamnosus RO011 + L. Standard therapy assessed using the
2022 [22]
RCT group helveticus RO052 (95:5 4 × 109 CFU L. modified Vesicari
of diarrhea episodes in those
rhamnosus RO011 + L. supplemented with L.
787 control group ratio) + standard score [32]
helveticus RO052 (95:5 rhamnosus RO011 + L.
therapy
ratio) + standard helveticus RO052
therapy twice daily,
5 days

significant reduction in
124 children with ages: No influence of the diarrhea episodes,
6 months–5 years (82 probiotic product upon augmentation of specific IgG
L. rhamnosus GG +
with Rotavirus and 42 Placebo + antibiotic diarrhea duration, antibody production against
Sindhu et al., 2014 [30]
Double-blind
with Cryptosporidium
antibiotic treatment (in
treatment (in case of Dosage: 1010 CFU once severity, fever, rotavirus
RCT case of positive stool per daily for 4 weeks
Species) positive stool culture) frequency of vomiting Cryptosporidium positive
culture)
65 in intervention group episodes, dehydration patients: no influence upon
59 in control group status or hospital stay diarrhea duration compared to
placebo; no impact on specific
antibody levels
Legend: CFU—colony forming units; C. difficile—Clostridium difficile; IV—intravenous, L. helveticus—

Lactobacillus helveticus; L. rhamnosus—Lactobacillus rhamnosus; ORS—oral rehydration solution; RCT—randomized
controlled trial.
3.2. Saccharomyces boulardii

S. boulardii has been regarded as the most effective agent in reducing duration of
diarrhea (including the risk of an evolution of loose stools over 2 days) and is apparently
superior to other strains such as B. lactis, L. rhamnosus, L. reuteri and L. paracasei, according
to a meta-analysis conducted on 84 studies [33]. Moreover, its advantages over B. clausii
in shortening diarrhea extent have been highlighted within a randomized trial, which
also showed comparable performance of the two strains in terms of hospitalization, fever
duration and number of vomiting episodes [34]. These results contradict former scientific
reports such as that of Gaon et al., which claimed that S. boulardii’s efficacy is similar to the
efficacy of a combination between L. casei and L. acidophilus in diminishing diarrhea and
vomiting, when compared to placebo and is independent of Rotaviral etiology (Table 2) [35].
Table 2 details characteristics and results of studies which analyzed overall and
pathogen-specific impact of S. boulardii in pediatric gastroenteritis. One randomized con-
trolled trial conducted in India certified the advantages of S. boulardii over a similar product
in rotavirus-associated diarrhea, without any adverse events, but only in terms of hospital-
ization duration. No difference from controls was seen in terms of fever duration, vomiting
episodes, proportion of children requiring parenteral rehydration or with diarrhea lasting
for more than one week [36]. Similarly, another study conducted by Dalgic et al. established
a significant decrease in duration of hospitalization and diarrhea in children diagnosed with
rotavirus infection, supplemented with both S. boulardii and zinc, as opposed to controls.
Moreover, the authors also demonstrated that this adjuvant therapeutic combination can
also accentuate resolution of vomiting [37]. On the other hand, a Bolivian randomized
controlled trial reported that number of recurrent vomiting episodes is decreased in pa-
tients receiving an oral rehydration therapy in combination with S. boulardii, B. longum, L.
rhamnosus and L. acidophilus as opposed to those which only benefited from the addition of
S. boulardii in their treatment or who received placebo together with oral rehydration solu-
tions (ORS). Still, S. boulardii alone showed a better outcome than the four-strain product
and placebo in shortening the number of days with fever and diarrhea in children infected
with rotavirus [38]. Apparently, a three-day treatment with S. boulardii performed even
better in inhibiting release of watery stools in pre-school children who tested positive for
rotavirus, unlike in those who were negative for the virus [39].
Nutrients 2023, 15, 643 6 of 18
Persistent, prolonged elimination of rotavirus in feces has been reported even in

vaccinated children and represents a source of community-acquired infection [40]. S.
boulardi might be a potential inhibitor of rotavirus fecal shedding, with absence of fecal
virus detection after 5 days of administration, as suggested by a multicenter, case-control
clinical trial. This conclusion was, however, supported by a very limited number of
cases [41].
Table 2. Characteristics of clinical studies which assessed overall and pathogen specific impact of S.
boulardii supplementation in childhood diarrhea.
Reference (Author, Population and Study Pathogen Specific
Type of Study Main Outcome
Year) Group Assignment Intervention/Study Duration of Benefits
Control Group
Dosage:
89 children with ages: S. boulardii group
6–24 months 1010 CFU/g twice daily
Similar significant
29 in control group Group 2: S. boulardii for 5 days No specific benefits in
reduction in vomiting,
Double-blind (group 1). Group 3: Pasteurized Group 1: Pasteurized Group with: relation to the
Gaón et al., 2003 [35] diarrhea duration and
RCT 30 in S. boulardii cow milk with L. casei cow milk + ORS Pasteurized cow milk presence/absence of
number of stools in
(group 2) and L. acidophilus with L. casei rotavirus fecal antigen
both study groups
30 in Lactobacilli group and L. acidophilus:
(group 3) 1010 –1012 CFU/g twice
daily for 5 days
diarrhea duration and
hospitalization period
60 children with ages: No influence on fever
The study included
Double-blind 3 months–5 years Dosage: 250 mg and vomiting duration
Das et al., 2016 [36] S. boulardii Placebo only rotavirus positive
RCT 30 in intervention group 2×/day for 5 days nor on proportion of
patients
30 in control group children who required
parenteral rehydration
or presented diarrhea
lasting for >7 days
Group 1: S. boulardii
Group 2: zinc (Zn)
Group 3: lactose-free Dosage:
480 children with ages: formula (LF) S. boulardii—250 mg Statistically significant
1–28 months, divided Group 4: S. boulardii + once daily 5 days decrease in
Single Group 8 (control group): The study included
into 7 intervention Zn Zn—10 mg 2×/day in diarrhea duration and
Dalgic et al., 2011 [37] Blind −ORS and/or only rotavirus positive
groups and 1 control Group 5: S. boulardii + infants < 6 months; hospitalization time in
RCT parenteral rehydration patients
group (60 patients LF 20 mg 2×/day in groups 2 and 4 versus
included in each group) Group 6: Zn + LF, infants/children controls
Group 7: Zn + LF + S. > 6 months
boulardii + ORS and/or
parenteral rehydration
Dosage:
For S. boulardii— Statistically significant
4 × 1010 lyophilized reduction in diarrhea
cells/dose 2×/day for duration in both study
5 days groups versus control;
64 hospitalized children
Group GB: S. boulardii + For combined probiotic S. boulardii alone
with ages: 1–23 months
ORS product—(L. acidophilus performed better than
divided in 3 groups
Group GARLB: 6.625 × 107 lyophilized the combined product The study included
Double-blind Group GC (control):
Grandy et al., 2010 [39] combined probiotic Placebo cells/dose, L. rhamnosus in this regard only rotavirus positive
RCT 20 children
product (L. acidophilus, Significant reduction in patients
Group GB: 21 children
L. rhamnosus, B. longum 3.625 × 107 lyophilized diarrhea and vomiting
Group GARLB: cells/dose, B. longum
and S. boulardii) duration when
23 children 8.75 × 106 lyophilized comparing the merged
cells/dose and S. intervention groups
boulardii) 1.375 × 107 versus placebo
lyophilized cells/dose)
2×/day for 5 days
Statistically significant
decrease in frequency Rotavirus positive
176 patients with ages: and duration of patients—statistically
Corrêa et al., 2011 [39]
Double-blind 6–48 months
S. boulardii Placebo—excipients Dosage: 4 × 109 viable diarrhea if S. boulardii significant decrease in
RCT 90 in intervention group cells 2×/day for 5 days was administered frequency of diarrhea
86 in control group during the first three after 3 days of
days of gastroenteritis intervention
evolution
Dosage: S. boulardii 5; ×, Significant increase in

Rotavirus positive
stool consistency
100 children with ages: 109 , living cells 2×/day starting from day three
patients: absence of
for 5 days fecal virus detection
Double-blind 3–36 months of intervention
Mourey et al., 2020 [41] S. boulardii + ORS + Zn Placebo + ORS + Zn Zn—10 mg 1×/day in after 5 days of
RCT 49 in intervention group Significant decrease in
infants < 1 year; 20 mg treatment in old
51 in control group time of recovery from
1×/day in children > 1 patients belonging to
diarrhea in the
year the intervention group
intervention group
Legend: CFU—colony forming units; L. acidophilus—Lactobacillus acidophilus; L. casei—Lactobacillus casei;

LF—lactose-free formula; ORS—oral rehydration solution; RCT—randomized controlled trial; S. boulardii—
Saccharomyces boulardii; Zn—zinc.
3.3. Lactobacillus acidophilus

L. acidophilus has been one of the bacteria widely used alone or as part of combined
products for the treatment of acute diarrhea in children, in spite of insufficient evidence
available [2]. The suppositions surrounding the potential beneficial effects of this strain
emerged from evidence supporting its involvement in inhibition of bacterial invasion
Nutrients 2023, 15, 643 7 of 18
of epithelial intestinal cells, a consistent characteristic of other Lactobacilli as well [42].

L. acidophilus can also augment specific immune reactions and is stable at high temperatures,
so it is unsurprising that several compounds appeared on international markets, which
claimed to deliver relief of gastroenteritis-associated symptoms [43]. However, one study
and a meta-analysis reported no benefit regarding its complementary use in those pedi-
atric gastroenteritis cases in which an etiological factor was identified from the analyzed
stool specimens [44,45]. In similar fashion, one randomized controlled trial reported no
clear advantage of L. acidophilus over placebo in cases where rotavirus or norovirus was
identified, neither in terms of reducing symptom duration, nor in terms of diminishing
stool viral load [46]. Some evidence emerged regarding the advantages of L. acidophilus
in shortening hospitalization duration or number of days with fever, but only in patients
with unknown etiology of the diarrhea or in whom a rotavirus infection was excluded, as
detailed in Table 3 [44,47,48]. Salazar-Lindo et al. also reported a lower number of stools
in those children supplemented with L. acidophilus suffering from mild diarrhea, but in
their study cohort an infectious agent (namely rotavirus) was identified in only a very
limited number of patients [49]. Given the inconsistent results reported by various stud-
ies, a meta-analysis conducted by authors belonging to the Working Group on Probiotics
and Prebiotics of the ESPGHAN concluded that there is insufficient evidence available to
support the administration of L. acidophilus in childhood acute gastroenteritis [50].
3.4. Lactobacillus reuteri

L. reuteri strains are able to modulate lipopolysaccharide-induced intestinal inflamma-
tion and reduce mucosal damage caused by enteric infections in rats [51]. Both anti-bacterial
and anti-inflammatory effects have been associated with their use, as demonstrated in a
murine model in which the administration of L. reuteri antagonized the extension of enteral
mucosa inflammation and C. difficile infection [52]. Moreover, two in vitro studies also con-
firmed L. reuteri’s potential in combating E. coli growth [53], modulating immune response
against Salmonella typhimurium [54] and another study conducted on rats related its use
with the development of mucosal rotavirus-specific IgA production [55]. A randomized
controlled trial conducted in pre-school children asserted the protective effect of L. reuteri
against infectious diarrhea, which lasted through a follow-up period of 3 months after
previous administration of the product for the same amount of time (Table 3) [56].
Shornikova et al. reported amelioration of diarrhea in a small pediatric cohort which
received L. reuteri, as opposed to placebo, with most of the patients belonging to the
intention-to-treat group not experiencing any watery stools after two days of probiotic
supplementation. Given that rotavirus infection was identified in 75% of the study pop-
ulation, the authors proposed L. reuteri as a potential therapeutic adjuvant in rotavirus
enteritis. However, the study failed to identify any significant increase in specific rotavirus
IgA antibody titer in the L. reuteri recipient group [57]. Another research study by these
authors, performed on a rotavirus cohort in children aged between 6 and 36 months,
confirmed the significant reduction in the duration of watery diarrhea associated with
L. reuteri administration, as well as a good restoration of the enteral microbiota in this
setting (Table 3) [58].
A Botswanian pediatric randomized controlled trial which included subjects vacci-
nated against rotavirus found no significant association between the administration of
L. reuteri and acute gastroenteritis outcome, whether viral or bacterial. No notable repli-
cation inhibition of bacteria such as Shigella, Campylobacter, Enteropathogenic E. coli or
Cryptosporidium was reported, but the study did not separately evaluate the subpopulation
in which enteric viral infections were found in feces samples, as most of those children
also presented another viral/bacterial co-infection [59]. Moreover, a Polish study found no
benefit of L. reuteri on diarrhea-related outcomes, regardless of rotavirus vaccination status,
but the infectious etiology was unknown in most of the patients enrolled [60].
Nutrients 2023, 15, 643 8 of 18
3.5. Lactobacillus plantarum

Lactic acid bacteria have the ability to attach to cellular monolayers, exerting protec-
tion against rotavirus, as well as against the transmissible gastroenteritis virus (TGEV),
according to Maragkoudakis et al. [61]. Out of all the Lactobacillus species studied, L. plan-
tarum had the highest attachment ability and was found to have an antiviral effect against
both viruses, as proven by the same experimental study [61]. Another study performed
on mice proved that exopolysaccharides released by L. plantarum effectively reduce the
number of diarrheic episodes and rotaviral shedding [62]. The decrease in rotavirus load
in subjects supplemented with a L. plantarum product was later confirmed by research
conducted in children, which also showed a significant decrease in diarrhea duration and
in its severity (assessed through daily changes in Vesikari score—Table 3 [32]) [63].
probiotic L. acidophilus, L. reuterii and L. plantarum in childhood diarrhea.
Control Group
Patients with positive

Significant decrease in
stool studies (positive
diarrhea duration of IV
L. acidophilus mixture stool culture, positive
290 children with ages:
(80% L. acidophilus, 10% Dosage: 1 × 109 CFU/g rehydration among the
stool for C. difficile toxin,
Pinto et al., 2016, Retrospective 6–60 months 2×/day (no study group
L. bulgaricus, Standard treatment positive rotavirus
2016 [44,47] cohort study 65 in study group information regarding No influence of the
5% B. bifidum, antigen)—no benefits
225 in control group duration of treatment) probiotic
5% S. thermophilus from probiotic use as
supplementation upon
opposed to those with
length of hospital stay
negative stool studies
No significant benefit of
probiotic products in
98 children with ages: reducing mean diarrhea Rotavirus positive
Double-blind 6 months–12 years Dosage: 1.5 × 1010 duration, mean ORS patients—no beneficial
Khanna et al., 2005 [46] L. acidophilus + ORS ORS tyndalized cells 1×/day
RCT 48 in intervention group requirement, mean effect in the
50 in control group for 3 days rehydration period and intervention group
duration of hospital
stay
Rotavirus/Norovirus
290 children with ages: No significant reduction positive patients—no
9–60 months L. acidophilus + ORS + Placebo + ORS + Zn + in diarrhea and significant decrease in
Hong Chau et al., Double-blind
143 in intervention Zn + antimicrobials antimicrobials were Dosage: 1 × 108 CFU hospitalization stool load and no
2018 [46] RCT cells 2×/day for 5 days
group were needed needed duration, nor in stool influence of
147 in control group frequency intervention upon
symptom duration
Shorter mean duration

of diarrhea during
hospital stay in the
intervention group
No influence on
40 children with ages: Dosage: 1010 –1011 dehydration correction No influence of the
Shornikova et al., Double-blind 6–36 months CFU/g 1×/day for and electrolyte levels of intervention treatment
L. reuteri + ORS Placebo + ORS 5 days/hospitalization
1997 [57] RCT 19 in intervention group the probiotic upon rotavirus IgA
21 in control group period (if shorter than supplementation antibody production
5 days) Significant reduction in
vomiting after the
second day of treatment
in the intervention
group
Large dose of L. reuteri

Dosage:
yielded a significant
Small dose: 2.5 × 106 – The study included
Group 1: L. reduction in duration
66 children with ages: 5 × 106 CFU/mL only rotavirus positive
reuteri—small dose + and frequency of
6–36 months 1×/day for a maximum patients
Shornikova et al., Double-blind ORS diarrhea after 2 days of
20 in group 1 Placebo + ORS of 5 days No influence of L.
1997 [58] RCT Group 2: L. treatment
21 in group 2 reuteri upon rotavirus
25 in control group
reuteri—large dose + Large dose: 5 × 108 – Good restoration of
IgA and IgG antibody
ORS enteral microbiota in
2.5 × 109 CFU/mL titers
both intervention
1×/day for 5 days
groups
No significant impact of
the probiotic strain Patients with positive
upon recurrence of stool culture for Shigella,
272 children with ages: L. reuteri + Placebo +
diarrhea, length of Campylobacter,
Multicentric 2–60 months ORS/parenteral IV ORS/parenteral IV
Pernica et al., 2022 [59] double-blind 135 in intervention rehydration + antibiotic rehydration + antibiotic Dosage: 1 × 108 CFU/g hospital stay, enteropathogenic E. Coli
1×/day for 60 days developmental of or Cryptosporidium: no
RCT group treatment (were treatment (were
sepsis, 7-day and notable replication
137 in control group needed) needed)
60-day mortality rate inhibition of the
during the follow-up identified bacteria
period of 60 days
Nutrients 2023, 15, 643 9 of 18
Table 3. Cont.
Control Group
Children not vaccinated

against
duration of
rotavirus—significant
hospitalization in the
reduction in hospital
intervention group
stay in the intervention
91 children with ages: No influence of
group; no influence of
Szymański et al., Double-blind <5 years L. reuteri + standard Placebo + standard Dosage: 2 × 108 CFU intervention therapy
intervention therapy
2019 [60] RCT 44 in intervention group rehydration therapy rehydration therapy 1×/day for 5 days upon diarrhea duration,
upon diarrhea duration
47 in control group frequency and
Children vaccinated
recurrence, duration of
against
IV rehydration, nor
rotavirus—similar
upon improvement of
primary and secondary
Vesikari scale
outcome in both groups
stool frequency and
diarrhea duration
between group I and The study included
Group I: L. plantarum placebo in day 3 of only rotavirus positive
1–69 months Group 2: Placebo +
LRCC5310 hospitalization patients
Shin et al., 2020 [63] RCT 15 in group 1 standard Dosage: not specified
Group 3: Saccharomyces Significant decrease in Significant reduction in
8 in group 2 treatment
species diarrhea duration and rotavirus fecal titer in
27 in group 3
in changes of Vesikari group 1 versus placebo
scale when comparing
merged intervention
groups with placebo
Legend: CFU—colony forming units; IV—intravenous, L. acidophilus—Lactobacillus acidophilus; L. plantarum—

Lactobacillus plantarum; L. reuteri—Lactobacillus reuteri; ORS—oral rehydration solution; RCT—randomized
controlled trial; S. thermophilus—Streptococus thermophilus; Zn—zinc.
3.6. Combinations of Multiple Probiotic Strains

Table 4 provides insights regarding the specific beneficial use of combined probiotic
products in childhood diarrhea. A double-blind randomized controlled trial reported
effective reduction of diarrhea duration in children who were administered twice daily a
combined suspension, consisting of 6 different strains: B. longum, B. lactis, L. acidophilus,
L. rhamnosus, L. plantarum and Pediococcus pentosaceus. The study also established that each
individual component of the combined aforementioned suspension can inhibit in vitro
rotavirus infection, without cytotoxic effects on the population of cells analyzed [64]. A B.
longum and L. acidophilus mixture can also significantly shorten diarrhea duration, accord-
ing to a Korean study [65]. Another similar study demonstrated significant reduction in
hospitalization duration in children infected with rotavirus who received a mixed probiotic
preparation consisting of L. acidophilus, L. rhamnosus, B. longum and S. boulardii for at least
5 days as opposed to oral/parenteral rehydration alone [66]. A preparation containing
Bacillus mesentericus, Clostridium butyricum and Enterococcus faecalis also seems to effectively
decrease diarrhea severity in combination with symptomatic and rehydration therapy after
3 days of daily two-dose administration in patients infected with rotavirus, but not in
those infected with Salmonella [67]. Similarly, the administration of a suspension containing
L. casei, L. rhamnosus, Streptococcus thermophilus (S. thermophilus), B. breve, L. acidophilus,
L. bulgaricus and B. infantis twice daily for a minimum of 5 days reduced the number of
hospitalization days related to rotaviral diarrhea [68]. A combination of 8 probiotic strains
(L. acidophilus, L. paracasei, L. bulgaricus, L. plantarum, Bifidobacterium breve, Bifidobacterium
infantis, Bifidobacterium longum and S. thermophilus) has also been proposed as an adjuvant
therapeutic agent in rotavirus diarrhea, as it promoted a shorter recovery time and sig-
nificantly decreased the requirement of oral rehydration therapy and stool volume loss
after just two days of administration [69]. Furthermore, the simultaneous administration of
L. rhamnosus and L. reuteri supposedly reduces the detection rate of rotavirus fecal antigen
after 5 days of treatment, which suggests that these two probiotics positively interfere
with viral elimination time. Still, this evidence is supported by a study with very limited
follow-up time [70].
3.7. Synbiotic Products

Prebiotic supplements in the form of pectin-derived acidic oligosaccharides, short-
chain galacto-oligosaccharides, long-chain oligosaccharides added to a fermented milk
concentrate have been proven to enhance protection against rotavirus infection in suckling
Nutrients 2023, 15, 643 10 of 18
rats, through a presumed interaction with viral particle attachment to the enterocyte,
which consequently inhibits viral replication [71,72]. Synbiotic products, containing both
prebiotics and probiotics seem to also stimulate immune response against enteric viruses
through modulation of the interferon signaling pathway [73]. Hence, synbiotics have been
proposed as additional products to classical therapy in severe rotavirus enteritis by a review
mainly based on in vitro studies [74]. The authors acknowledged, however, that the paucity
of randomized controlled trials mandated future research investigating the preventive and
therapeutic benefits of synbiotics in rotavirus diarrhea [74].
Evaluation of etiology-based performance of synbiotics in the management of diarrhea
in children has been so far based on two randomized-controlled trials, one of them includ-
ing only patients in whom stool samples were positive for rotavirus and the other one
conducting a separate analysis on children with diarrhea triggered by the same etiological
agent [75,76]. As detailed in Table 4, Dewi et al. proved that a combination of L. casei,
L. rhamnosus, S. thermophilus, B. breve, L. acidophilus, B. infantis and L. bulgaricus and fructo-
oligosaccharides (FOS) can aid in decreasing diarrhea duration in children with rotaviral
gastroenteritis, whereas Islek et al. reported the augmentation of the same shortening
in diarrhea timespan in the study subgroup with rotavirus infection in which B. lactis
together with inulin were administered, as opposed to children infected with adenovirus
or Entamoeba histolytica, in whom the synbiotic produced no significant difference [75,76].
Another three studies have also supported products consisting of multiple probiotic strains
and FOS as complementary agents to standard treatment that can yield a shorter recovery
of stool consistency and overall decrease in duration of diarrhea [77–79]. Moreover, L. para-
casei combined with arabinogalactan and xylo-oligosaccharides can improve stool output
frequency, positively impact hospital stay and decrease parental working days absences,
according to an Australian study [80]. However, all these four studies have provided no
information regarding diarrhea etiology for any of the pediatric patients enrolled [77–80].
combined probiotic strains and synbiotic supplementation in childhood diarrhea.
Control Group
Rotavirus positive
patients—significant
diarrhea duration after
decrease in diarrhea
Combined product: 7 days of treatment
and vomiting duration
29 children with ages: B. longum, B. No significant
Dosage: 109 CFU/g after 7 days of
Double-blind 3 months–7 years lactis, L. acidophilus, L. difference in abdominal
Lee et al., 2015 [64]
RCT 13 in intervention group rhamnosus, L. plantarum
Placebo (108 CFU/each strain) pain, vomiting, fever
treatment; no significant
1×/day for 1 week difference in abdominal
16 in control group and Pediococcus duration, nor in
pain, fever duration,
pentosaceus paraclinical data
nor in paraclinical data
between the two groups
between the two groups
at the end of treatment
at the end of treatment
Dosage:
2.2 × 109 CFU/g of diarrhea duration in the
57 children with ages: probiotic mixture of B. intervention group The study included
Double-blind 9–16 months Combined product:
Park et al., 2017 [65]
RCT 28 in intervention group B. longum, L. acidophilus
Placebo longum 2 × 1010 CFU/g No impact of the only rotavirus positive
and L. acidophilus combined product upon patients
29 in control group
fever duration, diarrhea
2 × 109 CFU/g
and vomiting frequency
2×/day for 3 days
75 children with ages: Dosage:

Nitazoxanide— Significant reduction in
28 days–24 months Group 1: Nitazoxanide
15 mg/kg/day divided duration of diarrhea
25 in group 1 Group 2: combined The study included
Standard into 2 doses for 3 days and hospitalization
Teran et al., 2009 [66] Single-blind RCT (nitazoxanide group) product—L. acidophilus, only rotavirus positive
treatment Combined product— period in both
25 in group 2 L. rhamnosus, B. longum patients
intervention groups
(probiotic group) and S. boulardii 1.25 × 108 CFU/g versus placebo
25 in control group 2×/day for 5 days
Dosage: a tablet of the

combined probiotic
product contains:
3.48 × 108 CFU of a Rotavirus positive
mixture of E. faecalis Significant reduction in patients: significant
(3.17 × 108 CFU), C. diarrhea duration and reduction in diarrhea
butyricum Vesikari score in the severity after 3 days of
Combined product: E. intervention group probiotic treatment
Open Label 3 months–14 years (2 × 107 CFU) and
Huang et al., 2014 [67] faecalis, C. butyricum, B. Suportive treatment No influence of Salmonella positive
RCT 82 in intervention group B.mesentericus
mesentericus intervention therapy patients: no significant
77 in control group (1.1 × 107 CFU)
upon mild stool reduction in diarrhea
children < 6 years—
frequency and severity in patients
2 × 1 tabl/day
hospitalization duration belonging to
children 6–12 years—
intervention group
2 × 2 tabl/day
children > 12 years—
2 × 3 tabl/day
for 7 days
Nutrients 2023, 15, 643 11 of 18
Table 4. Cont.
Control Group
Combined product: hospitalization duration
60 patients with ages: L. casei, L. rhamnosus, S. in the intervention
The study included
Sobouti et al., 2016 [68] Single-blind RCT
3 months–7 years termophilus, B. breve, L. ORS/IV rehydration Dosage: 1 × 109 CFU/g group
only rotavirus positive
32 in intervention group acidophilus, L. bulgaricus, therapy 2×/day for 5 days No association was
patients
28 in control group B. infantis + ORS/IV found between
rehydration therapy probiotic treatment and
degree of dehydration
Dosage: each sachet of recovery time in the
the combined probiotic intervention group
Combined product: L. product contains Significant decrease in
224 children with ages: acidophilus, L. paracasei, stool frequency starting
6 months–2 years L. bulgaricus, L. 9 × 1010 CFU/g from the second day of
The study included
Double-blind Placebo + ORS/IV children < 5 kg— only rotavirus positive
Dubey et al., 2008 [69] 113 in intervention plantarum, B. breve, B. treatment
RCT rehydration therapy 2 sachets/day for patients
group infantis, B. longum, S. No significant
111 in control group thermophilus + ORS/IV 4 days difference between the
rehydration therapy children—5–10 kg— two groups in term of
4 sachets/day for volume of
4 days ORS/parenteral
solutions administered
hospital stay duration,
duration of diarrhea
Dosage: after start of treatment
and in reduction of Significant reduction in
69 children with ages: Combined product: L. 2.2 × 1010 CFU of a loose stool frequency on fecal rotavirus antigen
Rosenfeldt et al., Double-blind 6–36 months rhamnosus, L. reuteri + Placebo + ORS/IV mixture of L. rhamnosus positivity rate on day 5
2002 [70] RCT 30 in intervention group ORS/IV rehydration rehydration therapy (1.7 × 1010 CFU), L. the 5th day of follow-up among the intervention
in intervention versus
39 in control group therapy reuteri (0.5 × 1010 CFU) control group
group
2×/day for 5 days No significant
difference between the
two groups in term of
fever duration
Dosage: a sachet of the

synbiotic product
contains
1 × 109 CFU/dose of a
mixture of L. casei
(4 × 108 CFU), L.
Synbiotic product: L. rhamnosus
casei, L. rhamnosus, S. (3.5 × 108 CFU), S.
69 children with ages: thermophilus Significant decrease in
thermophilus, B. breve, L. Placebo + ORS/IV The study included
6–59 months diarrhea recovery time
Dewi et al., 2015 [75] Double-blind RCT
34 in intervention group
acidophilus, B. infantis, L. rehydration therapy + (1 × 108 CFU), B. breve No impact upon
only rotavirus positive
bulgaricus, FOS + Zn (5 × 107 CFU), L. patients
35 in control group hospital stay
ORS/IV rehydration acidophilus
therapy + Zn
(5 × 107 CFU), B.
infantis (4 × 107 CFU),
L. bulgaricus
(1 × 107 CFU) and FOS
(990 mg) 1×/day for
5 days
Rotavirus positive
Significant decrease in patients: the shortest
diarrhea duration and diarrhea duration
Dosage: a sachet of the stool frequency, among those patients
156 children with ages: synbiotic product especially in those who belonging to the
Synbiotic product: B.
2–60 months Placebo + standard contains a mixture of B. started the intervention intervention group
Islek et al., 2014 [76] Double-blind RCT lactis, inulin + standard
79 in intervention group treatment lactis (5 × 1010 CFU) treatment within the Adenovirus positive
treatments
77 in control group and inulin (900 mg) first 24 h of symptom patients: no influence
1×/day for 5 days onset on symptom duration
No impact on vomiting E. histolytica: no
nor on fever duration influence on symptom
duration
Legend: B. bifidum—Bifidobacterium bifidum; B. breve—Bifidobacterium breve; B. lactis—Bifidobacterium lactis; B.

infantis—Bifidobacterium infantis; B. longum—Bifidobacterium longum; B. mesentericus—Bacilus mesentericus; CFU—
colony forming units; C. butyricum—Clostridium butyricum; C. difficile—Clostridium difficile; E. Coli—Escherichia
Coli; E. faecalis—Enterococcus faecalis; E. histolytica—Entamoeba histolytica; FOS—fructo-oligosaccharides: IV—
intravenous, L. acidophilus—Lactobacillus acidophilus; L. bulgaricus—Lactobacillus bulgaricus; L. casei—Lactobacillus
casei; L. helveticus—Lactobacillus helveticus; L. paracasei—Lactobacillus paracasei; L. plantarum—Lactobacillus
plantarum; L. rhamnosus—Lactobacillus rhamnosus; L. reuteri—Lactobacillus reuteri; LF—lactose-free formula;
ORS—oral rehydration solution; RCT—randomized controlled trial; S. boulardii—Saccharomyces boulardii; S.
thermophilus—Streptococus thermophilus; Zn—zinc.
4. Discussion
The latest position paper of the Working Group on Probiotics and Prebiotics of the
ESPGHAN, published in 2022, provides weak recommendations for the use of L. rham-
nosus and S. boulardii in the management of acute pediatric gastroenteritis, based on low
evidence [68]. An even lower level of evidence sustained the administration of L. reuteri for
the same purpose, whereas a recommendation was issued against the use of Bacillus clausii
and against the combination of L. reuteri and L. helveticus in childhood diarrhea, similarly
to their previous publication [18,81]. The authors have provided no specific advice for
Nutrients 2023, 15, 643 12 of 18
diarrhea with an established etiology and have also mentioned the potential impact of
rotavirus vaccine coverage in influencing their analysis of previously published data [81].
This review tried to add novelty to the existing literature data by assessing the impact
of probiotic and synbiotic use upon symptom duration, severity and immune response in
both viral and bacterial gastroenteritis in children. Most of the studies conducted so far
which assessed the impact of probiotic use upon childhood enteric infections have focused
solely on rotavirus diarrhea and provided the basis for two previous meta-analyses [82,83],
as rotavirus still remains the leading cause of diarrhea-associated complications, especially
in underdeveloped countries [84,85]. However, norovirus seems to overcome rotavirus as
the etiological diarrheic agent which most commonly requires medical care in children, in
those countries with high anti-rotavirus vaccination coverage, such as the United States [86].
Several theories have emerged regarding the possible inhibition of replication exerted by
probiotics upon enteric viruses, and probiotic supplementation has been recommended
for prevention of rotaviral diarrhea, as well as for diminishing symptom duration [82,85].
As previously presented and detailed in Tables 1–4, several strains have proven their
benefits in rotavirus-associated diarrhea, including individual strains, as well as combined
probiotic preparations. The majority of these studies involved supplementation with either
L. rhamnosus or S. boulardii, and combined suspensions included at least one of these two
strains, which still represent the most studied and validated probiotics in the pediatric
literature [18,87]. One study which analyzed a combined probiotic product was omitted
from Table 4, due to the lack of information regarding the exact content of the product used,
as only a commercial name was provided in the manuscript abstract and main text [88].
However, very few studies separately analyzed the impact of probiotic use upon recovery
from bacterial diarrhea [23,30,59]. This might be explained by the small study populations
included within randomized controlled trials, and the even more size-limited sub-cohorts
in which a bacterial etiology was identified. Experimental research studies have suggested
that probiotics such as S. boulardii and several Lactobacillus strains show antimicrobial
effects, but with limited sensitivity against the analyzed pathogens [89,90].
On the other hand, several studies have evaluated the impact of probiotic strains such
as L. reuteri or of a product consisting of B. lactis, L. rhamnosus, and L. acidophilus on diarrhea
severity and duration, in spite of not reporting any information regarding the source of
infection, which might have greatly influenced the analyzed outcome parameters [91–93].
In similar fashion, one Indian study asserted that S. boulardii reduces time until resolution
of watery stools and duration of diarrhea after 5 days of treatment, but conducted no
separate etiology-based evaluation, due to the very limited number of cases in which the
source of diarrhea (rotavirus/Vibrio cholerae) was known [94]. Synbiotics containing FOS
or inulin might also positively influence childhood gastroenteritis outcome, but there is
insufficient data to assess the true impact of their use in particular infectious settings [95,96].
Consequently, the most recently published Cochrane systematic review underlines that
there is insufficient data to allow pathogen-specific analysis of the role of probiotic supple-
mentation in acute gastroenteritis, due to the paucity of the studies which have identified
etiological agents of diarrhea or have conducted a separate statistical evaluation, focused
on a certain pathogen [97]. Furthermore, the question of adequate, safety/efficacy bal-
anced dosage of even the most widely used strains still remains into place and experts in
the field suggest conducting trials comparing administration of different dosages of the
same/various strains [98].
It is also worth mentioning that most of the studies conducted so far on the matter of
probiotic efficacy in acute pediatric gastroenteritis included hospitalized children, and a
very limited number of them were performed in outpatient settings or included follow-up
of patients’ outcome after discharge from the hospital [30,31]. A decrease in the duration
of diarrhea in relation to L. reuteri use was reported within a Turkish study performed in
an ambulatory care unit [92]. Still, as represented in Tables 1–4, most of the studies which
evaluated pathogen-particular benefits of probiotics have only evaluated their efficacy after
5–7 days of administration.
Nutrients 2023, 15, 643 13 of 18
Recent literature data supports the administration of probiotics also as a prophy-

lactic measure against several enteric infections. Two studies conducted on a murine
model showed that S. boulardii can effectively inhibit tissue inflammation and bacterial
translocation, which provide protection against Salmonella [99,100]. Prevention of rotavirus
gastroenteritis seems on the other hand to be enhanced by L. rhamnosus administration,
especially in hospitalized children [101], as well as by supplemented formula feeding,
containing strains such as Bifidobacterium animalis subspecies lactis BB12 alone/in combina-
tion with S. thermophilus [102]. L. acidophilus also enhanced protection against rotavirus,
according to a meta-analysis conducted by Di et al. [103]. L. reuteri on the other hand has
been regarded as a possible prophylactic agent against diarrhea in pre-school children [104],
helping maintain the integrity of the intestinal mucosa epithelial barrier, offering protection
against its disruption, often caused by enterotoxigenic E. coli infection [105]. Moreover,
L. plantarum interferes with binding of enteropathogenic E. coli to the intestinal epithelial
cells [106]. The results obtained among in vitro studies still require confirmation among
large-cohort studies and as Depoorter et al. suggest in their review, there is overall insuf-
ficient proof to routinely recommend probiotics for prevention of acute gastroenteritis in
children [107].
5. Conclusions
Rotavirus infection remains the most frequently evaluated etiology in relation to
probiotic efficacy, with multiple studies proposing a decrease in its related diarrhea and
hospitalization duration with widely used probiotics such as S. boulardii, L. reuteri and L.
rhamnosus, as well as synbiotic products containing at least one of these three strains, as
complementary treatment to supportive therapy. There is, however, insufficient data on
the impact of probiotics in relation to rotavirus immunization status or their influence on
the diarrhea episodes treated in outpatient settings. Clinical reports are scarce regarding
potential probiotic benefit in bacterial diarrhea, but some strains have been shown to inhibit
in vitro growth of certain microbial pathogens. Future studies, conducted on larger cohorts,
are warranted to assess the individual and additive effects of probiotic strains on outcome
of pediatric gastroenteritis with identified causative agents.
Author Contributions: M.O.S. and C.O.M. conceptualized and designed the study, conducted liter-
ature search and drafted the initial manuscript. M.O.S., C.O.M. and L.E.M. reviewed and revised
the manuscript. H.A. participated in collecting literature data and helped in drafting the manuscript
tables. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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nutrients

Academic Editors: Stefano

Nutrients 2023, 15, 643. https://doi.org/10.3390/nu15030643 https://www.mdpi.com/journal/nutrients

Ensuring the equilibrium and integrity of intestinal microflora facilitates a functioning

3.1. Lactobacillus rhamnosus

Rotavirus positive patients:

Rotavirus positive patients:

235 children with ages: Dosage: 60 million cells

816 patients with ages: Dosage: 4 × 109 CFU L. No significant changes

Rotavirus positive patients:

Legend: CFU—colony forming units; C. difficile—Clostridium difficile; IV—intravenous, L. helveticus—

3.2. Saccharomyces boulardii

Persistent, prolonged elimination of rotavirus in feces has been reported even in

Dosage: S. boulardii 5; ×, Significant increase in

Legend: CFU—colony forming units; L. acidophilus—Lactobacillus acidophilus; L. casei—Lactobacillus casei;

3.3. Lactobacillus acidophilus

of epithelial intestinal cells, a consistent characteristic of other Lactobacilli as well [42].

3.4. Lactobacillus reuteri

3.5. Lactobacillus plantarum

Patients with positive

Shorter mean duration

Large dose of L. reuteri

Children not vaccinated

Legend: CFU—colony forming units; IV—intravenous, L. acidophilus—Lactobacillus acidophilus; L. plantarum—

3.6. Combinations of Multiple Probiotic Strains

3.7. Synbiotic Products

75 children with ages: Dosage:

Dosage: a tablet of the

Dosage: a sachet of the

Legend: B. bifidum—Bifidobacterium bifidum; B. breve—Bifidobacterium breve; B. lactis—Bifidobacterium lactis; B.

Recent literature data supports the administration of probiotics also as a prophy-

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