Effect of Probiotic, Prebiotic, or Synbiotic Supplement on Children, Adolescents, or Infants: A Protocol of an Umbrella Review

Background: Many systematic reviews and meta-analyses have studied the association between probiotics, prebiotics, or synbiotics and children, adolescents, or Infants. With the promotion of probiotics, prebiotics, or synbiotics in our life and medical practice, more and more attention has been paid to them. Therefore, it is necessary to make a systematic summary of them. When the information was obtained in the identied systematic review, it will be compared with a control group that do not use probiotics, prebiotics, or synbiotics. In addition, our aim is to assess the quality of the included systematic reviews. Methods: We will conduct a comprehensive systematic search by summarizing systematic reviews of randomized controlled trials which have studied effect of probiotic, prebiotic, or synbiotic supplement on children, adolescents, or Infants. Four electronic databases (Embase, PubMed, Medline, and Cochrane Database of Systematic Reviews) will be searched. Two reviewers will independently screen the retrieved papers. Two reviewers will independently extract the data by reference to the JBI Data Extraction Form for Review for Systematic Reviews and Research Syntheses. We will also assess methodological quality and assessment of certainty in the ndings by A Measurement Tool to Assess Systematic Review version 2 (AMSTAR-2) and the GRADE (Grading of Recommendations Assessment, Development and Evaluation). We will calculate the corrected covered area (CCA). We will recalculate the summary effect and 95% CIs by using xed-effect or random-effect models. Discussion: Through quantitative and qualitative comparison by conducting an umbrella review, we hope our results will service better for future clinical practice.

JBI Data Extraction Form for Review for Systematic Reviews and Research Syntheses. We will also assess methodological quality and assessment of certainty in the ndings by A Measurement Tool to Assess Systematic Review version 2 (AMSTAR-2) and the GRADE (Grading of Recommendations Assessment, Development and Evaluation). We will calculate the corrected covered area (CCA). We will recalculate the summary effect and 95% CIs by using xed-effect or random-effect models.
Discussion: Through quantitative and qualitative comparison by conducting an umbrella review, we hope our results will service better for future clinical practice. Background Probiotic refers to live microorganisms that confer a health bene t on the host when administered in adequate amounts.
[1] Prebiotic is de ned as a substrate that is selectively utilized by host microorganisms conferring a health bene t. [2] The latest de nition of a synbiotic is that a mixture of living microorganisms and substrate(s) that is selectively utilized by host microorganisms for the bene t of host health. [3] It is all acknowledged that probiotic, prebiotic, and synbiotic can together modulate gut microbiota and are widely used to prevent or treat diseases on children, adolescents, or Infants. [4] According to the reporting from the European Society for Paediatric Gastroenterology Hepatology and Nutrition Committee on Nutrition and the European Society for Paediatric Gastroenterology Hepatology, probiotics have a positive effect on promoting the health of premature infants. [5] Probiotic plus prebiotic supplemention or synbiotic supplementation can contribute to reducing necrotizing enterocolitis morbidity in premature infants, and the combination of probiotics and prebiotics or synbiotic supplementation may bring better e cacy in premature infants when compared with single strain.
[6] Bi LW [7] also agreed that the miture of probiotic can better decrease the incidences of necrotizing enterocolitis, gut-associated sepsis, and mortality in preterm infants than single strains. What's more, by conducting an overview, Xiong T[8] found that a combination of probiotics could reduce the risk of necrotizing enterocolitis in preterm Infants and certainty evidence is moderate. The underlying mechanism may be that combination can better balance gut microecology disrupted by antibiotic treatment or defects in the development of congenital gut microbes.
Probiotics and prebiotics can pose successful defense against respiratory virus infection. [9] Based on the gut-lung axis theory, probiotic and prebiotic supplements can decrease the incidence of upper respiratory tract infections and shorten the disease duration. In addition, according to Carty's reporting [10], they thought that synbiotic supplements can better protect human from sufferring from respiratory tract infections than single use of probiotics or prebiotics. Anastasia [11] also agreed that by manipulating upper respiratory tract microbiome, Infants may have better outcome after exposed to respiratory tract infection. By conducting a meta-analysis of randomized controlled trials, Minmin Su [12] found that probiotics can signi cantly reduce the incidence of Ventilator-associated pneumonia, which further prove that probiotic supplements could be useful for treating respiratory tract infection. Baron [16] held that infant antibiotic exposure can result in disrupting balance of the gut microbiota, further causing the increasing of overweight or obesity in children. By following the birth cohort of 165 children and their mothers, Stanislawski [17] found that the gut microbiota in the two years before birth can predict the risk of obesity at age 12, potentially offering an opportunity to prevent childhood obesity. By summarizing the effect of probiotics on body weight and other obesityrelated anthropometric measures in overweight and obese patients, Simone Perna [13] found that by modulating the gut microbiota, probiotics supplementation may effectively reduce body mass Index (BMI), waist circumference (WC), and hip circumference (HC), further proving that probiotics supplementation can effectively treat respiratory tract infections.
Some researchers have proposed that probiotics may prevent the development of allergic diseases in children. By conducting Meta-analysis, Pelucchi C [18] and Yin DG [19] both agreed that the use of probiotics in pregnancy and infancy can reduce the risk of Atopic Dermatitis. Tan-Lim CSC [20] found that mixture of Lactobacillus paracasei ST11, Bi dobacterium longum BL999), and LP (Lactobacillus paracasei ssp paracasei F19), or mixture of Lactobacillus rhamnosus GG and Bi dobacterium animalis ssp lactis Bb-12 could decrease the risk of atopic dermatitis in children. However, their included literature are major low-quality evidence, reducing credibility with their results. Sorensen K [21] believed that compared with the amino acid formula alone, the hospitalization rate and overall drug use (including antimicrobial agents and antibiotics) of infants allergic to milk protein were lower in the amino acid formula containing synbiotics. However, there are some controversies between different researchers. Sestito S [22] didn't recommend pre/probiotic supplements as preventive treatment for allergic disease. Due to the low evidence about probiotic supplents, EAACI guideline [23] objected to the use of prebiotics, probiotics or synbiotics in pregnancy, when breastfeeding or in infancy for preventing food allergy. EAACI guidelines [24] do not address whether the use of probiotics, probiotics or synbiotics in adolescents and young adults with allergies and asthma can be considered an effective transitional treatment.
There are still many other diseases that probiotics, prebiotics or synbiotics can be used to treat on children, adolescents, or Infants, such as infantile colic [25]. However, there are different arguments about the role of probiotics, probiotics or synbiotics to treat the same disease. Allen SJ[26] held probiotics can effectively shorten the duration and reduce stool frequency in acute infectious diarrhoea. In contrast, Collinson S [27] held that probiotics may have little effect on diarrhea lasting 48 hours or more. In addition, probiotics have a broad impact on the treatment of diseases, so it is necessary for us to make a comprehensive summary of the role of probiotics in the human body. More importantly, we are not sure about the quality of the literature, so to use authoritative evaluation tools to examine the quality level of the literature is imperative.
However, there is no comprehensive and systematic umbrella review of the existing literature on the effects of probiotics, probiotics or symbiotic supplements on children, adolescents or infants. Such an umbrella review of existing systematic reviews will not only contribute to make a thorough discussion about the effect of probiotic, prebiotic, or synbiotic supplemention on children, adolescents, or Infants, but will also help assessing the quality of the existing evidence.

Objective
To assimilate the large amount of literature available on effect of probiotic, prebiotic, or synbiotic supplemention on children, adolescents, or Infants, we plan to conduct an umbrella review of meta-analyses of randomized controlled trial. Furthermore, we will evaluate the quality of the included systematic reviews, in hope for providing reliable evidence for clinical practice.

Methods
We will implement this protocol according to PRISMA-P [Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols] guidelines[28] (see Additional le 1). We have completed the registration of this protocol in PROSPERO (International Prospective Register of Systematic Reviews; registration number: CRD42021244923 ). We will update the modi cation of the protocol at any time in the future.
Search strategy establishment of the database and the formal start of retrieval. We will manually search for references to eligible papers. We will only include English literature.

Eligibility criteria
We will only include meta-analysis of randomized controlled trials which explored the effect of probiotic, prebiotic, and synbiotics on children, adolescents, or Infants. We will only consider articles that meet the following criteria: 1. We will consider including populations who are under the age of 18.
2. The difference between the experimental group and the control group is the presence or absence of probiotics, prebiotic, or synbiotic intervention. We will exclude these studies if the effect sizes observed are not related to the effect of probiotics, prebiotic, or synbiotic.
3. We will also exclude meta-analyses that do not report the necessary data, such as the relative risk (RR), effective rate, or odds ratio risk (OR) and 95% con dence intervals (CI).
4. Meta-analyses of randomized controlled trials that are published in full-text format and in English comply with systematic review criteria. We will include other grey literature sources. We will not include network meta-analysis, letter to the editor, abstract, protocols, or conference poster. We will also exclude literature where complete data are unavailable after connecting with the author.
In order to include the relevant literature as comprehensively as possible, we will not set a limit for the publication date.
Systematic reviews conducted by different authors are likely to contain partially overlapping literature if the exposures and results of these studies are the same, leading to biased conclusions. [29] In addition, the median updating time of such literature are 5.5 years for the systematic review. [30] Referencing the criteria of the previous umbrella review, [31] we the literature into two categories, namely, outdated (more than 6 years after the beginning of our search) and current (less than 6 years after the beginning of our search). If there are multiple different studies evaluating the same exposures and outcomes, and some of these studies are outdated and some are current, we will exclude the outdated studies during the full-text screening phase. If multiple articles evaluating the same exposures and outcomes are only outdated or not, we will calculate the degree of overlap by the corrected covered area (CCA). [29] The method used to calculate CCA will refer to previously published literature. [29,31]   And we will divide CCA into the following levels very high (CCA >15%), high (CCA 11-15%), moderate (CCA 6-10%), or slight (CCA 0-5%). [29] We will generate a graphical crossover table (citation matrix) that overlaps the systematic reviews as columns and the primary literature included in these systematic reviews as rows. [29] The selection criteria for overlapping systematic review after review are as follows: [31] 1.We will include all non-overlapping systematic review. For overlapping systematic review, we will rst include the nonobsolete Cochrane literature. [32] By examining the effects of different inclusion criteria on the comprehensiveness and complexity of medical intervention reviews, some researchers concluded that the data obtained from the Cochrane review was the most comprehensive, and that the quality of Cochrane reviews was higher than that of systematic reviews in other journals. [31,33] 2. IF there are a high degree of overlap (CCA ≥11%) between two or more reviews, we will select reviews as following grading criteria: the rating is highest or moderate quality by reference to the AMSTAR 2 quality assessment tool; most recent; pooled effect estimates or a meta-analysis is provided; and the number of studies or participants is the highest. [31,32] 3. For a slight or moderate degree of overlap (CCA ≤10%), we will retain both reviews, and further compare their results. [31] Literature screening Two reviewers will independently select literature by reading the titles and abstracts. After removing articles by reading the titles and abstracts, we will further nd the full text for the remained articles. Discrepancy will be solved by discussing with a third reviewer. we will handle the screening of studies in EndNote.

Data extraction and data synthesis
Two reviewers will extract the corresponding content by reference to the JBI Data Extraction Form for Review for Systematic Reviews and Research Syntheses. [34] (see Additional le 2) We will extract the following data items: rst author's name, publication year, name of diseases, the number of studies included in meta-analyses, total sample size, cases and controls, interventions,the dose of intervention, effect sizes and the corresponding 95% con dence interval, publication bias, and heterogeneity. The data will be analyzed by means of Epi Info (V.7.2) after we have entered the information.
We will recalculate the summary effect and 95% CIs using xed-effect or random-effect models. The I 2 statistic or Cochrane's Q test will be used to determine the magnitude of heterogeneity. For Cochrane's Q test, the result will be considered as signi cant heterogeneity when p<0.1; for the I 2 statistic, the result will be classi ed as signi cant heterogeneity when 50% ≤ I2. The 95% prediction interval (95% PI) for the effect size will be assessed. Publication bias and small-study effect will be estimated by Egger's test(a p value<0.1) or Begg's test(a p value<0.1). All statistical analyses will be conducted using Review Manager (RevMan, version 5.3 for Macintosh; The Cochrane Collaboration) and the statistical package PASW 20.0 for Macintosh (SPSS Inc.). If possible, we will conduct sensitivity, subgroup analyses, or meta-regression.
Assessment of methodological quality and assessment of certainty in the ndings Methodological quality will be assessed by checking A Measurement Tool to Assess Systematic Review version 2 (AMSTAR-2), [35] which including 16 items (7 critical domains and 9 non-critical domains). We will categorize the results as high, moderate, low, and critically low after assessing the methodological quality by AMSTAR-2. [35] The speci c classi cation criteria are as follows: No or 1 non-critical weakness will be appraised as high; more than 1 non-critical weaknes will be appraised as moderate; 1 critical aw with or without non-critical weakness will be appraised as low; if more than 1 critical aw with or without non-critical weakness will be appraised as critically low.
In addition, we will take the GRADE (

Discussion
We will summarize the evidence on the probiotic, prebiotic, or synbiotic supplemention for the treatment of diseases on children, adolescents, or Infants by conducting an umbrella review. An umbrella review is a tool which could better compare and contrast the ndings of reviews related to a review question, which could make it easier for decision makers to select evidence of higher quality. [34] We will also evaluate the quality of the systematic review by AMSTAR-2 and the GRADE. In addition, we will evaluate the degree of overlap by calculating CCA. Through quantitative and qualitative comparison, we hope that our results will provide a better basis for future clinical practice.

Declarations Ethics and dissemination
This is an umbrella review. We do not conduct any experiments on humans or animals, so we will not consider an ethical review. We will open the results of the umbrella review in a peer-reviewed journal.

Contributors
Chen Qiu will be the guarantor of the whole umbrella review. Shunlian Fu will be responsible for designing the structure of the whole umbrella review. This protocol was written after all authors discussed it. All authors agreed to publish this article.

Funding
The article is funded by 'Pilot project of collaboration between traditional Chinese medicine and western medicine for major and di cult diseases' (CYW2019079) and the funder was not involved in the writing.
Competing interests None declared.
All authors declared no competing interests.
Patient consent for publication Not required.