Catherine M. T. Sherwin, Wright State University, United States

REVIEWED BY

Silvia Salvatore, University of Insubria, Italy Julio Plaza-Diaz, Children’s Hospital of Eastern Ontario (CHEO), Canada

*CORRESPONDENCE

Xiaoquan Du,

[email protected]

†These authors have contributed equally to this work and share first authorship

RECEIVED 28 January 2023 ACCEPTED 10 July 2023 PUBLISHED 24 July 2023

CITATION

Yang Q, Hu Z, Lei Y, Li X, Xu C, Zhang J, Liu H and Du X (2023), Overview of systematic reviews of probiotics in the prevention and treatment of antibioticassociated diarrhea in children. Front. Pharmacol. 14:1153070. doi: 10.3389/fphar.2023.1153070

COPYRIGHT

© 2023 Yang, Hu, Lei, Li, Xu, Zhang, Liu and Du. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Qingrui Yang1†, Zeyu Hu1†, Yuyu Lei1, Xinzhu Li1, Chao Xu1, Jie Zhang1, Haitao Liu2 and Xiaoquan Du2*

1The First Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, China, 2Department of Gastroenterology, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, China

Background: Antibiotics alter the microbial balance commonly resulting in antibiotic-associated diarrhea (AAD). Probiotics may prevent and treat AAD by providing the gut barrier and restoring the gut microflora. This study will overview the Systematic Reviews (SRs) of probiotics in preventing and treating AAD in children. It will also assess the reporting, methodological, and evidence quality of the included SRs to provide evidence for their clinical practice.

Methods: After searching PubMed, Embase, Cochrane Library, CNKI, CBM, VIP, and WanFang Data databases, and finally included SRs of probiotics in the prevention and treatment of AAD in children, which were published before 1 October 2022. The reporting, methodological, and evidence quality of the included SRs were assessed by PRISMA 2020 statement, AMSTAR 2 tool, and GRADE system.

Results: A total of 20 SRs were included, and the results of PRISMA 2020 showed that 4 out of 20 SRs with relatively complete reporting, and the others within some reporting deficiencies, with scores ranging from 17 points to 26.5 points; the results of AMSTAR 2 showed that 3 SRs belonged to moderate quality level, 10 SRs belonged to low-quality level and 7 SRs being extremely low-quality level; the results of the GRADE system showed that a total of 47 outcomes were reported for the included SRs, three were high-level evidence quality, 16 were medium-level evidence quality, 24 were low-level evidence quality, and four were extremely low-level evidence quality; the results of the Meta-analysis showed that high doses (5–40 billion CFUs per day) of probiotics had a significant effect in the prevention of AAD, but it is too early to conclude the effectiveness and safety of other probiotic drugs for AAD in children, except for Lacticaseibacillus rhamnosus and Saccharomyces boulardii.

Conclusion: Current evidence shows that probiotics effectively prevent and treat AAD in children, and the effect of probiotics on pediatric AAD may be a potential dose-response effect. However, the conclusion should be treated with caution due to deficiencies in the methodological, reporting, and evidence quality of the included SRs. Therefore, the methodological, reporting, and evidence quality of relevant SRs still need further improvement.

Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022362328

KEYWORDS

children, antibiotic-associated diarrhea, probiotics, systematic review, overview of systematic reviews, PRISMA 2020, AMSTAR 2, grade

Antibiotic-associated diarrhea (AAD) is defined as diarrhea that occurs in the long-term use of antimicrobial drugs leading to dysbiosis of the intestinal flora (Bartlett, 2002). With the increasing degree of intestinal dysbiosis, the clinical manifestations of AAD can progress from mild diarrhea to acute and severe disease such as pseudomembranous colitis or toxic megacolon (seen in Clostridium difficile infection) (Bartlett, 2002; Zheng et al.,

1. 2021). The incidence and severity of clinical manifestations of AAD are related to the type of antibiotic, duration of use, patient health status, and the type of pathogen to which the patient is exposed (McFarland, 2008; Hayes and Vargas, 2016). Some studies showed that the incidence of childhood AAD in the United States ranged from 6% in outpatients to 80% in hospitalized children (McFarland et al., 2016). The incidence of childhood AAD in China has only been studied in hospitalized children, with incidence rates ranging from 16.80% to 70.59% (Zheng et al., 2021).

Currently, antibiotic-induced dysbiosis of the intestinal flora is the primary mechanism of AAD pathogenesis, and the basic therapeutic approach is re-establishing intestinal flora homeostasis (Zheng et al., 2021). Clinical commonly used bioactive agents, such as probiotics (living microorganisms, when administered with sufficient amounts of probiotics, may bring health benefits to the host) (Hill et al., 2014), prebiotics (a substrate that is selectively utilized by the microorganisms of the host, conferring a health benefit) (Gibson et al., 2017), synbiotics (a mixture comprising live microorganisms and substrates selectively utilized by host microorganisms that confers a health benefit on the host) (Swanson et al., 2020), and postbiotics (preparation of inanimate microorganisms and their components that confers a health benefit on the host) (Salminen et al., 2021). The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) recommendations for probiotics to prevent antibiotic-associated diarrhea high doses (≥5 billion CFU/day) of Lacticaseibacillus rhamnosus (L. rhamnosus) GG or Saccharomyces boulardii (S. boulardii) started simultaneously with antibiotic treatment (certainty of evidence: moderate; grade of recommendation: strong) (Szajewska et al., 2023) There are many systematic reviews (SRs) that have explored the efficacy and adverse effects of probiotics in pediatric AAD (Johnston et al., 2006; Szajewska et al., 2006; Johnston et al., 2011; Szajewska and Kołodziej,

1. 2015a; Szajewska and Kołodziej, 2015b; Goldenberg et al., 2015; Szajewska et al., 2016; Xu et al., 2017; Guo et al., 2019; Storr and Stengel, 2021), however, their methodological, reporting and evidence quality of evidence are unclear. An overview of systematic reviews is a comprehensive approach that collects relevant systematic reviews of the treatment, etiology, diagnosis, and prognosis of the same disease or health problem (Lunny et al., 2017; Lunny et al., 2018). The

principal objective of this overview was to clarify the benefits of probiotics for the prevention or treatment of AAD in children, which promotes evidence-based decisionmaking. Therefore, this study will overview SRs related to probiotics in preventing and treating AAD in children. It will also assess the methodological, reporting, and evidence quality of the included SRs to provide evidence for their clinical practice.

1. 2.1 Project registration
2. 2.2 Data sources
3. 2.3 Inclusion criteria

1. 2.3.1 Type of study Systematic review or Meta-analysis.
2. 2.3.2 Study population
3. 2.3.3 Interventions The treatment group was probiotics or probiotics
4. 2.3.4 Outcome indexes Any efficacy and safety indexes.

1. 2.4 Exclusion criteria
2. 2.5 Literature screening and data extraction
3. 2.6 Quality assessment

Two researchers independently evaluated the reporting, methodological, and evidence quality of the included SRs using PRISMA 2020 (Page et al., 2021a; Page et al., 2021b), AMSTAR 2 (Shea et al., 2017) and the GRADE system (Atkins et al., 2004; Balshem et al., 2011), cross-checking in parallel and consulting a third party in case of disagreement. PRISMA 2020 consists of 27 items, and each item is scored as 1) fully satisfied (i.e., complete reporting) is scored as 1; 2) partially satisfied (i.e., partial reporting) is scored as 0.5; and 3) not satisfied (i.e., not reported) is scored as 0. AMSTAR 2 consists of 16 items, of which 7 are key items; each item is evaluated as “yes” (fully reported), “partially yes” (partially reported), and “partially yes” (partially reported). Combining the results of the

key and non-key item assessments, each included SR was rated as high, moderate, low or very low in quality. Escalation factors for GRADE are large effect size, dose-effect relationship, and negative bias, and the downgrading factors are risk of bias, inconsistency, indirectness, imprecision, and publication bias. The level of evidence for the indicators was evaluated as high, moderate, low, or very low. Two researchers (YL and XL) independently assessed the evidence quality.

1. 2.7 Statistical analysis
2. 3.1 Literature search

A total of 207 studies were obtained for the initial review, and 20 SRs were finally included after a hierarchical screening process (Johnston et al., 2006; Shi et al., 2006; Szajewska et al., 2006; Chen et al., 2010; Lu, 2010; Johnston et al., 2011; Fang et al., 2013; Chai et al., 2015; Goldenberg et al., 2015; You and Gao, 2015; Yang et al., 2016a; Yang et al., 2016b; Szajewska et al., 2016; Zhou et al., 2016;

Chai et al., 2017; He et al., 2017; Xu et al., 2017; Guo et al., 2019; Liu et al., 2020; Liu et al., 2022), and the literature screening process and results are shown in Figure 1.

3.2 Study characteristics

The basic information of the included studies is shown in Table 2. Among the 20 SRs included, 13 SRs (Shi et al., 2006; Chen et al., 2010; Lu, 2010; Fang et al., 2013; Chai et al., 2015; You and Gao, 2015; Yang et al., 2016a; Yang et al., 2016b; Zhou et al.,

1. 2016; Chai et al., 2017; He et al., 2017; Liu et al., 2020; Liu et al.,

1. 2022) were in Chinese and seven SRs (Johnston et al., 2006; Szajewska et al., 2006; Johnston et al., 2011; Goldenberg et al.,

1. 2015; Szajewska et al., 2016; Xu et al., 2017; Guo et al., 2019) were in English, published from 2006 to 2022. All SRs were included in randomized controlled trial studies (RCTs), and all used Metaanalysis to process the data. The main probiotics include Bacillus spp., Bifidobacterium spp., Lacticaseibacillus spp., Lactococcus spp., Saccharomyces spp., and Streptococcus spp. The daily dosage of probiotics varied greatly from 1 million to 2 trillion CFUs/day. Twelve SRs (Szajewska et al., 2006; Chen et al., 2010; Johnston et al., 2011; Chai et al., 2015; Goldenberg et al., 2015; Yang et al.,
2. 2016a; Yang et al., 2016b; Szajewska et al., 2016; Chai et al., 2017;

Guo et al., 2019; Liu et al., 2020; Liu et al., 2022) used the Cochrane systematic review tool, seven SRs (Johnston et al., 2006; Shi et al., 2006; Lu, 2010; Fang et al., 2013; Zhou et al., 2016; He et al., 2017; Xu et al., 2017) used the Jadad scale, and one SR (You and Gao, 2015) did not report a risk of the bias assessment tool.

3.3 Reporting quality

The results of the PRISMA 2020 are shown in Table 3: the scores of the included 20 SRs ranged from 16.5 to 26.5, four SRs (Johnston et al., 2006; Johnston et al., 2011; Goldenberg et al., 2015; Guo et al., 2019) (20%) had relatively complete reports, and 16 SRs (Shi et al., 2006; Szajewska et al., 2006; Chen et al., 2010; Lu, 2010; Fang et al., 2013; Chai et al., 2015; You and Gao, 2015; Yang et al., 2016a; Yang et al., 2016b; Szajewska et al., 2016; Zhou et al., 2016; Chai et al., 2017; He et al., 2017; Xu et al., 2017; Liu et al., 2020; Liu et al., 2022) (80%) had some reporting deficiencies. Among the reporting deficiencies, the main ones were found in item 24: Program and registration, followed by item 15: Other analysis in the methods section and item 22: Other analysis in the results section, as well as other information related to the item on funding.

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NR, not reported; C, treatment group; T, control group; PP, probiotic preparations; CWM, conventional western medicine treatment; RRR, Relative Risk Reduction (percentage of reduction of AAD); NNT, number needed to treat; MA, Meta-Analysis. Strain of probiotics: BA, Bififidobacteria anamalis subsp. lactus; BB, Bififidobacterium breve; BC, Bacillus clausii; BI, Bififidobacterium infantis; BL, Bififidobacterium lactis; BS, Bacillus subtilis; CB, Clostridium acidophilus; LB, Lactobacillus bularicus; LC, Lactococcus casei; LD, Lactobacillus delbrueckii subsp. bulgaris; LGG, Lacticaseibacillus rhamnosus GG; LL, Lactococcus lactis; LP, Lactococcus plantarum; LR, Lactococcus rhamnosu Saccharomyces boulardii; SF, Saccharomyces flflorentinus; ST, Streptococcus thermophilus. Outcomes: ① incidence of AAD; ② adverse effects; ③ duration of diarrhea; ④ total effective rate; ⑤ mean hospital stay; ⑥ incidence of CDAD; ⑦ mean stool frequency; ⑧ cure rate; ⑨ antidiarrheal time

1. TABLE 3 Quality of reporting of included systematic reviews assessed using the PRISMA 2020 statement.

3.4 Methodological quality

The results of the AMSTAR 2 are shown in Table 4: in the 20 SRs included, three SRs (Johnston et al., 2011; Goldenberg et al., 2015; Guo et al., 2019) (15%) were of medium quality, 10 SRs (Johnston et al., 2006; Szajewska et al., 2006; Chen et al., 2010; Fang et al., 2013;

1. Yang et al., 2016a; Zhou et al., 2016; Chai et al., 2017; Xu et al., 2017; Liu et al., 2020; Liu et al., 2022) (50%) were of low quality, and seven SRs (Shi et al., 2006; Lu, 2010; Chai et al., 2015; You and Gao, 2015;
2. Yang et al., 2016b; Szajewska et al., 2016; He et al., 2017) (35%) were

of very low quality. The main reason for the lower quality level was that item 10, item 2, item 12, item 3, item 7, and item 16 were not reported.

3.5 GRADE quality of evidence

Based on the preventive and therapeutic effects of probiotics on ADD in clinical studies, as well as the adverse effects produced, the results of the quantitative analysis of the

1. TABLE 4 Methodological quality of included systematic reviews assessed using the AMSTAR 2 tool.

outcome indicators and the quality of evidence results of the 20 SRs from these three aspects are summarized and reported below, as detailed in Table 5.

3.5.1 Indicators of preventive effects

1. 3.5.1.1 AAD incidence Sixteen SRs (Johnston et al., 2006; Shi et al., 2006; Szajewska
2. 3.5.1.2 CDAD incidence Three SRs (Szajewska et al., 2006; Szajewska et al., 2016; He et al.,

2017) reported the incidence of Clostridium difficile-associated

diarrhea (CDAD) belonging to severe AAD. The GRADE system showed that one was of high quality and two were of moderate quality, suggesting that probiotics were superior to placebo in the incidence of CDAD, with a statistically significant difference (p < 0.05).

3.5.2 Indicators of treatment effects

3.5.2.1 Duration of diarrhea

Duration of diarrhea was reported in 10 SRs (Szajewska et al., 2006; Johnston et al., 2011; Goldenberg et al., 2015; Yang et al., 2016a; Yang et al., 2016b; Zhou et al., 2016; He et al., 2017; Guo et al., 2019; Liu et al., 2020; Liu et al., 2022) and data were not combined for Meta-analysis in one SR (Szajewska et al., 2006). The GRADE system showed that two were of medium quality, six were of low quality, and one very low quality. Four of the SRs (Johnston et al., 2011; Goldenberg et al., 2015; He et al., 2017; Guo et al., 2019) with probiotics alone and five SRs (Yang et al., 2016a; Yang et al., 2016b; Zhou et al., 2016; Liu et al., 2020; Liu et al., 2022) by probiotics combined with conventional Western medical treatment showed superiority overview placebo and conventional Western medical treatment in reducing the duration of diarrhea, with statistically significant differences (p < 0.05).

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C, treatment group; T, control group; PP, probiotic preparations; CWM, conventional western medicine treatment. Outcomes: ① incidence of AAD; ② adverse effects; ③ duration of diarrhea; ④ total effective rate; ⑤ mean hospital stay; ⑥ incidence of CDAD; ⑦ mean stool frequency; ⑧ cure rate; ⑨ antidiarrheal time OR, ratio; RR, relative risk; MD, weighted mean difference; SMD, standardized mean difference; RD, risk difference; −1: downgrade one level; 0: no downgrade; ✱: greater risk of bias in randomization, allocation concealment, and blinding; $: greater heterogeneity in combined results, I2 > 50%; #: potential for large publication bias.

1. 3.5.2.2 Total effective rate Seven SRs (Lu, 2010; You and Gao, 2015; Yang et al., 2016a;
2. 3.5.2.3 Mean hospital stay Five SRs (You and Gao, 2015; Yang et al., 2016a; Zhou et al.,

vomiting, belching, sputum, taste disturbance, loss of appetite, headache, chest pain, gastrointestinal distention, reflux, abdominal pain, constipation, rash, allergic reaction to antibiotics and mycosis stomatitis, but most studies did not report the group in which the ADR occurred (treatment or control group). There are six SRs (Johnston et al., 2006; Johnston et al., 2011; Goldenberg et al., 2015; Yang et al., 2016a; Guo et al., 2019; Liu et al., 2022) in the literature describing the specifics of ADR, of which only three SRs (Johnston et al., 2011; Goldenberg et al., 2015; Guo et al., 2019) combined data for Meta-analysis of ADR, and the GRADE system showed one of low quality and two of very low quality, which showed no statistically significant differences between the two groups (p > 0.05). In addition, two SRs (Szajewska et al., 2006; Szajewska et al., 2016) did not mention the specific occurrence of ADR, and five SRs (You and Gao, 2015; Yang et al., 2016b; Chai et al., 2017; He et al., 2017; Liu et al., 2020) mentioned that no ADR was seen. The above indicates that the incidence of ADRs in probiotics is low, suggesting that probiotics are safe to prevent and treat AAD.

4.1 Major findings

The principle objective of this overview was to clarify the benefits of probiotics for preventing or treating AAD in children, which promotes evidence-based decision-making. The main used microorganisms in probiotic preparations in 20 SRs are bacteria of the Lactobacillaceae family, particularly L. rhamnosus and L. acidophilus, as well as L. plantarum, L. casei, L. lactis and L. bulgaricus. Probiotics frequently contain bacteria of the genera Bifidobacterium (B. longum, B. infantis, B. breve), Clostridium, Lactococcus, Enterococcus, Bacillus, and strains of S. thermophiles. In addition, strains of Saccharomyces species, such as S. boulardii also present in these preparations (Table 2). We established some interesting findings through an in-depth review of the 20 studies.

Firstly, 16 studies reported the incidence of AAD, and five of them (Johnston et al., 2006; Johnston et al., 2011; Goldenberg et al., 2015; Xu et al., 2017; Guo et al., 2019) analyzed the incidence of AAD by intention-to-treat (ITT) analysis (overall patients as randomized were analyzed), results showed definite benefits of probiotics compared to active, placebo or no treatment controls. The pooled results of a per-protocol (PP) analysis (patients for whom data were available were analyzed as randomized) of one study (Xu et al., 2017) were similar to the ITT analysis (bifidobacterial preparations for the prevention or treatment of AAD in children). However, the ITT analysis was unreliable if the rate of lost to follow-up (LTFU) was high. Therefore, we chose the PP analysis for the pooled data results of the other four studies (Johnston et al., 2006; Johnston et al., 2011; Goldenberg et al., 2015; Guo et al., 2019). In addition, given that the definition of probiotics requires that “sufficient amounts” be given to achieve health benefits, it is unclear what the daily dose of probiotics should be. No dose-ranging studies have been reported to determine the minimum effective dose of probiotics in the prevention of AAD, and some studies (Ouwehand, 2017) suggest that doses near the lower range may not provide benefit, while doses

in the higher range may be associated with an increased risk of adverse events. The daily doses of probiotics included in the 20 SRs were highly variable (1 million to 2 trillion CFU/d), with reductions in the incidence of AAD ranging from 47% to 70% after treatment with different probiotic dose interventions (corresponding probiotic doses of 325–650 million CPU/d for S. boulardii and 1-4 million CPU/d for C. butyricum and B. infantis) and a reduction in the duration of diarrhea of 0.6d–1.95 d (corresponding probiotic doses of L. GG 100 million-40 billion CPU/d and S. boulardii 162.5–650 million CPU/d) (Table 2). It suggests that the effect of probiotics on pediatric AAD may be a potential dose-response effect and that the use of probiotics during antibiotic use reduces the incidence of AAD. Notably, the SRs published in English are more in-depth than most published in Chinese regarding diarrhea incidence, especially in exploring the heterogeneity of the combined results. Several studies (Johnston et al., 2006; Johnston et al., 2011; Goldenberg et al., 2015; Guo et al., 2019) have critically evaluated each subgroup (e.g., probiotic type, probiotic dose, antibiotic class, and definition of diarrhea) by using multiple criteria. Subgroup analyses regarding probiotic dose compared low doses (<5 billion CFU/day) with high doses (≥5 billion CFU/ day). For example, one study (Guo et al., 2019) reported a benefit of high-dose probiotics in AAD prevention, with a 63% reduction in the incidence of AAD with high-dose probiotics compared to controls (RR: 0.37, 95% CI: 0.30 to 0.46, p = 0.06, I2 = 36%) and the NNT (i.e., number needed to treat) of 6 for prevention of one case of diarrhea (NNT: 6, 95% CI: 5–9).

1. 4.2 Outcome indicators for systematic reviews

The included 20 SRs had some limitations in their analysis of outcome indicators. First, clinical efficacy may be affected because the effects of probiotics are strain-specific and dose-specific, and it is challenging to standardize specific interventions, doses, and regimens in clinical studies. For the preventive effect of probiotics, eight SRs (Johnston et al., 2006; Szajewska et al., 2006; Chen et al., 2010; Johnston et al., 2011; Goldenberg et al., 2015; Szajewska et al., 2016; Xu et al., 2017; Guo et al., 2019) have performed subgroup analyses of AAD incidence according to probiotic species, and the results suggest that it is too early to conclude the efficacy and safety of other probiotic drugs for AAD in children, except L. rhamnosus and S. boulardii. Four SRs (Johnston et al., 2006; Johnston et al., 2011; Goldenberg et al., 2015; Guo et al., 2019) performed subgroup analyses of AAD incidence according to probiotic dose subgroup analysis, with moderate quality evidence suggesting a significant role for high-dose (5 40 billion colony forming units per day) probiotics in the prevention of AAD. In addition, since multiple SRs were studying the same disease and data were collated and evaluated for the analysis of the same outcome indicators, there may be some overlap in the original studies included in different SRs. For example, two SRs (Johnston et al., 2011; Goldenberg et al., 2015) had the same Meta-analysis results for two outcome indicators (Table 5). On the other hand, the naming of the outcome indicators included in the SRs is highly variable, irregular, and even contradictory. Using of outcome indicators with different definition criteria may potentially affect the

credibility of the conclusions. Therefore, there is a need to further promote the development of Core Outcome Set (COS) studies in the future, intending to address the problems of arbitrariness, inconsistency, and lack of recognition of clinical research outcome indicators (Williamson et al., 2012; Zhang et al., 2021).

1. 4.3 Reporting quality of systematic reviews
2. 4.4 Methodological quality of systematic reviews

According to the results of AMSTAR 2, the deficiencies of key item 2 (reported the predefined protocol) and item 7 (List of excluded studies and reason) were found to be more obvious: ① 85% of the SRs did not provide a pre-study design plan, which would affect the rigour of the study results; ② 70% of the SRs did not provide a list of excluded literature in the screening process, which might have literature inclusion bias. In addition, the results of nine non-critical item assessments showed that: ① 75% of SRs did not describe the basis of study design selection (item 3), which may prevent a complete efficacy assessment of a certain intervention due to the type of study design included; ② 95% of SRs did not give information on the source of funds for inclusion in the original study (item 10), and 40% of SRs did not report potential conflicts of interest (item 16), which may affect the credibility of evidence-based conclusions; ③ 85% of SRs did not evaluate the impact of individual study risk of bias on the results of Meta-analysis (item 12), and inadequate assessment of the risk of bias may lead to biased results. Therefore, the methodological quality of relevant SRs still needs to be improved.

1. 4.5 Quality of evidence for systematic reviews
2. 4.6 Study limitations

(1) A comprehensive literature search was conducted for this study, but due to language limitations, only Chinese and English SRs were included, which may be subject to potential publication bias. (2) The methodological, report, and evidence quality of the included SRs have certain shortcomings. There may be subjectivity in the study process, which reduces the reliability of the study results.

Overviews, as a comprehensive and relatively novel research method, assess the evidence from systematic reviews at a higher level, contain a richer and more comprehensive amount of information and can provide more focused evidence support for clinical researchers (McKenzie and Brennan, 2017; LópezLópez et al., 2022). A total of 20 SRs were included in this study, which comprehensively compared the efficacy of probiotics in preventing and treating AAD in children. The results showed that probiotics alone or probiotics combined with conventional western medical treatment could not only effectively prevent the incidence of AAD and CDAD, but also improve the overall efficiency and clinical cure rate, shorten the duration of diarrhea, mean frequency of diarrhea, the average hospitalization time and antidiarrheal time, and the incidence of adverse effects was low, the safety of probiotics was good. However, the results of existing evidence show that

the methodological, reporting and evidence quality of SRs of probiotics for AAD in children are generally low. There is still a need to improve the quality of evidence-based evidence to better explain the clinical application value of probiotics for AAD in children in the future. The results of this study need to be applied with reasonable interpretation.