World Journal of

WJ G Gastroenterology
Submit a Manuscript: https://www.f6publishing.com World J Gastroenterol 2019 September 7; 25(33): 4999-5016

DOI: 10.3748/wjg.v25.i33.4999 ISSN 1007-9327 (print) ISSN 2219-2840 (online)

META-ANALYSIS

Efficacy of Lactobacillus rhamnosus GG in treatment of acute

pediatric diarrhea: A systematic review with meta-analysis

Ya-Ting Li, Hong Xu, Jian-Zhong Ye, Wen-Rui Wu, Ding Shi, Dai-Qiong Fang, Yang Liu, Lan-Juan Li

ORCID number: Ya-Ting Li Ya-Ting Li, Jian-Zhong Ye, Wen-Rui Wu, Ding Shi, Dai-Qiong Fang, Lan-Juan Li, State Key
(0000-0002-0761-4967); Hong Xu Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated
(0000-0001-6453-4683); Jian-Zhong Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province,
Ye (0000-0001-8174-2580); Wenrui China
Wu (0000-0002-8457-9675); Ding Shi
(0000-0003-3988-9321); Dai-Qiong Ya-Ting Li, Jian-Zhong Ye, Wen-Rui Wu, Ding Shi, Dai-Qiong Fang, Lan-Juan Li, Collaborative
Fang (0000-0002-0758-3988); Yang Innovation Center for the Diagnosis and Treatment of Infectious Diseases, School of Medicine,
Liu (0000-0003-0246-4418); Lan-Juan Zhejiang University, Hangzhou 310003, Zhejiang Province, China
Li (0000-0001-6945-0593).
Hong Xu, Department of Orthopedics, Xiaoshan Traditional Chinese Medical Hospital,
Author contributions: Li YT, Xu H,
Hangzhou 310003, Zhejiang Province, China
and Ye JZ contributed equally to
this work; Li YT and Xu H
Yang Liu, Department of Orthopedics, Clinical Sciences, Lund, Lund University, Lund 22185,
identified eligible articles and
extracted applicable data; Li YT,
Sweden
Xu H, and Ye JZ contributed to the
design of the study; Wu WR
Corresponding author: Lan-Juan Li, MD, PhD, Academic Research, Doctor, Professor, Senior
contributed to the analysis and Researcher, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The
interpretation of the outcomes; Liu First Affiliated Hospital, School of Medicine, Zhejiang University, No. 79, Qingchun Road,
Y, Fang DQ, and Shi D participated Hangzhou 310003, Zhejiang Province, China. [email protected]
in writing and editing the article; Telephone: +86-571-87236759
all authors approved the final draft Fax: +86-571-87236459
of the manuscript.

Supported by the National Natural

Science Foundation of China, No.
81330011.
Abstract
BACKGROUND
Conflict-of-interest statement: Diarrhea is a major infectious cause of childhood morbidity and mortality
None. worldwide. In clinical trials, Lactobacillus rhamnosus GG ATCC 53013 (LGG) has
PRISMA 2009 Checklist statement: been used to treat diarrhea. However, recent randomized controlled trials (RCTs)
The guidelines of the PRISMA 2009 found no evidence of a beneficial effect of LGG treatment.
Statement have been adopted in
this manuscript. AIM
To evaluate the efficacy of LGG in treating acute diarrhea in children.
Open-Access: This article is an
open-access article which was METHODS
selected by an in-house editor and The EMBASE, MEDLINE, PubMed, Web of Science databases, and the Cochrane
fully peer-reviewed by external
Central Register of Controlled Trials were searched up to April 2019 for meta-
reviewers. It is distributed in
accordance with the Creative analyses and RCTs. The Cochrane Review Manager was used to analyze the
Commons Attribution Non relevant data.
Commercial (CC BY-NC 4.0)
license, which permits others to RESULTS
distribute, remix, adapt, build Nineteen RCTs met the inclusion criteria and showed that compared with the
upon this work non-commercially, control group, LGG administration notably reduced the diarrhea duration [mean
and license their derivative works difference (MD) -24.02 h, 95% confidence interval (CI) (-36.58, -11.45)]. More

WJG https://www.wjgnet.com 4999 September 7, 2019 Volume 25 Issue 33

 Li YT et al. Lactobacillus GG for acute diarrhea

on different terms, provided the effective results were detected at a high dose ≥ 1010 CFU per day [MD -22.56 h,
original work is properly cited and 95%CI (-36.41, -8.72)] vs a lower dose. A similar reduction was found in Asian
the use is non-commercial. See:
http://creativecommons.org/licen
and European patients [MD -24.42 h, 95%CI (-47.01, -1.82); MD -32.02 h, 95%CI (-
ses/by-nc/4.0/ 49.26, -14.79), respectively]. A reduced duration of diarrhea was confirmed in
LGG participants with diarrhea for less than 3 d at enrollment [MD -15.83 h,
Manuscript source: Unsolicited 95%CI (-20.68, -10.98)]. High-dose LGG effectively reduced the duration of
manuscript rotavirus-induced diarrhea [MD -31.05 h, 95%CI (-50.31, -11.80)] and the stool
Received: April 28, 2019 number per day [MD -1.08, 95%CI (-1.87, -0.28)].
Peer-review started: April 28, 2019
CONCLUSION
First decision: May 30, 2019
High-dose LGG therapy reduces the duration of diarrhea and the stool number
Revised: July 4, 2019
per day. Intervention at the early stage is recommended. Future trials are
Accepted: July 19, 2019
Article in press: July 19, 2019 expected to verify the effectiveness of LGG treatment.
Published online: September 7,
2019 Key words:Lactobacillus rhamnosus GG; Acute diarrhea; Children; Rotavirus; Probiotics;
Systematic review; Meta-analysis
P-Reviewer: Tuna Kirsaclioglu CT,
Reyes VEE, Rhoads JM
S-Editor: Yan JP ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
L-Editor: Wang TQ
E-Editor: Wu YXJ Core tip: The treatment effectiveness of Lactobacillus rhamnosus GG (LGG) for acute
diarrhea in children was assessed in our study. LGG was confirmed to effectively reduce
the duration of diarrhea and the stool number per day. LGG was particularly efficacious
in patients treated at a dose > 1010 CFU/day, those treated at an early stage of illness, and
those diagnosed with rotavirus-positive diarrhea.

Citation: Li YT, Xu H, Ye JZ, Wu WR, Shi D, Fang DQ, Liu Y, Li LJ. Efficacy of
Lactobacillus rhamnosus GG in treatment of acute pediatric diarrhea: A systematic review
with meta-analysis. World J Gastroenterol 2019; 25(33): 4999-5016
URL: https://www.wjgnet.com/1007-9327/full/v25/i33/4999.htm
DOI: https://dx.doi.org/10.3748/wjg.v25.i33.4999

INTRODUCTION
The World Health Organization and United Nations International Children's
Emergency Fund define diarrhea as more than three loose or watery stools during a
24-h period. A duration of 14 days is the proposed criterion for acute diarrhea or
persistent diarrhea. Diarrhea is a major infectious cause of childhood morbidity and
mortality worldwide, especially in developing countries [1] . As the second most
common cause of death among children under 5 years of age[2], the frequency of acute
diarrhea in one year is approximately two to three episodes per child[1]. Previous data
showed that the incidence of diarrhea was 6 to 12 episodes in 12 months per child in
developing countries[3].
The goals of treatment are prevention or resolution of dehydration and reduction of
the diarrhea duration and infectious period [4] . Oral rehydration, gut motility
inhibitors, and antibiotics are used to treat acute gastroenteritis[4]. Oral rehydration
contributes to a reduced likelihood of dehydration but has no appreciable effects on
bowel movements or the duration of diarrhea and is not utilized to its full extent[5].
Antibiotics should be considered if pathogenic bacteria are detected. Smectite and
zinc remain under-utilized as adjuvant therapies[6,7].
Probiotic supplements have gained considerable popularity in the global market
and are predicted to generate 64 billion United States dollars in revenue by 2023[8].
Probiotics have health benefits for hosts[9] and have been evaluated in the treatment of
diarrhea, and multiple mechanisms of diarrhea improvement have been identified.
Probiotics modulate the host immune response[10]. Furthermore, colonic bacterial
metabolites such as short-chain fatty acids increase colonic Na and fluid absorption
through a cyclic adenosine monophosphate-independent mechanism[5]. In clinical
trials, the well-known probiotics Saccharomyces boulardii, Lactobacillus reuteri DSM
17938, and Lactobacillus rhamnosus GG ATCC 53013 (LGG) have been used to treat
diarrhea[2,4]. Previously, rotavirus-induced diarrhea was considered an adaptation
disease associated with LGG treatment[11]. Wolvers D revealed that the probiotic dose
mediated the effectiveness of treatment, and 10 1 0 -10 1 1 CFU per day was

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Li YT et al. Lactobacillus GG for acute diarrhea

recommended[12]. In addition, a greater effect was observed in the early stage of

illness, and a poorer effect on invasive bacterial diarrhea versus watery diarrhea was
observed. LGG treatment has been endorsed by leading experts[13-15]. However, most
recent randomized controlled trials (RCTs) conducted by Schnadower et al[8] yielded
no evidence of a beneficial effect of LGG treatment. Therefore, we conducted a meta-
analysis to evaluate the available validated data and update existing knowledge and
thus provide guidance to patients.

MATERIALS AND METHODS

Literature search
Relevant studies published before April 2019 were retrieved from the EMBASE,
MEDLINE, PubMed, Web of Science databases, and the Cochrane Central Register of
Controlled Trials (CENTRAL, the Cochrane Library). The search strategy was
conducted with medical subject headings and the search terms “diarrhoea, diarrhea,
diarrh*, gastroenteritis, probiotic*, Lactobacillus rhamnosus GG, Lactobacillus GG, and
LGG”. No language restrictions were applied. Additional studies were identified by
manually searching review articles.

Study selection
Nineteen RCTs describing LGG interventions for acute diarrhea were included. The
PRISMA statement and the guidelines from the Cochrane Collaboration were
followed for this evidence-based medicine study[16,17]. The participants were children
aged less than 18 years. The dose of LGG was provided in various forms at different
times. Antibiotic-associated diarrhea and persistent diarrhea were excluded. Other
applications of LGG, such as preventive strategies, were not included. Some particular
article types without complete data were excluded, such as abstracts and letters. We
also excluded studies using mixtures of more than one probiotic strain. The primary
outcomes were directly related to the development of persistent diarrhea, including
the duration of diarrhea and diarrhea lasting ≥ 3 and ≥ 4 d. Secondary outcomes
included the hospital stay duration, stool frequency, and improvement in stool
consistency and vomiting.

Data extraction
Two investigators (Li YT and Xu H) independently identified eligible articles and
extracted applicable data following the inclusion criteria.
2 Quality control was assessed
by another reviewer (Wu WR). The data set included the baseline characteristics of the
participants, the duration of diarrhea, the hospital stay duration, the time to
improvement in stool consistency, the mean number of stools per day during diarrhea
episodes, the proportion of patients with vomiting, the duration of vomiting, stool
frequency on days 2 and 3 after treatment, and the number
2 of patients with diarrhea
lasting ≥ 3 or 4 d. Cochrane Review Manager (Version 5.1. Copenhagen: The Nordic
Cochrane Centre, The Cochrane Collaboration, 2011) and STATA version 12.0
(StataCorp LP, College Station, TX, United States) were used for data analyses. Any
discrepancies were resolved by discussion.

Risk of bias
All included trials were evaluated following the Cochrane Collaboration’s risk of bias
tool. Seven domains were examined to identify the bias risk: selection bias, including
random sequence generation and allocation concealment, performance bias, including
blinding of participants and personnel, detection bias, including blinding of outcome
assessments, attrition bias, including incomplete outcome data, reporting bias,
including selective reporting, and other bias. Adequate allocation concealment was
implemented to ensure blinding of the participants and investigators to avoid
influences on the measures. Randomization was performed based on confirmed
allocation concealment. Unclear allocation concealment was noted when no method
was mentioned. The integrity of the data was evaluated, including the proportion of
excluded participants (http://www.cochrane-handbook.org).

Statistical analysis
The Cochrane Review Manager was used to analyze the relevant data. The mean
differences (MDs) in continuous data under LGG or placebo treatment were
measured. Dichotomous results are pooled and presented as risk ratios. Additionally,
95% confidence intervals (CIs) are reported for all types of outcomes. I2 and χ2 values
were calculated to quantify and reflect heterogeneity. A P-value < 0.05 indicates that
heterogeneity should not be ignored; thus, a random-effects model was used. A fixed-
effects model was employed when no statistically significant inconsistency was

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 Li YT et al. Lactobacillus GG for acute diarrhea

detected. Publication bias was assessed by funnel plot asymmetry[18]. Sensitivity

analyses were conducted to detect the robustness of results by assessing
randomization, missing data, blinding, and allocation concealment. Each individual
study was systematically removed from the meta-analysis, and the effect was
recalculated and estimated from the remaining studies (Supporting information
Figure S1). Regression analysis was conducted, and the relationships between the
duration of diarrhea and other covariates, including publication year, participant age,
the duration of diarrhea before study enrollment, and the LGG dosage, were
examined. Subgroup analyses were performed to diminish significant inconsistency.
Preplanned subgroup analyses were performed according to the following clinical
characteristics and results from sensitivity or regression analysis: (1) The dosage of
LGG per day. A dosage of 1010 CFU/day was observed to be a critical element of
effective treatment in the study by Szajewska et al[13]. In addition, a larger dose was
suggested in other studies[19,20]; (2) The etiology of diarrhea. Diarrhea mortality and
severe diarrhea were most frequently caused by rotavirus in children[21]. Compared to
control children, several rotavirus-positive children with watery stools in a probiotic
group were reported to exhibit a marked reduction in diarrhea symptoms after 24 h[22].
A meta-analysis performed by Szajewska et al[23] in 2007 concluded that the duration
of rotavirus-induced diarrhea was significantly attenuated by LGG supplementation;
(3) The site of treatment (inpatient vs outpatient); (4) Vaccination status; (5)
Geography of the clinical trials. The location of the study affected the sanitary habits,
exposure to various pathogens, and nutrient status of the participants. All studied
environmental factors contribute to various outcomes; (6) Early probiotic
administration. A beneficial effect of probiotics was reported in the course of disease
when initiated early[12]; and (7) Publication date.

RESULTS
Study selection
A total of 349 potentially relevant studies were identified. The process of screening
was carried out according to the flow diagram shown in Figure S2 (Supporting
information). The characteristics of each included study are summarized in Table 1.
With 988 participants in a 2007 meta-analysis and 2683 participants in a 2013 meta-
analysis, a total of 4073 participants in 19 RCTs were identified in the literature. Two
experimental arms in the study of Basu et al [24] were listed separately to exhibit
different doses of probiotics, which were marked as Basu 2009a and Basu 2009b.
Therefore, the figures, tables, and full texts of 18 articles were reviewed[8,24-40]. A large
number of trials were conducted in Europe and Asia. Patients were recruited from
outpatient, inpatient, and emergency departments. Inconsistency existed in the daily
doses and routes of LGG supplementation during the treatment period. Different
criteria were used to define diarrhea in the included studies. Diarrhea resolution was
commonly defined as passage of the first normal stool or the last watery stool.
Antibiotic treatment before recruitment was assessed, and different studies varied
regarding the use of antibiotics. Similarly, the duration of treatment varied. Studies of
moderate to high quality were adequately assessed and are summarized in Figure S3
(Supporting information).

Evaluation before enrollment (days)

Before enrollment, age was assessed in 16 studies, and the duration of diarrhea was
reported in nine studies (Supporting information Figures S4 and S5). No obvious
difference in age was found. The statistical differences and high heterogeneity
resulting from the duration of diarrhea [MD -6.21 h, 95%CI (-9.04, -3.38)] could be
reduced by subgrouping according to the outcomes of the sensitivity analysis
(Supporting information Figure S1). The subgroup excluding the study of Ritchie et
al [37] performed in 2010 showed acceptable heterogeneity, and no statistical
significance was observed for the duration of diarrhea before study enrollment [MD -
0.9 h, 95%CI (-4.02, 2.22)] (I2 = 10%). Sensitivity analysis revealed differences in the
duration of diarrhea before study enrollment between the two groups in the study of
Ritchie et al [37] , which recruited aboriginal children in the Northern Territory of
Australia. Social disadvantages and poverty contributed to malnutrition in these
children [4] . However, no significant differences in the primary and secondary
outcomes were found by sensitivity analysis, which is inconsistent with the findings
reported in previous meta-analyses[4,13] (Supporting information Figure S1).

Duration of diarrhea
A reduced duration of diarrhea was found in the LGG group compared to that in the

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 Table 1 Characteristics of the included trials

Article Type of article Age group Country Patient n (exp/ Inclusion criteria Exclusion criteria LGG Control Duration of Etiology
source control) (dosage) group intervention
Basu et al [25], RCT; 1 center; Children India Inpatients 323/323 ≥ 3 watery stools/day without visible Systemic illness other than 120 × 106; ORF 7d Bacterial diarrhea excluded;
2007 Duration: 1 yr blood or mucus; <10 white blood cells/ diarrhea on admission; systemic CFU/day Rotavirus-induced diarrhea
high-power field and no red cells, mucus complications of diarrhea 75.8%
flakes, or bacteria on stool microscopy; during hospitalization; failure
negative hanging drop preparation; to provide informed consent
negative bacterial stool culture
Basu et al [24], RCT; 1 center; Children India Inpatients 188/185 ≥ 3 watery stools/day without Symptoms of illness other 2 × 1010; ORF 7 d or until Bacterial diarrhea excluded;
2009a Duration: 1 yr macroscopic blood or mucus, <10 white than diarrhea; development of CFU/day diarrhea Rotavirus diarrhea 57.1%
blood cells/high-power field, and no any systemic complication of stopped
red blood cells, mucus flakes, or bacteria diarrhea during hospitalization;
on stool microscopy; negative hanging failure to provide informed

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drop preparation; negative bacterial stool consent
culture
Li YT et al. Lactobacillus GG for acute diarrhea

Basu et al [24] RCT; 1 center; Children India Inpatients 186/185 ≥ 3 watery stools/day without Symptoms of illness other 2 × 1012; ORF 7 d or until Bacterial diarrhea excluded;
2009b Duration: 1 yr macroscopic blood or mucus, <10 white than diarrhea; development of CFU/day diarrhea Rotavirus-induced diarrhea
blood cells/high-power field, and no any systemic complication of stopped 56.06%
red blood cells, mucus flakes, or bacteria diarrhea during hospitalization;
on stool microscopy; negative hanging failure to provide informed
drop preparation; negative bacterial stool consent
culture

5003
Canani et RCT; 6 centers; 3-36 mo Italy Outpatients 100/92 > 2 loose or liquid stools/day for <48 h Malnutrition; severe 12 × 109; No details 5d Stool culture in only a few
al[26], 2007 Duration: 12 mo dehydration; coexisting CFU/day given participants and no data
acute systemic illness; presented
immunodeficiency; underlying
severe chronic disease; cystic
fibrosis; food allergy or other
chronic GI diseases; use of
probiotics in the previous 3
wk; antibiotics or any other
antidiarrheal medication in the

2
previous 3 wk; poor compliance
Costa et al[27] RCT; 1 center Boys, 1-24 Brazil Inpatients 61/63 Acute diarrhea (3 or more watery or loose Systemic infections requiring 1010; CFU/ Inulin 320 Unclear Rotavirus-induced diarrhea
2003 mo stools per 24 h during at least one 24-h antibiotics; severe malnutrition day mg/day 50%; Bloody diarrhea
period in the 72 h before admission) with (weight for age < 65% of NCHS excluded
moderate or severe dehydration after standards; bloody diarrhea
correction with rapid IV fluids
Czerwionka- RCT; 1 center Unclear Poland Inpatients 50/50 Infants and children with acute infectious Bloody stools; coexisting disease 50 ml/kg/ Unclear Unclear Bloody diarrhea excluded;
Szaflarska et diarrhea and failed oral rehydration that may influence the course of day Rotavirus-induced diarrhea
al[28], 2009 diarrhea 58%

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 Schnadower RCT 3-48 mo United University- 483/488 ≥ 3 watery stools per day, with or without Pancreatitis, bilious emesis, or 1 × 1010; CFU Matching 5d Norovirus GI or GII
et al[8] 2018 States affiliated vomiting, for fewer than 7 d hematochezia; a known allergy twice daily placebo 19.6%; Rotavirus 17.7%;
PED to L. rhamnosus GG or to Adenovirus 9.1%;
microcrystalline cellulose or a Clostridium difficile 7.4%;
known allergy to erythromycin, Shigella 5.0%
clindamycin, and beta-lactam
antibiotic agents; caregiver did
not speak English or Spanish;
children receiving antibiotics
Guandalini et RCT; 1-36 mo Listed as Inpatients 147/140 Infants and children with > 4 liquid or Previous probiotic usage; ≥ 10 × 109; ORF As tolerated Rotavirus 35%; Bacteria
al[29], 2000 multicenter; follows and untreated underlying CFU/250 for 4-6 h, 24%; Parasites 4.5%; No
Duration: 1 yr outpatients chronic small bowel disease; mL/day with then ad pathogens 34.5%; Bloody
inflammatory bowel disease; ORF libitum diarrhea 8.7%
any underlying chronic disease
or immunosuppressive disease
or treatment

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Guarino et RCT; 1 center 3-36 mo Italy Outpatients 52/48 semiliquid stools/day for 1 to 5 d Antibiotic treatment in the last 6 × 109; CFU/ ORF ≤5d Rotavirus-induced
al[30], 1997 Duration: 3 mo Infants and children with ≥ 3 watery 3 wk, breastfeeding; a weight: day with ORF diarrhea 61%
stools/day for < 48 h height ratio < the 5th percentile
Isolauri et RCT; 1 center ≤ 36 mo Finland Inpatients 21/21 Infants and children with > 3 watery Not stated 2 × 1010; No probiotic 5d Rotavirus-induced
al[31], 1994 Duration: not stools/day for < 7 d and stools positive CFU/day diarrhea 100%
stated for rotavirus; average dehydration of
approximately 5% in both groups
Jasinski et RCT; 12 centers; 1-36 mo Africa Inpatients 45/52 > 3 watery stools in 12 h or 1 liquid or Antibiotic or probiotic ORS + LGG ORS with no Unclear Bacterial pathogens 68%;
al[32], 2002 Duration: not and semiliquid stool with mucus, pus, or blood; use in the last 5 d; chronic 1010 CFU⁄ day LGG Rotavirus 40.0%; parasites

5004
stated outpatients <5d diseases of the small or large 6%; No pathogens
intestine; immunosuppression; identified: probiotic group
phenylketonuria 25%
Misra et al[33], RCT; 1 center; ≤ 36 mo Egypt Inpatients 105/105 > 3 stools per day (watery or assuming the Parents refused consent; 1 × 106-9 CFU/ Crystalline Unclear Rotavirus 25.6%; Bloody
2009 Duration: not Europe shape of the container) children living outside the day micro diarrhea excluded; White
stated America municipal area; bloody cellulose blood cells in stools 14.3%;
India diarrhea; severe dehydration; Bacterial diarrhea 4.7%
shock, inability to take and
retain oral foods; suspected
systemic infection
Nixon et al[34], RCT 6-72 mo United PED 77/78 More than 2 loose stools in the last 24 h Risk factors for non-viral LGG powder Inulin 5d Unclear
2012 States diarrhea (prolonged diarrhea twice daily
lasting more than 7 d, gross
blood, antibiotic exposure, or
inflammatory bowel disease);
immune compromise; risk
factors for probiotic-associated
systemic illness or an allergy to
milk products
Pant et al[35], RCT; 1 center; 1-24 mo Thailand Inpatients 20/19 Infants and children with > 3 watery stools Exclusive breastfeeding; 109-10 CFU Placebo 2d Bloody stools 33.3%;
1996 Duration: 6 wk in last 24 h and diarrhea for < 14 d septicemia twice daily
Li YT et al. Lactobacillus GG for acute diarrhea

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 Raza et al[36], RCT; 1 center 1-24 mo Pakistan Inpatients 21/19 Undernourished infants and children with Severe malnutrition; septicemia 2 × 1011-12 Placebo 2d Rotavirus 17.9%;
1995 Duration: 2 mo > 3 watery stools in the last 24 h for < 14 d CFU/day Astrovirus 2.5%
and at least moderate dehydration Bloody diarrhea
Ritchie et RCT; 1 center; 4-24 mo Australia Unclear 33/31 Aboriginal children with acute diarrhea Oxygen required during the > 15 × 109 Identical 3d Bacterial pathogens
al[37], 2010 Duration: 21 mo defined as ≥ 3 loose stools during 24 h study period; chronic cardiac, CFU/day placebo 12.5%; Rotavirus 8.5%;
before presentation for < 7 d and able to renal, or respiratory disease; Parasites 6%
tolerate ORF previous gastrointestinal
surgery; proven sucrose
intolerance; suspected on
known immunodeficiency;
probiotic use before enrollment;
younger than 4 mo of age
Shornikova et RCT; 1 center; 1-36 mo Russia Inpatients 59/64 ≥ 1 watery stool in the last 24 h and Not stated 1010 CFU/day Placebo 5d Rotavirus 27.4%; Bacterial
al[38], 1997 Duration: 1 yr diarrhea for < 5 d diarrhea 21%
Sindhu et RCT 6-60 mo India Unclear 65/59 Diarrhea was defined as ≥ 3 loose watery Coinfections (the presence 1010 CFU and 170 mg of 4 wk Rotavirus 52.4%;
al[39], 2014 stools within a 24-h period of both rotavirus and 170 mg of cellulose Cryptosporidium species

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Cryptosporidium); severe microcrystalline 47.6%
/day cellulose
Li YT et al. Lactobacillus GG for acute diarrhea

malnutrition; probiotic
consumption in the preceding
month; allergy to probiotics;
acute abdomen or colitis
Sunny et al[40] Open-label; 6-60 mo India OPD or 100/100 Passage of three or more loose stools in the Severe malnutrition; dysentery; 1 × 1010 CFU ORS and zinc 5d Rotavirus 24.1%
2014 RCT PED last 24 h clinical evidence of coexisting per day 20 mg/d
acute systemic illnesses; clinical
evidence of chronic disease;

5005
probiotic use in the preceding
three weeks; antibiotic use

The study of Guandalini et al[29] was conducted in Poland, Pakistan, Egypt, Croatia, Italy, Slovenia, Netherlands, Greece, Israel, the United Kindom, and Portugal. RCT: Randomized controlled trial; PED: Pediatric emergency
department; OPD: Outpatient department; LGG: Lactobacillus rhamnosus GG.

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 Li YT et al. Lactobacillus GG for acute diarrhea

matched group according to 15 RCTs submitted to meta-analysis, which included

3721 participants [MD -24.02 h, 95%CI (-36.58, -11.45)] (Figure 1A). Significantly
heterogeneous results were detected among the included trials (I2 = 98%). Our data
support the results of the prior meta-analyses [4] indicating that LGG treatment
reduced participants’ duration of diarrhea.
Subgroup analyses were conducted based on clinical features such as age,
geographical location, treatment time, outpatient or inpatient settings, the time of
enrollment, and literature quality scores. Differences in methodological quality could
not explain the statistically significant heterogeneity (Supporting information Figure
S6). Regression analysis between the duration of diarrhea and LGG dose revealed that
different doses of LGG contributed to the heterogeneity (P = 0.009, adjusted R-
squared = 40.21%), suggesting that subgroups according to a high or low dose of LGG
should be assessed. A reduced duration of diarrhea was noted in the studies applying
> 1010 CFU/day of LGG [MD -22.56 h, 95%CI (-36.41, -8.72)] (Figure 1A). In contrast,
although only three studies used lower dosages, no statistically significant differences
were detected in the groups receiving lower dosages [MD -30.95 h, 95%CI (-83.28, -
21.39)] (Figure 1A). A reduced duration of diarrhea was supported in the studies with
participants who received LGG treatment before the second day of diarrhea
symptoms [MD -1.58 h, 95%CI (-3.05, -0.11)] and during the second to third days of
diarrhea symptoms [MD -15.83 h, 95%CI (-20.06, -10.98)] (Figure 1B). However,
Ritchie et al [37] enrolled participants with diarrhea for more than 3 d, and no
statistically significant differences were found in the duration of diarrhea [MD 1.2 h,
95%CI (-21.42, 23.82)] (Figure 1B). A reduced diarrhea duration was reported in
studies performed in both Asia and Europe [MD -24.42 h, 95%CI (-47.10, -1.82); MD -
32.02 h, 95%CI (-49.26, -14.79), respectively]. Paradoxically, the reduction in the
diarrhea duration in other regions was not statistically significant [MD -9.35 h, 95%CI
(-20.77, 2.07)] (Figure 1C). In the etiological analysis, the effectiveness of LGG was
clearly demonstrated in rotavirus-induced diarrhea cases [seven RCTs; MD -31.05 h,
95%CI (-50.31, -11.80)] (Figure 2). Analysis with the studies carried out in the 1990s
and 2000s revealed a clear reduction in the diarrhea duration [MD -36.32 h, 95%CI (-
62.20, -10.45); MD -29.40 h, 95%CI (-50.56, -8.25), respectively] (Supporting
information Figure S7). In contrast, no reduction in the diarrhea duration was
observed in the analysis with studies carried out in the 2010s [MD -3.43 h, 95%CI (-
13.25, 6.39)] (Supporting information Figure S7). No studies evaluated the
effectiveness of LGG in children vaccinated against rotavirus.

Diarrhea ≥ 3 d
A meta-analysis of four RCTs was performed using a fixed-effects model. The risk of
experiencing diarrhea for 3 or more days was reduced when patients received LGG
[odds ratio (OR) 0.54, 95%CI (0.38, 0.77)] (Figure 3A).

Diarrhea ≥ 4 d
Three studies were pooled (n = 479) and showed a reduction in the risk of diarrhea
lasting for 4 or more days for participants treated with LGG [OR 0.58, 95%CI (0.4,
0.84)] (Figure 3B).

Stool number and consistency

Stool number and consistency were evaluated in most trials. Eight trials reported the
mean number of stools in one day during diarrhea episodes. A notable decrease in the
stool number per day was noted in the LGG group [MD -0.9, 95%CI (-1.56, -0.23)]
(Figure 4A). However, a significantly reduced stool number was observed in the high-
dose LGG groups receiving no less than 1010 CFU/day [MD -1.08, 95%CI (-1.87, -
0.28)], while the lower-dose groups showed no significant reduction [MD -0.25 d,
95%CI (-1.43, 0.93)] (Figure 4A). After the intervention, stool frequency was evaluated
on days 2 and 3. Seven trials provided data on day 2, and the overall effect did not
differ between the two groups [MD -0.46, 95%CI (-1.06, 0.15)] (Figure 4B). In addition,
similar frequencies were observed in the two groups on day 3, with no differences
between them [MD 0.34, 95%CI (-0.29, 0.97)] (Figure 4C). Three trials calculated the
mean time to improvement in stool consistency, and an obvious reduction was
reported [MD -5.65, 95%CI (-7.49, -3.80)] (Figure 4D).

Hospital stay duration

A total of 1823 participants from six RCTs were analyzed. Due to statistically
significant heterogeneity, a random-effects model was used, which revealed a
significant reduction in the hospital stay duration in the two groups [MD -39.16 h,
95%CI (-72.24, -6.07)] (Figure 5A). A reduction in the hospital stay duration was found
in rotavirus-positive children [MD -21.12 h, 95%CI (-26.96, -15.28)] (Figure 5B).

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Li YT et al. Lactobacillus GG for acute diarrhea

Figure 1

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 Li YT et al. Lactobacillus GG for acute diarrhea

Figure 1 Lactobacillus GG vs control with regard to the duration of diarrhea (hours). A: High dose and low dose; B: The duration of diarrhea before
Lactobacillus rhamnosus GG participants’ enrollment: ≤2 d (>1 d), ≤3 d (>2 d), and ≤4 d (>3 d); C: Geography of the clinical trials: Asia, Europe, and other continents.
LGG: Lactobacillus rhamnosus GG; CI: Confidence interval; SD: Standard deviation.

Vomiting
Vomiting in different trials was reported as the number of participants with vomiting
[number (%)] or as the duration of vomiting (hours). Compared with the placebo
group, no difference in the risk of vomiting was reported in the experimental group
[OR 1.11, 95%CI (0.59, 2.12)] (Figure 6A). Furthermore, no reduction in the duration of
vomiting was noted with LGG treatment [MD -2.02 h, 95%CI (-4.24, 0.21)] (Figure 6B).

Adverse effects
Probiotics have been proposed to be well-tolerated and safe therapeutic agents. Most
authors did not report adverse effects. Raza et al[36] reported one case of myoclonic
jerks in their trial. Lower rates of respiratory infection, wheezing, and even vulvar
abscess were noted in Schnadower’s trial[8,39], but these effects were not thought to be
correlated with LGG use[40]. Aggarwal et al[40] reported no adverse effects, and a meta-
analysis performed in 2013 showed comparable rates of adverse effects among study
groups[13]. In our study, eight studies effectively evaluated the safety of LGG. Adverse
effects were reported on a coded reporting form or during daily telephone calls[26,34]. In
Schnadower’s study, the caregivers completed a daily diary that was collected by
telephone or through email[8]. However, the reporting methods were unclear in five
articles[24,37,39-41]. In general, no adverse effects or similar rates of side effects were
documented in the LGG and placebo groups.

Risk of bias in the included studies

The risk of bias in 18 articles was assessed according to the Cochrane Handbook for
Systematic Reviews of Interventions. One trial employed alternating group allocation,
and the random sequence generation method was not reported in five trials. Other
RCTs provided detailed randomization methods, which mainly included computer-
generated strategies, resulting in a low risk of selection bias. Allocation concealment
was not applied in two trials and was not mentioned in seven. Nine trials used the
sealed envelope technique for allocation concealment. Double blinding was strictly
executed in 12 trials, while four trials allowed openness to patients or doctors, and

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 Li YT et al. Lactobacillus GG for acute diarrhea

Figure 2

Figure 2 Lactobacillus GG vs control with regard to mean duration of diarrhea (hours) in children with rotavirus diarrhea. LGG: Lactobacillus rhamnosus GG;
CI: Confidence interval; SD: Standard deviation.

two trials did not report a detailed blinding method. For detection bias, investigators
were blinded to the group assignments in ten trials, while blinding assessments were
not performed in three trials. Most trials provided complete data with a loss to follow-
up rate less than 10%, although one trial had an unknown risk of incomplete outcome
data, reflecting a low risk of attrition bias (Supporting information Figure S3).

Publication bias
According to Egger’s[18] regression asymmetry test, no small sample or publication
bias was found in a funnel plot [P = 0.10, 95%CI (-11.33, -1.14)] (Supporting
information Figure S8).

DISCUSSION
Findings and agreement or disagreement with other studies
Nineteen trials comparing a control group with an experimental group treated with
LGG were identified in this meta-analysis. In summary, the analysis revealed that
treatment with LGG reduced both the duration of diarrhea and the hospital stay
duration, especially in specific patient subsets. A striking finding was the time to
improvement in stool consistency, which more investigators have confirmed since
2010[8,34,40]. In the whole range of diarrhea cases, the management of stools with this
probiotic strain showed a modest beneficial effect on the number of stools per day and
the time to improvement in stool consistency. However, no reduction in stool
frequency was observed on days 2 and 3. Compared with the placebo group, the risk
of diarrhea lasting more than 3 and 4 d was reduced by LGG administration. In both
groups, similar rates of vomiting and adverse effects were observed.
Evidence from RCTs confirmed the beneficial effect of LGG on rotavirus-induced
diarrhea[42]. In addition to interference with viral replication, most recent studies have
shown that LGG prevented injuries to the epithelium and ameliorated rotavirus-
induced diarrhea by modulating immune cells, such as dendritic cells and
inflammatory cytokines[43,44]. The marked statistical difference in the diarrhea duration
with a higher dosage of probiotics reflected greater effectiveness, which confirmed the
dose dependence of dendritic cell activation. Treatment efficacy was related to the
dose of LGG[45]. As confirmed in the study of Szajewska et al[13] in 2013, the importance
of a daily LGG dose is high, and a dosage of 1010 CFU/day is needed for a positive
effect. The statistical heterogeneity between studies can be explained by the timing of
the LGG intervention, which was directly correlated with indicators such as the
duration of diarrhea before study enrollment. Although the heterogeneity persisted in
the subgroup with the shortest duration of diarrhea before study enrollment,
probiotics should be applied early in the course of disease. Moreover, symptoms are
usually mild at the early stage. Differences in prominent pathogens, sanitation
conditions, and common comorbidities lead to dissimilarities between various study
locations. Due to differences in the treatment effect among regions, the implications
for clinical practice should be evaluated. The nutrient intake and dietary structure of
humans have continuously changed in recent decades, which may have caused the
reduced effectiveness of LGG reflected in the results of the trials conducted in the
2010s.
Probiotics manipulate and restore the gut microbiota, thus benefitting the

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 Li YT et al. Lactobacillus GG for acute diarrhea

Figure 3

Figure 3 Lactobacillus GG vs control with regard to the presence of diarrhea. A: Diarrhea lasting > 3 d; B: Diarrhea lasting > 4 d. LGG: Lactobacillus rhamnosus
GG; CI: Confidence interval.

prevention of diarrhea. Various therapeutic interventions designed to alter the

microbiota range from probiotic administration to fecal microbiota trans-
plantation[46,47]. However, due to the limited number of included studies and the self-
limiting nature of disease, strategies should also be discussed in detail. Vomiting was
reported as an adverse event in numerous studies[48,49], and it is one of the most
common symptoms associated with diarrhea[50,51]. Additionally, less frequent clinical
symptoms were observed in the probiotic groups [4] , although our meta-analysis
showed no improvement in the risk or duration of vomiting.

Safety
The safety of probiotic supplementation is generally certain. Nevertheless,
pathologies correlated with the use of probiotic products to treat gastrointestinal
disorders have been identified, such as endocarditis, sepsis, and bacteremia[52-54].
Unfortunately, the most prevalent strain implicated in the adverse effects was
Lactobacillus rhamnosus. Conversely, most authors in our analysis did not report
adverse effects or the adverse effects were not thought to be correlated with LGG
treatment. In addition to the interventions, the primary illness contributed the most to
the participant drop-out rate. A higher frequency of negative effects attributed to
probiotics was found in catheterized (82.5%) and immunosuppressed (66%)
participants[55]. Further safety evaluations of probiotics are necessary in the clinical
setting, especially for susceptible individuals, such as those with immunodeficiency,
immunosuppression, or malnourishment.

Application prospects
Preventing or correcting dehydration through treatment with zinc or 0.9% saline
solution is the main approach used for diarrhea management[56]. However, during
diarrhea episodes, infectious symptoms are not fully alleviated and the gut microbiota
is not restored by rehydration measures[57]. Probiotics were investigated as therapeutic
agents for diarrhea. The mechanisms by which probiotics alleviate diarrhea are
described below. Host defenses are reinforced by enhanced antimicrobial peptide
secretion. Probiotics prevent disruption of gut barrier integrity and stimulate the
expression of junctional adhesion and tight junction molecules[58-61]. They produce
short-chain fatty acids and induce the production of IgA to resist infections[62-64]. In
epithelial cells and mucin, probiotics compete for binding sites to arrest pathogen
colonization[65]. Probiotics can specifically and nonspecifically interfere with the viral
cycle, thus impeding the progression of rotavirus-induced diarrhea [66-68] . The
prevalence of diarrhea is seasonal, and almost all cases of rotavirus-induced diarrhea

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 Li YT et al. Lactobacillus GG for acute diarrhea

Figure 4

Figure 4 Lactobacillus GG vs control with regard to stool number and consistency. A: The average stool number per day (high dose and low dose); B: Stool
frequency on day 2; C: Stool frequency on day 3; D: The mean time to improvement in stool consistency. LGG: Lactobacillus rhamnosus GG; CI: Confidence interval;
SD: Standard deviation.

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 Li YT et al. Lactobacillus GG for acute diarrhea

Figure 5

Figure 5 Lactobacillus GG vs control. A: The duration of hospital stay (hours); B: The hospital stay duration of rotavirus-positive children (hours). LGG:
Lactobacillus rhamnosus GG; CI: Confidence interval; SD: Standard deviation.

occur from January to May in Russia[38]. By contrast, in regions where rotavirus is not
prevalent, bacterial diarrhea commonly occurs from June to October[38]. Influenza
seasons, dietary habits, and antibiotic use must be considered when evaluating
heterogeneity in further studies. The efficacy of probiotic treatment was altered based
on host and environmental factors[12]. Overall, our study supported the previous
systematic reviews which concluded that LGG is an effective treatment for children
with acute diarrhea.

Conclusions and limitations

Although most studies have suggested that LGG is efficacious, limited identification
of pathogens, small sample sizes, varying therapeutic strategies, and methodological
limitations such as articles without a strictly blinded design, including a lack of a
standard clinical parameter format, weakened the conclusions and precluded further
analyses across studies [69] . For example, Czerwionka-Szaflarska et al [28] did not
specifically define the treatment applied, although a significantly reduced duration of
diarrhea was detected. Salazar-Lindo et al [41] partially depicted the duration of
diarrhea in children with or without LGG treatment. Although factors varied in the
trials, according to the same criterion for both groups, no evidence suggests that a
poor study design leads to overestimation of probiotic efficacy [4] . Appropriate
subgroups, such as those stratified by etiology and nutritional status, are
indispensable. In 2016, approximately 8.4% of children (480000) presenting with
diarrhea ultimately died due to the condition worldwide (https://data.unicef.
org/topic/child-health/diarrhoeal-disease/). Assessments of the availability of
vaccines, the applicability of probiotics, and the effectiveness of current treatments
under severe conditions and cost-effect analyses must be performed to optimize
therapeutic strategies for acute diarrhea management in children.
In summary, the following conclusions were cautiously established: LGG reduces
the duration of diarrhea, particularly in patients with rotavirus-positive diarrhea
receiving a dosage no less than 1010 CFU per day and in patients treated at the early
stage. In addition, studies conducted in Asia and Europe showed greater treatment
efficacy. The therapeutic effect of LGG supplementation on the stool number per day
and hospital stay duration associated with rotavirus-induced diarrhea is high.

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 Li YT et al. Lactobacillus GG for acute diarrhea

Figure 6

Figure 6 Lactobacillus GG vs control with regard to vomiting. A: The number of participants with vomiting [number (%)]; B: The duration of vomiting (hours).
LGG: Lactobacillus rhamnosus GG; CI: Confidence interval; SD: Standard deviation.

ARTICLE HIGHLIGHTS
Research background
Diarrhea is a major infectious cause of childhood morbidity and mortality worldwide.
Preventing or correcting dehydration through treatment with zinc or 0.9% saline solution is the
main approach for diarrhea management; however, during diarrhea episodes, infectious
symptoms are not fully alleviated by rehydration measures. Probiotics restore the gut microbiota
and have been reported to reduce the duration of diarrhea.

Research motivation
Although previous studies have reported that Lactobacillus rhamnosus GG (LGG) is an effective
therapeutic agent for acute diarrhea in children, a recent large, high-quality RCT found no
adequate evidence of a beneficial effect of LGG treatment.

Research objectives
To evaluate the efficacy of LGG in treating acute diarrhea in children and provide some
reference for future trials of treatments for diarrhea.

Research methods
The EMBASE, MEDLINE, PubMed, Web of Science databases, and the Cochrane Central Register
of Controlled Trials were searched up to April 2019 for meta-analyses and randomized
controlled trials (RCTs). Cochrane Review Manager was used to analyze the relevant data and
primary outcomes, including the duration of diarrhea and diarrhea lasting ≥ 3 and ≥ 4 d.
Secondary outcomes included the hospital stay duration, stool frequency, and improvement in
stool consistency and vomiting.

Research results
The systematic review identified 19 RCTs that met the inclusion criteria and indicated that
compared with the control group, LGG administration notably reduced the diarrhea duration
[mean difference (MD) -24.02 h, 95% confidence interval (CI) (-36.58, -11.45)]. Greater reductions
were detected at a high dose of ≥ 1010 CFU per day [MD -22.56 h, 95%CI (-36.41, -8.72)] and in
LGG participants with diarrhea for less than 3 days at study enrollment [MD -15.83 h, 95%CI (-
20.68, -10.98)]. The study locations contributed to differences in the reduction in the diarrhea
duration in Asia and Europe [MD -24.42 h, 95%CI (-47.01, -1.82); MD -32.02 h, 95%CI (-49.26, -
14.79), respectively]. High-dose LGG treatment was confirmed to effectively reduce the duration
of rotavirus-induced diarrhea [MD -31.05 h, 95%CI (-50.31, -11.80)] and stool number [MD -1.08,
95%CI (-1.87, -0.28)].

Research conclusions
The following conclusions were cautiously established: compared to control children, children

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 Li YT et al. Lactobacillus GG for acute diarrhea

who received a course of LGG had better outcomes, including a markedly reduced duration of
diarrhea, especially those with rotavirus-positive diarrhea, those who received no less than 1010
CFU per day, and those treated at the early stage. Furthermore, studies conducted in Asia and
Europe reported greater treatment efficacy. The therapeutic effect of LGG supplementation on
the stool number per day and hospital stay duration associated with rotavirus-induced diarrhea
was high.

Research perspectives
Our study found better outcomes among children with acute diarrhea who were treated by LGG
supplementation. Limited identification of pathogens, small sample sizes, and a lack of a
standard clinical parameter format precluded further analyses across studies, thus weakening
the evidence required to guide clinical practice. Investigations are required to assess the cost-
effectiveness of treating diarrhea with probiotics.

REFERENCES
1 Walker CLF, Rudan I, Liu L, Nair H, Theodoratou E, Bhutta ZA, O'Brien KL, Campbell H, Black RE.
Global burden of childhood pneumonia and diarrhoea. Lancet 2013; 381: 1405-1416 [PMID: 23582727
DOI: 10.1016/S0140-6736(13)60222-6]
2 do Carmo MS, Santos CID, Araújo MC, Girón JA, Fernandes ES, Monteiro-Neto V. Probiotics,
mechanisms of action, and clinical perspectives for diarrhea management in children. Food Funct 2018; 9:
5074-5095 [PMID: 30183037 DOI: 10.1039/c8fo00376a]
3 Savarino SJ, Bourgeois AL. Diarrhoeal disease: Current concepts and future challenges. Epidemiology of
diarrhoeal diseases in developed countries. Trans R Soc Trop Med Hyg 1993; 87 Suppl 3: 7-11 [PMID:
8108853 DOI: 10.1016/0035-9203(93)90529-y]
4 Allen SJ, Martinez EG, Gregorio GV, Dans LF. Probiotics for treating acute infectious diarrhoea.
Cochrane Database Syst Rev 2010; CD003048 [PMID: 21069673 DOI:
10.1002/14651858.CD003048.pub3]
5 Binder HJ, Brown I, Ramakrishna BS, Young GP. Oral rehydration therapy in the second decade of the
twenty-first century. Curr Gastroenterol Rep 2014; 16: 376 [PMID: 24562469 DOI:
10.1007/s11894-014-0376-2]
6 Bryce J, Terreri N, Victora CG, Mason E, Daelmans B, Bhutta ZA, Bustreo F, Songane F, Salama P,
Wardlaw T. Countdown to 2015: Tracking intervention coverage for child survival. Lancet 2006; 368:
1067-1076 [PMID: 16997661 DOI: 10.1016/S0140-6736(06)69339-2]
7 Pérez-Gaxiola G, Cuello-García CA, Florez ID, Pérez-Pico VM. Smectite for acute infectious diarrhoea in
children. Cochrane Database Syst Rev 2018; 4: CD011526 [PMID: 29693719 DOI:
10.1002/14651858.CD011526.pub2]
8 Schnadower D, Tarr PI, Casper TC, Gorelick MH, Dean JM, O'Connell KJ, Mahajan P, Levine AC, Bhatt
SR, Roskind CG, Powell EC, Rogers AJ, Vance C, Sapien RE, Olsen CS, Metheney M, Dickey VP, Hall-
Moore C, Freedman SB. Lactobacillus rhamnosus GG versus Placebo for Acute Gastroenteritis in
Children. N Engl J Med 2018; 379: 2002-2014 [PMID: 30462938 DOI: 10.1056/NEJMoa1802598]
9 Guarner F, Schaafsma GJ. Probiotics. Int J Food Microbiol 1998; 39: 237-238 [PMID: 9553803 DOI:
10.1016/S0168-1605(97)00136-0]
10 Lomax AR, Calder PC. Probiotics, immune function, infection and inflammation: A review of the
evidence from studies conducted in humans. Curr Pharm Des 2009; 15: 1428-1518 [PMID: 19442167
DOI: 10.2174/138161209788168155]
11 Szajewska H, Mrukowicz JZ. Probiotics in the treatment and prevention of acute infectious diarrhea in
infants and children: A systematic review of published randomized, double-blind, placebo-controlled trials.
J Pediatr Gastroenterol Nutr 2001; 33 Suppl 2: S17-S25 [PMID: 11698781 DOI:
10.1097/00005176-200110002-00004]
12 Wolvers D, Antoine JM, Myllyluoma E, Schrezenmeir J, Szajewska H, Rijkers GT. Guidance for
substantiating the evidence for beneficial effects of probiotics: Prevention and management of infections
by probiotics. J Nutr 2010; 140: 698S-712S [PMID: 20107143 DOI: 10.3945/jn.109.113753]
13 Szajewska H, Skórka A, Ruszczyński M, Gieruszczak-Białek D. Meta-analysis: Lactobacillus GG for
treating acute gastroenteritis in children--updated analysis of randomised controlled trials. Aliment
Pharmacol Ther 2013; 38: 467-476 [PMID: 23841880 DOI: 10.1111/apt.12403]
14 Szajewska H, Guarino A, Hojsak I, Indrio F, Kolacek S, Shamir R, Vandenplas Y, Weizman Z; European
Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Use of probiotics for management of
acute gastroenteritis: A position paper by the ESPGHAN Working Group for Probiotics and Prebiotics. J
Pediatr Gastroenterol Nutr 2014; 58: 531-539 [PMID: 24614141 DOI:
10.1097/MPG.0000000000000320]
15 Guarino A, Guandalini S, Lo Vecchio A. Probiotics for Prevention and Treatment of Diarrhea. J Clin
Gastroenterol 2015; 49 Suppl 1: S37-S45 [PMID: 26447963 DOI: 10.1097/MCG.0000000000000349]
16 Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner
EH, Higgins JPT, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JPA,
Geddes JR. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of
adults with major depressive disorder: A systematic review and network meta-analysis. Lancet 2018; 391:
1357-1366 [PMID: 29477251 DOI: 10.1016/S0140-6736(17)32802-7]
17 Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ,
Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of
studies that evaluate healthcare interventions: Explanation and elaboration. BMJ 2009; 339: b2700 [PMID:
19622552 DOI: 10.1136/bmj.b2700]
18 Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical
test. BMJ 1997; 315: 629-634 [PMID: 9310563 DOI: 10.1136/bmj.315.7109.629]
19 Johnston BC, Goldenberg JZ, Vandvik PO, Sun X, Guyatt GH. Probiotics for the prevention of pediatric
antibiotic-associated diarrhea. Cochrane Database Syst Rev 2011; CD004827 [PMID: 22071814 DOI:
10.1002/14651858.CD004827.pub3]
20 Johnston BC, Ma SS, Goldenberg JZ, Thorlund K, Vandvik PO, Loeb M, Guyatt GH. Probiotics for the

WJG https://www.wjgnet.com 5014 September 7, 2019 Volume 25 Issue 33

Li YT et al. Lactobacillus GG for acute diarrhea

prevention of Clostridium difficile-associated diarrhea: A systematic review and meta-analysis. Ann Intern
Med 2012; 157: 878-888 [PMID: 23362517 DOI: 10.7326/0003-4819-157-12-201212180-00563]
21 Cunliffe NA, Kilgore PE, Bresee JS, Steele AD, Luo N, Hart CA, Glass RI. Epidemiology of rotavirus
diarrhoea in Africa: A review to assess the need for rotavirus immunization. Bull World Health Organ
1998; 76: 525-537 [PMID: 9868844 DOI: 10.1146/annurev.publhealth.19.1.527]
22 Simakachorn N, Pichaipat V, Rithipornpaisarn P, Kongkaew C, Tongpradit P, Varavithya W. Clinical
evaluation of the addition of lyophilized, heat-killed Lactobacillus acidophilus LB to oral rehydration
therapy in the treatment of acute diarrhea in children. J Pediatr Gastroenterol Nutr 2000; 30: 68-72
[PMID: 10630442 DOI: 10.1097/00005176-200001000-00020]
23 Szajewska H, Skórka A, Ruszczyński M, Gieruszczak-Białek D. Meta-analysis: Lactobacillus GG for
treating acute diarrhoea in children. Aliment Pharmacol Ther 2007; 25: 871-881 [PMID: 17402990 DOI:
10.1111/j.1365-2036.2007.03282.x]
24 Basu S, Paul DK, Ganguly S, Chatterjee M, Chandra PK. Efficacy of high-dose Lactobacillus rhamnosus
GG in controlling acute watery diarrhea in Indian children: A randomized controlled trial. J Clin
Gastroenterol 2009; 43: 208-213 [PMID: 18813028 DOI: 10.1097/MCG.0b013e31815a5780]
25 Basu S, Chatterjee M, Ganguly S, Chandra PK. Efficacy of Lactobacillus rhamnosus GG in acute watery
diarrhoea of Indian children: A randomised controlled trial. J Paediatr Child Health 2007; 43: 837-842
[PMID: 17803667 DOI: 10.1111/j.1440-1754.2007.01201.x]
26 Canani RB, Cirillo P, Terrin G, Cesarano L, Spagnuolo MI, De Vincenzo A, Albano F, Passariello A, De
Marco G, Manguso F, Guarino A. Probiotics for treatment of acute diarrhoea in children: Randomised
clinical trial of five different preparations. BMJ 2007; 335: 340 [PMID: 17690340 DOI:
10.1136/bmj.39272.581736.55]
27 Costa-Ribeiro H, Ribeiro TC, Mattos AP, Valois SS, Neri DA, Almeida P, Cerqueira CM, Ramos E,
Young RJ, Vanderhoof JA. Limitations of probiotic therapy in acute, severe dehydrating diarrhea. J
Pediatr Gastroenterol Nutr 2003; 36: 112-115 [PMID: 12500005 DOI:
10.1097/00005176-200301000-00021]
28 Czerwionka-Szaflarska M, Murawska S, Swincow G. Evaluation of influence of oral treatment with
probiotic and/or oral rehydration solution on course of acute diarrhoea in children. Przegl Gastroenterol
2009; 4: 166-172
29 Guandalini S, Pensabene L, Zikri MA, Dias JA, Casali LG, Hoekstra H, Kolacek S, Massar K, Micetic-
Turk D, Papadopoulou A, de Sousa JS, Sandhu B, Szajewska H, Weizman Z. Lactobacillus GG
administered in oral rehydration solution to children with acute diarrhea: A multicenter European trial. J
Pediatr Gastroenterol Nutr 2000; 30: 54-60 [PMID: 10630440 DOI:
10.1097/00005176-200001000-00018]
30 Guarino A, Canani RB, Spagnuolo MI, Albano F, Di Benedetto L. Oral bacterial therapy reduces the
duration of symptoms and of viral excretion in children with mild diarrhea. J Pediatr Gastroenterol Nutr
1997; 25: 516-519 [PMID: 9360205 DOI: 10.1097/00005176-199711000-00005]
31 Isolauri E, Kaila M, Mykkänen H, Ling WH, Salminen S. Oral bacteriotherapy for viral gastroenteritis.
Dig Dis Sci 1994; 39: 2595-2600 [PMID: 7995184 DOI: 10.1007/BF02087695]
32 Jasinski C TM, Tanzi MN, Schelotto F, Varela G, Zanetta E, Acuña A, and Arenas C, del Pilar Gadea M,
Sirok A, Betancor L, Grotiuz G, Sandín D, Combol A, Xavier B, Vignoli R, Nairac A. Efficacy of
Lactobacillus GG in oral rehydration solution. Pediatrica 2002; 22: 231-243
33 Misra S, Sabui TK, Pal NK. A randomized controlled trial to evaluate the efficacy of lactobacillus GG in
infantile diarrhea. J Pediatr 2009; 155: 129-132 [PMID: 19559297 DOI: 10.1016/j.jpeds.2009.01.060]
34 Nixon AF, Cunningham SJ, Cohen HW, Crain EF. The effect of Lactobacillus GG on acute diarrheal
illness in the pediatric emergency department. Pediatr Emerg Care 2012; 28: 1048-1051 [PMID:
23023475 DOI: 10.1097/PEC.0b013e31826cad9f]
35 Pant AR, Graham SM, Allen SJ, Harikul S, Sabchareon A, Cuevas L, Hart CA. Lactobacillus GG and
acute diarrhoea in young children in the tropics. J Trop Pediatr 1996; 42: 162-165 [PMID: 8699584 DOI:
10.1093/tropej/42.3.162]
36 Raza S, Graham SM, Allen SJ, Sultana S, Cuevas L, Hart CA. Lactobacillus GG promotes recovery from
acute nonbloody diarrhea in Pakistan. Pediatr Infect Dis J 1995; 14: 107-111 [PMID: 7746691 DOI:
10.1097/00006454-199502000-00005]
37 Ritchie BK, Brewster DR, Tran CD, Davidson GP, McNeil Y, Butler RN. Efficacy of Lactobacillus GG in
aboriginal children with acute diarrhoeal disease: A randomised clinical trial. J Pediatr Gastroenterol Nutr
2010; 50: 619-624 [PMID: 20400916 DOI: 10.1097/MPG.0b013e3181bbf53d]
38 Shornikova AV, Isolauri E, Burkanova L, Lukovnikova S, Vesikari T. A trial in the Karelian Republic of
oral rehydration and Lactobacillus GG for treatment of acute diarrhoea. Acta Paediatr 1997; 86: 460-465
[PMID: 9183482 DOI: 10.1111/j.1651-2227.1997.tb08913.x]
39 Sindhu KN, Sowmyanarayanan TV, Paul A, Babji S, Ajjampur SS, Priyadarshini S, Sarkar R,
Balasubramanian KA, Wanke CA, Ward HD, Kang G. Immune response and intestinal permeability in
children with acute gastroenteritis treated with Lactobacillus rhamnosus GG: A randomized, double-blind,
placebo-controlled trial. Clin Infect Dis 2014; 58: 1107-1115 [PMID: 24501384 DOI: 10.1093/cid/ciu065]
40 Aggarwal S, Upadhyay A, Shah D, Teotia N, Agarwal A, Jaiswal V. Lactobacillus GG for treatment of
acute childhood diarrhoea: An open labelled, randomized controlled trial. Indian J Med Res 2014; 139:
379-385 [PMID: 24820831]
41 Salazar-Lindo E, Miranda-Langschwager P, Campos-Sanchez M, Chea-Woo E, Sack RB. Lactobacillus
casei strain GG in the treatment of infants with acute watery diarrhea: A randomized, double-blind,
placebo controlled clinical trial [ISRCTN67363048]. BMC Pediatr 2004; 4: 18 [PMID: 15345099 DOI:
10.1186/1471-2431-4-18]
42 Ahmadi E, Alizadeh-Navaei R, Rezai MS. Efficacy of probiotic use in acute rotavirus diarrhea in
children: A systematic review and meta-analysis. Caspian J Intern Med 2015; 6: 187-195 [PMID:
26644891]
43 Liu F, Li G, Wen K, Wu S, Zhang Y, Bui T, Yang X, Kocher J, Sun J, Jortner B, Yuan L. Lactobacillus
rhamnosus GG on rotavirus-induced injury of ileal epithelium in gnotobiotic pigs. J Pediatr Gastroenterol
Nutr 2013; 57: 750-758 [PMID: 24280990 DOI: 10.1097/MPG.0b013e3182a356e1]
44 Jiang Y, Ye L, Cui Y, Yang G, Yang W, Wang J, Hu J, Gu W, Shi C, Huang H, Wang C. Effects of
Lactobacillus rhamnosus GG on the maturation and differentiation of dendritic cells in rotavirus-infected
mice. Benef Microbes 2017; 8: 645-656 [PMID: 28670908 DOI: 10.3920/BM2016.0157]
45 Cai S, Kandasamy M, Rahmat JN, Tham SM, Bay BH, Lee YK, Mahendran R. Lactobacillus rhamnosus
GG Activation of Dendritic Cells and Neutrophils Depends on the Dose and Time of Exposure. J Immunol

WJG https://www.wjgnet.com 5015 September 7, 2019 Volume 25 Issue 33

 Li YT et al. Lactobacillus GG for acute diarrhea

Res 2016; 2016: 7402760 [PMID: 27525288 DOI: 10.1155/2016/7402760]

46 Khoruts A. Targeting the microbiome: From probiotics to fecal microbiota transplantation. Genome Med
2018; 10: 80 [PMID: 30376869 DOI: 10.1186/s13073-018-0592-8]
47 Vemuri RC, Gundamaraju R, Shinde T, Eri R. Therapeutic interventions for gut dysbiosis and related
disorders in the elderly: Antibiotics, probiotics or faecal microbiota transplantation? Benef Microbes 2017;
8: 179-192 [PMID: 28008784 DOI: 10.3920/BM2016.0115]
48 Boudraa G, Benbouabdellah M, Hachelaf W, Boisset M, Desjeux JF, Touhami M. Effect of feeding
yogurt versus milk in children with acute diarrhea and carbohydrate malabsorption. J Pediatr
Gastroenterol Nutr 2001; 33: 307-313 [PMID: 11593127 DOI: 10.1097/00005176-200109000-00015]
49 Kurugöl Z, Koturoğlu G. Effects of Saccharomyces boulardii in children with acute diarrhoea. Acta
Paediatr 2005; 94: 44-47 [PMID: 15858959 DOI: 10.1111/j.1651-2227.2005.tb01786.x]
50 Henriksson R, Bergström P, Franzén L, Lewin F, Wagenius G. Aspects on reducing gastrointestinal
adverse effects associated with radiotherapy. Acta Oncol 1999; 38: 159-164 [PMID: 10227436 DOI:
10.1080/028418699431564]
51 Uhnoo I, Svensson L, Wadell G. Enteric adenoviruses. Baillieres Clin Gastroenterol 1990; 4: 627-642
[PMID: 1962727 DOI: 10.1016/0950-3528(90)90053-J]
52 Cannon JP, Lee TA, Bolanos JT, Danziger LH. Pathogenic relevance of Lactobacillus: A retrospective
review of over 200 cases. Eur J Clin Microbiol Infect Dis 2005; 24: 31-40 [PMID: 15599646 DOI:
10.1007/s10096-004-1253-y]
53 De Groote MA, Frank DN, Dowell E, Glode MP, Pace NR. Lactobacillus rhamnosus GG bacteremia
associated with probiotic use in a child with short gut syndrome. Pediatr Infect Dis J 2005; 24: 278-280
[PMID: 15750472 DOI: 10.1097/01.inf.0000154588.79356.e6]
54 Molinaro M, Aiazzi M, La Torre A, Cini E, Banfi R. [Lactobacillus Rhamnosus sepsis in a preterm infant
associated with probiotic integrator use: A case report.]. Recenti Prog Med 2016; 107: 485-486 [PMID:
27727257 DOI: 10.1701/2354.25230]
55 Gouriet F, Million M, Henri M, Fournier PE, Raoult D. Lactobacillus rhamnosus bacteremia: An
emerging clinical entity. Eur J Clin Microbiol Infect Dis 2012; 31: 2469-2480 [PMID: 22544343 DOI:
10.1007/s10096-012-1599-5]
56 World Health Organization. The Treatment of Diarrhea: A Manual for Physicians and other Senior
Health Workers. Geneva: World Health Organization 2005;
57 Das RR. Zinc in acute childhood diarrhea: Is it universally effective? Indian J Pharmacol 2012; 44: 140;
author reply 140-140; author reply 141 [PMID: 22345893 DOI: 10.4103/0253-7613.91891]
58 Karczewski J, Troost FJ, Konings I, Dekker J, Kleerebezem M, Brummer RJ, Wells JM. Regulation of
human epithelial tight junction proteins by Lactobacillus plantarum in vivo and protective effects on the
epithelial barrier. Am J Physiol Gastrointest Liver Physiol 2010; 298: G851-G859 [PMID: 20224007 DOI:
10.1152/ajpgi.00327.2009]
59 Mennigen R, Nolte K, Rijcken E, Utech M, Loeffler B, Senninger N, Bruewer M. Probiotic mixture
VSL#3 protects the epithelial barrier by maintaining tight junction protein expression and preventing
apoptosis in a murine model of colitis. Am J Physiol Gastrointest Liver Physiol 2009; 296: G1140-G1149
[PMID: 19221015 DOI: 10.1152/ajpgi.90534.2008]
60 Yang F, Wang A, Zeng X, Hou C, Liu H, Qiao S. Lactobacillus reuteri I5007 modulates tight junction
protein expression in IPEC-J2 cells with LPS stimulation and in newborn piglets under normal conditions.
BMC Microbiol 2015; 15: 32 [PMID: 25888437 DOI: 10.1186/s12866-015-0372-1]
61 Zyrek AA, Cichon C, Helms S, Enders C, Sonnenborn U, Schmidt MA. Molecular mechanisms
underlying the probiotic effects of Escherichia coli Nissle 1917 involve ZO-2 and PKCzeta redistribution
resulting in tight junction and epithelial barrier repair. Cell Microbiol 2007; 9: 804-816 [PMID: 17087734
DOI: 10.1111/j.1462-5822.2006.00836.x]
62 Fukushima Y, Kawata Y, Hara H, Terada A, Mitsuoka T. Effect of a probiotic formula on intestinal
immunoglobulin A production in healthy children. Int J Food Microbiol 1998; 42: 39-44 [PMID: 9706796
DOI: 10.1016/S0168-1605(98)00056-7]
63 Rautava S, Arvilommi H, Isolauri E. Specific probiotics in enhancing maturation of IgA responses in
formula-fed infants. Pediatr Res 2006; 60: 221-224 [PMID: 16864708 DOI:
10.1203/01.pdr.0000228317.72933.db]
64 Naidu AS, Bidlack WR, Clemens RA. Probiotic spectra of lactic acid bacteria (LAB). Crit Rev Food Sci
Nutr 1999; 39: 13-126 [PMID: 10028126 DOI: 10.1080/10408699991279187]
65 Bujňáková D, Kmeť V. Inhibitory potential of lactobacilli against Escherichia coli internalization by HT
29 cells. Folia Microbiol (Praha) 2012; 57: 269-272 [PMID: 22528301 DOI:
10.1007/s12223-012-0122-9]
66 Gonzalez-Ochoa G, Flores-Mendoza LK, Icedo-Garcia R, Gomez-Flores R, Tamez-Guerra P. Modulation
of rotavirus severe gastroenteritis by the combination of probiotics and prebiotics. Arch Microbiol 2017;
199: 953-961 [PMID: 28634691 DOI: 10.1007/s00203-017-1400-3]
67 Kang JY, Lee DK, Ha NJ, Shin HS. Antiviral effects of Lactobacillus ruminis SPM0211 and
Bifidobacterium longum SPM1205 and SPM1206 on rotavirus-infected Caco-2 cells and a neonatal mouse
model. J Microbiol 2015; 53: 796-803 [PMID: 26502964 DOI: 10.1007/s12275-015-5302-2]
68 Paim FC, Langel SN, Fischer DD, Kandasamy S, Shao L, Alhamo MA, Huang HC, Kumar A,
Rajashekara G, Saif LJ, Vlasova AN. Effects of Escherichia coli Nissle 1917 and Ciprofloxacin on small
intestinal epithelial cell mRNA expression in the neonatal piglet model of human rotavirus infection. Gut
Pathog 2016; 8: 66 [PMID: 27999620 DOI: 10.1186/s13099-016-0148-7]
69 Kolaček S, Hojsak I, Berni Canani R, Guarino A, Indrio F, Orel R, Pot B, Shamir R, Szajewska H,
Vandenplas Y, van Goudoever J, Weizman Z; ESPGHAN Working Group for Probiotics and Prebiotics.
Commercial Probiotic Products: A Call for Improved Quality Control. A Position Paper by the ESPGHAN
Working Group for Probiotics and Prebiotics. J Pediatr Gastroenterol Nutr 2017; 65: 117-124 [PMID:
28644359 DOI: 10.1097/MPG.0000000000001603]

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