Abstract
Background
Malnutrition remains a significant concern in many societies. This study systematically reviewed the effects of probiotics, prebiotics, and synbiotics on anthropometric measures in malnourished children, focusing on changes in weight, height, and respiratory infections (primary outcomes), and head circumference, hemoglobin, hematocrit, and body mass index (BMI) as secondary outcomes.
Methods
This systematic review and meta-analysis involved searching various databases in both Persian and English, including Scopus, Web of Science Core Collection, Cochrane Library, Science Direct, and PubMed up to October 5, 2024. Non-randomized controlled trials (RCTs) were excluded. The Cochrane Handbook Risk of Bias Version 2 tool was used to assess risk of bias, and RevMan 5.3 software was employed for analysis. Subgroup analyses were conducted based on the type of supplement received. Meta-regression was applied to identify factors influencing results, and the GRADE approach was used to evaluate evidence certainty.
Results
Twelve studies with a total of 3,086 children (aged up to 6 years, equally distributed between boys and girls) were included. All children were malnourished without underlying illnesses. Limitations of the study included variations in intervention type, dose, duration, and timing of outcome measurement. Meta-analysis revealed that probiotics, prebiotics, and synbiotics may increase weight (6 trials, mean difference: 0.33 kg, 95% CI: 0.15 to 0.50, low certainty of evidence), while probiotics and synbiotics may increase height compared to control groups (5 trials, mean difference: 0.44 cm, 95% CI: 0.02 to 0.85, low certainty of evidence). However, probiotics and synbiotics did not show a statistically significant effect on lower respiratory tract infections (5 trials, risk ratio: 0.84, 95% CI: 0.68 to 1.04, moderate certainty of evidence). Meta-regression indicated that intervention type, sample size, and follow-up duration were not significant moderators for outcomes related to weight, height, or respiratory infections.
Conclusion
The current evidence suggests that probiotics, prebiotics, and synbiotics supplements may help manage malnutrition-related outcomes in malnourished children, but further research with stronger study designs is needed to confirm these findings due to the low certainty of evidence.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12887-024-05179-y.
Keywords: Probiotics, Prebiotics, Synbiotics, Growth, Child, Malnutrition
Background
Malnutrition is a critical global health challenge caused by lack of energy, protein and essential nutrients. About one third of children in developing countries are malnourished. Shockingly, almost half of all under-five deaths are attributed to malnutrition. It is known that 30–55% of hospitalized children are malnourished [1].
Malnutrition impacts nearly every system in the body, making children who are malnourished more vulnerable to infections. Frequent infections cause a lack of macro and micronutrients and dysfunction of the mucous barrier. This leads to a vicious cycle of persistent malnutrition, immunodeficiency, increased risk of infections, and worsening nutritional status [2].
Globally, severe acute malnutrition directly impacts around 14 million children under 5 years old, leading to approximately 1 million annual deaths. Furthermore, it significantly contributes to childhood mortality, particularly in cases of diarrhea and pneumonia, the two major complications associated with malnutrition. These complications often result in prolonged hospitalization and increased mortality [3, 4].
The repercussions of malnutrition extend beyond immediate health concerns, affecting long-term outcomes. These include increased mortality post-hospital discharge, suboptimal growth, compromised physical and cognitive function, and a reduced likelihood of achieving higher education levels [5]. Addressing malnutrition is crucial not only for immediate health outcomes but also for breaking the cycle of long-term negative consequences [6].
Malnutrition in children is categorized into two types: uncomplicated and complicated. Uncomplicated malnutrition is identified in children without clear clinical evidence of severe illness, other medical conditions, or poor appetite. On the other hand, complicated malnutrition is identified in children exhibiting clinical signs of infection, metabolic and electrolyte imbalances, significant swelling, or a lack of appetite [7]. Malnutrition results from various factors, including inadequate food consumption and infections [8]. Thus, it is crucial to identify a safe and effective treatment for promoting weight gain in malnourished children [9, 10].
Various nutrients play a role in preventing the occurrence of chronic diseases and complications caused by malnutrition. Probiotics, increasingly utilized for weight gain, exhibit beneficial effects on the absorption of both micronutrients and macronutrients [11–13]. Widespread probiotic use has been shown to promote weight gain through the modulation of gut microbiota [14]. Probiotics are live microorganisms that, when administered in sufficient amounts, may be beneficial to the host [15]. Lactobacillus and Bifidobacterium are the most common species used in probiotics. They function by modulating the immune system, preventing pathogens from adhering to the intestinal lining, and enhancing nutrient absorption [8].
In addition to facilitating weight gain, probiotics provide several other benefits, such as decreasing the incidence of infectious and bloody diarrhea, antibiotic-associated diarrhea, upper respiratory tract infections, and necrotizing enterocolitis in very low birth weight infants. They also help manage irritable bowel syndrome, childhood allergies, anemia, and can influence growth patterns in children [16–22]. Recent meta-analyses provide evidence that probiotics are effective in shortening the duration of hospitalization for well-nourished children with acute diarrhea. Guidelines have been published recommending their use in treating acute gastroenteritis and in preventing antibiotic-associated diarrhea in both children and adults undergoing antibiotic treatment for any reason [23, 24].
Prebiotics are oligosaccharides that resist digestion by the host but undergo fermentation by gut microorganisms. These indigestible compounds, fermented by native colonic bacteria, yield beneficial physiological effects for the host. Prebiotics stimulate the activity of native gut bacteria, leading to the production of short-chain fatty acids, lowering the pH of the colon, inhibiting the growth of harmful pathogens, improving immune system function, and enhancing the absorption of minerals and trace elements [25].
The combination of probiotics and prebiotics is known as synbiotics, which offer a synergistic effect that exceeds the benefits of each component alone. Various studies have highlighted the positive impact of synbiotic supplementation on weight, height, and body mass index (BMI), which are key anthropometric indicators of child development [26].
This systematic review and meta-analysis synthesizes existing evidence on probiotics, prebiotics, synbiotics, and malnutrition, offering valuable insights into their potential as interventions for addressing malnutrition in children. This study aims to address the following research questions:
How do probiotic supplements impact growth indicators and respiratory infections in malnourished children?
How do prebiotic supplements influence growth indicators and respiratory infections in malnourished children?
How do synbiotic supplements affect growth indicators and respiratory infections in malnourished children?
Aim
The study specifically aims to assess the effects of probiotics, prebiotics, and synbiotics on various outcomes associated with children’s anthropometric measurements, including changes in height, weight, and respiratory tract infection (primary outcome) and changes in head circumference, hemoglobin and hematocrit and BMI (secondary outcome).
Methods
Inclusion and exclusion criteria
This systematic review and meta-analysis follows the guidelines established in the Cochrane Handbook for Systematic Reviews of Interventions [27] and follows the reporting standards specified by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [28]. The protocol for this study has been registered with the International Prospective Register of Systematic Reviews (PROSPERO) on September 8, 2023, under the registration code CRD42023458524, before the commencement of the study.
In this investigation, only studies designed as randomized clinical trials (RCTs) and published in both Persian and English languages were considered for inclusion. This specific inclusion criterion ensures a focus on rigorous research designs and allows for a comprehensive review by including studies published in two widely used languages, Persian and English. This dual-language criterion aims to encompass a broader range of literature, promoting inclusivity and a more comprehensive understanding of the subject matter.
Studies excluded from this review include cross-sectional and quasi-experimental clinical trials, review articles, animal studies, scoping reviews, cohort studies, narrative reviews, systematic reviews and meta-analyses, case-control studies, case reports, case series, book chapters, papers presented at conferences and conventions, as well as studies lacking a control group.
Type of participants
Children up to 6 years old who were suffering from malnutrition without any specific underlying illness.
Type of interventions
The intervention involved the intake of probiotics, prebiotics, and synbiotics, taking into account factors such as dosage, type of supplementation, duration of consumption, and the interval between doses, whether administered alone or in combination. The control group included any comparative group, such as a no-intervention group, placebo, or any other pharmacological supplement.
Type of outcome measures
The primary outcomes of the study were comprised of anthropometric changes, including alterations in height, weight, head circumference, and lower respiratory infections changes in hemoglobin, hematocrit, and BMI as secondary outcomes.
Search methods for identification of studies
We performed a systematic search. in English-language databases, including Scopus, Web of Science Core Collection, Cochrane Library, ScienceDirect, and PubMed. Additionally, we performed searches in Persian-language databases, such as Scientific Information Database (SID), Magiran, Irandoc, and Iranmedex, from the inception of these databases up to October 5, 2024. Furthermore, among the eligible articles, references were examined to identify studies that were not found in the initial search. The search strategy used for the PubMed database is included in the supplementary file (Table S1). We utilized Medical Subject Headings (MeSH) terms and free-text keywords for our search.
(“Probiotics” OR “Prebiotics” OR “Lactobacillus” OR “Bifidobacterium” OR “Enterococc” OR “Lactococc” OR “Saccharomyces” OR “Streptococcus salivarius” OR “Streptococcus thermophiles” OR “Streptococcus faecalis” OR “Streptococcus” OR “Synbiotic” OR “Symbiotic” OR Probiotics [MeSH Terms] OR prebiotics [MeSH Terms] OR Synbiotics [MeSH Terms]) AND (Malnutrition OR growth failure OR underweight OR failure to thrive OR " grows indices " OR Malnutrition [MeSH Terms]) AND (Infant* OR young infants OR “Children” OR Child* OR “childrens” OR “childs” OR boy[ OR boys OR boyhood OR girl OR girls OR “child” [MeSH Terms] OR Children [MeSH Terms] OR Infant [MeSH Terms] OR Infant [MeSH Terms]) AND (“randomized-controlled trial’’ OR “controlled clinical trial” OR randomized OR randomly OR trial OR RCT).
In the article identification process, two authors (MP and MMa) worked independently to identify relevant studies through titles and abstracts. Additionally, they conducted a thorough review of studies that met the predefined criteria, including a full-text examination. In instances where there was a disagreement between the two authors regarding the inclusion of articles, a discussion and exchange of opinions were initially undertaken to reconcile differences. If consensus could not be reached between the two authors, a third author (MMi) was consulted to provide further input and assist in the decision-making process. This collaborative approach ensures a robust and objective selection of articles for inclusion in the investigation.
Data collection
The data extraction process was conducted independently by two authors (MP and MMa), with oversight from the third author (MMi). The extracted items encompassed comprehensive information, including: Author and publication year, country, study design, study population, age and gender of participants, intervention/control group, duration of intervention, outcomes, conclusions, and adverse events.
This systematic approach to data extraction ensures that key information across multiple dimensions of the studies is systematically collected and can be analyzed for a comprehensive understanding of the research landscape.
Data synthesis
A meta-analysis was performed using RevMan 5.4 software. To assess the effect of the intervention on dichotomous outcomes, the relative risk (RR) with 95% confidence intervals (CIs) was used. For continuous outcomes, mean differences (MD) with 95% CIs were used. Subgroup analysis was conducted based on the type of intervention. Heterogeneity was assessed using the I² [23]. If I2 ≥ 50% and p < 0.05 from the Chi-squared test, heterogeneity is considered significant and a random-effects model is applied instead of a fixed-effects model [29].
Meta-regression was conducted based on the intervention types, duration of follow-up with the intervention, control group, and total sample size using CMA3 software. In cases where only the interquartile range was reported, the standard deviation (SD) was estimated by multiplying the interquartile range by 1.35, following the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions [30]. To assess the certainty of evidence, the GRADE approach was used. This approach comprises five key domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias. Each domain is evaluated on a four-point scale: very low, low, moderate, and high.
[31]. A meta-analysis was conducted on three outcomes: weight, height, and lower respiratory tract infection. For other outcomes, due to the few numbers of conducted studies, a narrative and descriptive synthesis approach was adopted. A summary of the results was compiled in a table format, providing an organized and comprehensive overview of the individual study outcomes. This method of synthesis allows for a qualitative understanding of the research landscape, acknowledging the diversity among the included studies and their respective findings.
Assessment of risk of bias in included studies
Two independently authors (MP and MMa) assessed the risk of bias for all included studies using the Cochrane Handbook risk of bias version 2 tool and is visually presented in Figs. 1 and 2. Applying the RoB 2 tool provides a systematic and structured approach to evaluating the potential for bias in the included RCTs [32]. RoB 2 tool, five key domains are evaluated: Bias arising from the randomization process, Bias due to deviations from intended interventions, Bias due to missing outcome data, Bias in measurement of the outcome, and Bias in selection of the reported result. For each included study, the overall risk of bias will be judged as: Low risk of bias, Some concerns, or High risk of bias. Any discrepancies in the risk of bias assessment were resolved through discussion or consultation with a third reviewer.
Fig. 1.
Risk of bias summary: review authors’ judgments about each risk of bias item for each included study
Fig. 2.
Risk of bias graph: review authors’ judgments about each risk of bias item presented as percentages across all included studies
Certainty of evidence
The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach was used to assess the quality of evidence. This method evaluates five factors: risk of bias, inconsistency, indirectness, imprecision, and publication bias. Based on these criteria, the evidence is classified into four levels: high, moderate, low, and very low [31].
Results
Articles search
Search details, selection, and reasons for excluding articles are visually presented in Fig. 3. The initial search across various databases yielded a total of 478 articles. Of these, 308 randomized controlled trials were screened and assessed for eligibility based on predefined criteria. Following the removal of duplicate records and Studies that were not eligible, 291 articles were excluded.
Fig. 3.
Diagram for the search and selection process of the articles included in the present systematic review and meta-analysis
Subsequently, 20 articles underwent a full-text assessment. Among these, 5 articles were excluded as they did not investigate the desired outcomes, 2 studies were excluded as the intervention was applied to healthy children, and 1 study was excluded because it administered probiotic supplements to breastfeeding mothers and assessed their impact on children’s growth parameters, warranting its exclusion. In the end, 12 eligible studies were included in this review (Fig. 3). Among the 12 included articles, a meta-analysis was performed for the outcome of weight (6 studies), height (5 studies) and lower respiratory tract infection (5 studies).
Review articles
The articles included in this review were published between 2002 and 2024. All 12 studies had full-text articles available in English. Among these studies, one in Beijing [19], two were conducted in Iran [33, 34], two in India [35, 36], one in Bangladesh [36], one in Pakistan [37], one in Hong Kong [38], one in Turkey [39], one in Brazil, Mexico, Portugal, and Spain [40], one in Indonesia [41], and one in Uganda [1].
The total number of participants included in this systematic review was 3,086. Among the included studies, there was only one study that assessed the combined effect of probiotics with synbiotics compared to a control group [42]. To investigate the effect of probiotics, seven studies [1, 19, 36, 38, 39, 41, 42] were included. One study [37] was included to examine the effect of prebiotics, and five studies [33, 35, 36, 40, 43] were included to assess the effect of synbiotics.
The interventions in this review targeted children aged between 2 months and 6 years. In the probiotic group, the intervention started at 2 months of age, in the prebiotic group, it began at 6 months, and in the synbiotic group, it was initiated at 12 months of age. In all studies, the interventions were administered orally. The dosage and duration of interventions varied among the studies, with intervention timeframes ranging from 4 weeks to 1 year. The gender distribution of the children in the studies was approximately equal, with an average equal number of boys and girls. Some of the studies specifically focused on children with severe malnutrition. The characteristics of the studies are detailed in Table 1.
Table 1.
Characteristics of studies included in the systematic review and meta-analysis
| Author, year, country |
Study design | Study population | Age of participants | Gender of participants Male, n (%) |
Intervention group (IG) | Control group (CG) | Duration of intervention | Outcomes | Adverse events | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Nuzhat et al., (2023) Bangladesh |
Randomized controlled single-blinded study |
Probiotic (n = 21) Placebo (n = 23) Synbiotic (n = 23) |
2–6 months | 38 (56.71) |
Probiotic (Bifidobacterium. infantis) Synbiotic (B. infantis EVC001 + Lacto-N-neotetraose) |
CG were given placebo (Lactos) | 4 weeks | Change in weight and Length | Not reported | |||||
|
Batool et al., (2023) Pakistan |
Randomized controlled double-blinded study |
Prebiotic (n = 106) Placebo (n = 107) |
6–59 months | 108 (52.9) | IG was provided RUTF and 4 g prebiotics | CG were given RUTF and starch as a placebo | 8 weeks | Change in weight/HB/ HCT | No reported. | |||||
|
Kambale et al., (2023) Congo |
Randomized controlled double-blinded study |
probiotic (n = 200) Placebo (n = 200) |
6–24 months | 212 (53.0) | IG was given 1 cc of a blend of Lacticasebacillus rhamnosus and Limosilactobacillus reuteri DSM 17,938 (dosage, 2 billion colony-forming units; 50:50) daily | CG were given placebo | 4 weeks | Incidence of pneumonic | Not reported | |||||
|
Sazawal et al., (2010) India |
Randomized controlled double-blinded study |
Probiotic and Prebiotic (n = 312) Control (n = 312) |
12 to 48 months | NI |
Probiotic and prebiotic milk contained an additional 1/9 × 107 colony-forming units per day of probiotic B lactic HN019 and 2/4 g/day of prebiotic oligosaccharides milk |
CG were given placebo | 1-year | Change in Weight and height velocity, HB and HCT | Not reported | |||||
|
Famouri et al., (2014) Iran |
Randomized controlled triple-blinded study |
synbiotic (n = 42) control (n = 42) |
12 to 59 months | 40 (47.6) | Synbiotic sachets contain 100 mg fructooligosaccharides and 150 million spore Bacillus coagulans | CG were given placebo | 6 months | Change in weight, height, and head circumference | Not reported | |||||
|
Aflatoonian et al., (2019) Iran |
Randomized controlled triple-blinded study |
Synbiotic (n = 37) Placebo (n = 32) |
24 to 59 months | 21 (30.4) | Synbiotic supplementation (109colony-forming units) 1 g daily | CG were given placebo | 30-days | Change in weight, height, ,BMI and respiratory infection | Not reported | |||||
|
Kara et al., (2019) Turkey |
Randomized, prospective study |
Probiotic (n = 38) control (n = 33) |
6 to 59 months | 25 (35.2) | IG additionally received five drops (0.35 cc) (approximately 109 microorganisms) of L. rhamnosus solution once a day | CG received a calorie and protein-appropriate diet | 3 months | Incidence of respiratory infection and changes in BMI | Not reported | |||||
|
Fisberg et al., (2002) Brazil, Mexico, Portugal, and Spain |
Randomized controlled double-blinded study |
Synbiotic (n = 310) control (n = 316) |
12 to 60 months | 332 (53.03) | IG was expected to consume 375 to 750 ml/day of pediasure with synbiotic | CG were given consume pediasure without symbiotic | 4 months | Change in weight | Not reported | |||||
|
Saran et al., (2002) India |
Randomized controlled study |
Probiotic (n = 50) control (n = 50) |
24 to 59 months | NI | IG was given a measured amount (50 mL) of the supplement (1 _ 108 organisms/g curd) daily | CG were given an isocaloric supplement daily | 6 months | Change in weight, height | Not reported | |||||
|
He et al., (2005) China |
Randomized controlled study |
Probiotic al (n = 201) control (n = 201) |
217 (53.9) | IG was given Thermophilus streptococci, Bulgaria lactobacilli, and bifidum bacteria in yogurt with normal diet | CG were given just normal diet | 9 months | Change in weight and height and incidence of respiratory infection | Not reported | ||||||
|
Grenov et al., (2017) Uganda |
Randomized controlled study | Probiotic (n = 200) placebo (n = 200) | 230 (58) | IG were given 1 daily dose of a blend of Bifidobacterium animalis subsp lactis and Lactobacillus rhamnosus (10 billion colony-forming units, 50:50) | CG were given placebo | 8–12 weeks |
Change in weight and incidence of respiratory infection |
Not reported | ||||||
|
Kamil et al., (2020) Indonesia |
Randomized controlled study |
Probiotic (n = 15) placebo (n = 15) |
19 (63.3) | IG were given gummy L. plantarum Dad-13 (108 − 9 CFU/3 g) | CG were given placebo | 50 days | Change in weight and height | Not reported | ||||||
RUTF = ready-to-use therapeutic foods; HB = hemoglobin; HCT = hematocrit; NI = No infoamation; BMI= Body mass index
Risk of bias assessment
The main sources of bias were deviations from intended interventions and missing outcome data. Among the twelve studies that presented results, 2 were deemed to have a low risk of bias, while 10 showed some concerns (Figs. 1 and 2).
Meta-analysis
Weight
The use of the probiotic, prebiotic and synbiotic may increase weight of malnourished children compared to the control group (MD 0.33, 95% CI 0.15 to 0.50, 6 trials, 1453 children, I2 = 68%, low certainty of evidence).
The analysis of subgroups based on the type of intervention (probiotic, prebiotic, and symbiotic) did not reveal any significant differences between these subgroups (Subgroup differences: Chi² = 1.62, df = 2, p = 0.45, I² = 0%) (Fig. 4).
Fig. 4.
Forest plot of the effect of probiotic, prebiotic and synbiotic on increase of weight (kg)
The results of the meta-regression analysis base on random effects showed that the type of intervention (p = 0.636), total sample size (p = 0.130), duration of follow-up (p = 0.444), and control group (p = 0.507) were not significant moderators for weight (Table 2).
Table 2.
Meta-regression analysis for identification of risk factors for primary outcomes
| variables | Number of studies | Regression coefficient (standard error) | 95% CI | P-value | Q(model) |
|---|---|---|---|---|---|
| Weight | |||||
| Total sample size | 6 | -0.000 (0.000) | -0.001 to 0.000 | 0.130 | 2.29 |
| Duration of follow-up with the intervention | 6 | 0.021 (0.028) | -0.033 to 0.076 | 0.444 | 0.59 |
| Type of interventions (Reference: Prebiotic) | 6 | --- | --- | 0.636 | 0.90 |
| Probiotic | --- | 0.208 (0.299) | -0.377 to 0.794 | 0.486 | --- |
| Synbiotic | --- | -0.017 (0.303) | -0.612 to 0.577 | 0.954 | --- |
| Type of control group (Reference: Placebo) | 6 | --- | --- | 0.507 | 1.36 |
| Normal diet | 6 | 0.219 (0.188) | -0.149 to 0.588 | 0.244 | --- |
| An isocaloric supplement daily | 6 | -0.060(9.296) | -18.2825 to 18.160 | 0.994 | --- |
| Height | |||||
| Total sample size | 5 | -0.000 (0.000) | -0.002 to 0.001 | 0.524 | 0.40 |
| Duration of follow-up with the intervention | 5 | -0.013 (0.057) | -0.125 to 0.098 | 0.816 | 0.05 |
| Type of interventions (Reference: probiotic) | 5 | -0.428(0.423) | -1.258 to 0.401 | 0.311 | 1.02 |
| Type of control group (Reference: Placebo) | 5 | --- | --- | 0.000 | 27.43 |
| Normal diet | 5 | 0.011(0.124) | -0.233 to 0.256 | 0.09 | --- |
| An isocaloric supplement daily | 5 | 1.291(0.258) | 0.784 to 1.798 | 0.000 | --- |
| Lower respiratory tract infection | |||||
| Total sample size | 5 | 0.001 (0.002) | -0.002 to 0.004 | 0.576 | 0.31 |
| Duration of follow-up with the intervention | 5 | 0.0312 (0.067) | -0.100 to 0.136 | 0.642 | 0.22 |
| Type of interventions (Reference: probiotic) | 5 | -0.109 (0.629) | -1.344 to 1.124 | 0.861 | 0.861 |
| Type of control group (Reference: Placebo) | 5 | --- | --- | 0.592 | 1.05 |
| Normal diet | 5 | 0.097(0.429) | -0.743 | 0.938 | --- |
| Calorie and protein-appropriate diet | 5 | -1.531(1.556) | -4.581 | 1.518 | --- |
Q = fit of model without heterogeneity; CI = confidence interval
Height
The use of the probiotic, and synbiotic may increase height of malnourished children compared to the control group (MD 0.44, 95% CI 0.02 to 0.85, 5 trials, 1238 children, I2 = 86%, low certainty of evidence).
The analysis of subgroups based on the type of intervention (probiotic, and synbiotic) did not reveal any significant differences between these subgroups (Subgroup differences: Chi² = 0.64, df = 1, p = 0.43, I² = 0%) (Fig. 5).
Fig. 5.
Forest plot of the effect of probiotic and synbiotic on height increment (cm)
The results of the meta-regression analysis based on random effects showed that the type of intervention (p = 0.311), total sample size (p = 0.524), and duration of follow-up (p = 0.816) were not significant moderators for height. However, studies in which the control group received an isocaloric supplement, compared to placebo (reference group), showed greater height (p = 0.000) (Table 2).
Lower respiratory tract infection
The use of probiotics and synbiotics likely did not demonstrate a statistically significant difference in lower respiratory tract infections among malnourished children compared to the control group (RR 0.84, 95% CI 0.68 to 1.04, 4 trials, 942 children, I² = 0%, Moderate certainty of evidence).
The analysis of subgroups based on the type of intervention (probiotic, and synbiotic) did not reveal any significant differences between these subgroups (Subgroup differences: Chi² = 0.06, df = 1, p = 0.81, I² = 0%) (Fig. 6).
Fig. 6.
Forest plot of the effect of probiotic and synbiotic on lower respiratory tract infection
The results of the meta-regression analysis based on random effects showed that the type of intervention (p = 0.861), total sample size (p = 0.576), duration of follow-up (p = 0.642), and control group (p = 0.592) were not significant moderators for lower respiratory tract infection (Table 2).
Certainty of evidence
The level of evidence for two outcomes (increase of weight and height increment), was downgraded to Low due to risk of bias and high heterogeneity and for the outcome of lower respiratory tract infection, due to the bias of the studies, it was reduced by one grade and evaluated as Moderate (Table 3).
Table 3.
Certainty of the evidence using the GRADE approach by outcomes
| No of studies | Design | Risk of bias | Inconsistency | Indirectness | Imprecision | Publication bias | Experimental group | control group | Difference (95% CI) |
Final judgment |
|---|---|---|---|---|---|---|---|---|---|---|
| Increase of weight (kg) | ||||||||||
| 6 | RCT | Seriousa | Seriousb | No serious | No serious | Suspected | 726 | 727 | 0.33 (0.15 to 0.50) |
⊕⊕⊖⊖ Low |
| Height increment (cm) | ||||||||||
| 5 | RCT | Seriousa | Seriousb | No serious | No serious | Suspected | 619 | 619 | 0.44 (0.02 to 0.85) |
⊕⊕⊖⊖ Low |
| Lower respiratory tract infection | ||||||||||
| 5 | RCT | Seriousa | No serious | No serious | No serious | Suspected | 671 | 666 | 0.84 (0.68 to 1.04) |
⊕⊕⊕⊖ Moderate |
GRADE: Grading of Recommendations Assessment, Development and Evaluation; CI: confidence interval; RCT: randomized controlled trial
GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the effect estimate
Moderate certainty: We are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of the effect
a- Downgrade by one level for risk of bias
b- Downgrade by one level because of substantial heterogeneity > 50%
Descriptive synthesis for studies excluded from the meta-analysis
BMI
Only 2 studies were conducted to investigate this outcome. One study focused on the effect of probiotics on BMI, and one study examined the impact of synbiotics. The general result was that the intended intervention had a positive effect on BMI, leading to an increase.
Kara et al. [39] concluded that after probiotic supplementation, the increase in BMI in the intervention group was significantly greater than in the control group (P = 0.008). Aflatoonian et al. [33] found that in the group receiving synbiotics, BMI significantly increased compared to the control group (P = 0.045).
Head circumference
Only one study, conducted by Famouri et al., [43] examined this outcome. The result of this study indicated that the synbiotics had no significant effect on the head circumference of children (P > 0.05).
Hemoglobin (HG) and hematocrit (HCT)
Only two studies have investigated hemoglobin and hematocrit levels. The result of one study showed that the administration of prebiotics had a significant effect on hemoglobin and hematocrit levels. In the other study, with a larger sample size, the administration of synbiotics supplement had no significant effect.
Batool et al., [37] found that after 8 weeks of prebiotic supplementation and comparison with the control group, prebiotics could significantly increase hemoglobin (P < 0.001) and hematocrit (P < 0.001) levels in malnourished children. Sazawal et al., [35] found that the synbiotics had no significant effect on hemoglobin (P = 0.37) and hematocrit (P = 0.24) levels. The results of the included studies are included in the supplementary file (Table S2).
Discussion
The current study represents a detailed review of the effects of probiotic, prebiotic, and synbiotic supplements on anthropometric parameters in a total of 3,086 children up to 6 years old who are affected by malnutrition. Notably, design of all studies included in this review were RCT. This methodological approach enhances the robustness of the findings by employing a rigorous and controlled study design.
Overall results indicated that this intervention was effective in increasing weight and height in children compared to the control group. However, analyses showed that these interventions had little to no effect on lower respiratory tract infections. For the outcome of BMI, it was found that probiotics [39] and synbiotics [33] led to an increase in BMI. However, the administration of synbiotics had no significant effect on the average head circumference of children [34]. The effects of prebiotics and synbiotics on hemoglobin and hematocrit levels were also examined. It was found that prebiotics led to an increase [37], but synbiotics had no significant effect [35]. For respiratory infections, two studies reported a reduction in the risk of infection [19, 39] and three studies reported no effect [1, 33, 38].
In a study that reviewed and analyzed the effects of adding synbiotics to infant formula, it was found that this intervention did not result in a statistically significant increase in growth indicators among formula-fed infants. These indicators include weight gain, length gain, head circumference gain, as well as weight-for-age z-scores and length-for-age z-scores. It’s important to note that this study did not specifically investigate the effect of synbiotics on malnourished infants [26].
In a different systematic review that explored the effect of probiotics on child growth, a total of 2,757 healthy children were included, with 1,598 of them from developing countries. The findings from five studies, four of which involved undernourished children and one with well-nourished children in developing countries, suggested that probiotic supplementation has the potential to enhance child growth in these settings, particularly for undernourished children. Conversely, seven other studies conducted in developed countries did not show a significant effect on child growth [44].
In another clinical trial involving 795 malnourished children, the aim was to assess the effects of probiotics and prebiotics on severe acute malnutrition outcomes in areas with a high prevalence of HIV infection. The study revealed that the use of prebiotics did not lead to improvements in severe acute malnutrition outcomes. However, it did contribute to a reduction in mortality among these children. Notably, this study also included children with HIV infection [45].
A systematic review on the effects of nutraceuticals on weight loss in adults with overweight or obesity found that increased consumption of nutraceuticals generally had no significant impact or only trivial effects on weight reduction [46]. Another systematic study investigating the effects of berberine and barberry on body mass index (BMI), body weight (BW), waist circumference (WC), and waist-to-hip ratio (WHR) in adults showed that neither berberine nor barberry caused significant changes in BMI or BW, and berberine did not significantly affect WC. However, only berberine led to a significant reduction in WHR [47].
The role of gut microbiota in relation to malnutrition is supported by evidence from studies such as those by Blanton, Barratt, Charbonneau, Ahmed, and Gordon (2016) [48], Gehrig et al. (2019) [49], and Subramanian et al. (2014) [50]. However, findings from a meta-analysis of randomized controlled trials conducted by Dror et al. (2017) [51] indicate contrasting effects of probiotic supplements containing Lactobacillus in adults versus children. The meta-analysis showed that these supplements led to weight loss in adults but resulted in partial weight gain in children and infants.
Despite these insights, more randomized clinical trials are deemed necessary to comprehensively evaluate the effectiveness of probiotics, prebiotics, and synbiotics, particularly when categorized by the type of malnutrition and geographic region. Additionally, more research is needed to investigate the role of probiotic supplementation in weight loss among adults and weight gain in children. This emphasizes the importance of conducting further investigations to identify appropriate interventions tailored to different populations and conditions.
Strengths and limitations
This systematic review has various strengths and limitations. Among its strengths, the following points can be mentioned: Registration in the PROSPERO database was completed. This systematic review considered all the studies that investigated the potential benefits of probiotics, prebiotics, and synbiotics about their potential effects on health-related outcomes in malnourished children. Details such as duration of supplement administration, and sample size, were also taken into account. The dropout rates in the included studies were low, meaning that data collection was conducted comprehensively, which may result in more robust conclusions regarding the clinical effectiveness of the interventions. The use of meta-regression to find the factors affecting the results was another strength in this study. However, due to the limited number of studies included in the meta-analysis and meta-regression, the results should be interpreted with caution.
This research had some limitations, including diversity in the type of intervention, prescribed dose, duration of intervention, and time of measuring the desired outcome in the included studies. This limitation made it impossible to conduct a meta-analysis for a number of outcomes (BMI, Head circumference, HG/HCT). The potential risk of bias in the included studies could impact the results of our meta-analysis. Certain biases, such as selection bias, performance bias, and detection bias, may have influenced the outcomes. These limitations suggest that future studies with a lower risk of bias are needed to confirm the observed effects. Another limitation of this study is the exclusion of grey literature, which may have provided additional insights and perspectives, potentially reducing publication bias associated with relying solely on peer-reviewed studies. The choice between using a random or fixed effects model should be pre-specified rather than determined by the I² value. This approach addresses a limitation of our study, as relying solely on the I² statistic for model selection may lead to misleading conclusions.
Implication for research
It is advisable to conduct more clinical trials to thoroughly explore and address the impact of probiotics, prebiotics, and synbiotics at different dosage levels across various age groups. Various interventions with repeated follow-ups are recommended to evaluate the effect of these interventions on anthropometric parameters in malnourished children. Research on the long-term impact of these supplements on growth, development, and overall health outcomes in malnourished children is recommended.
Conclusion
Current evidence indicates that probiotic, prebiotic, and synbiotic supplementation may help manage health-related outcomes in malnourished children. However, despite the findings of this study, it cannot be conclusively stated that these supplements are ineffective in improving the anthropometric parameters of malnourished children. Further research with stronger study designs and consideration of additional factors is necessary to reach a definitive conclusion.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Acknowledgements
None.
Abbreviations
- BMI
Body mass index
- BW
Body weight
- CI
Confidence interval
- HCT
Hematocrit
- HG
Hemoglobin
- MeSH
Medical Subgect Headings
- NR
Not reported
- PRISMA
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
- PROSPERO
International Prospective Register of Systematic Reviews
- RCT
Randomized controlled trial
- RUTF
Ready-to-use therapeutic foods
- SD
Standard deviation
- SEM
Standard error of the mean
- WC
Waist circumference
- WHR
Waist-to-hip ratio
Author contributions
MP contributes to the conceptualization, methodology, data curation, and writing of the original draft. SMAC provides supervision and contributes to the review and editing of the written content. MMa is involved in conceptualization, methodology, data curation, and writing. MMi takes on tasks such as visualization, investigation, supervision, software implementation, validation, and contributes to the review and editing of the written content.
Funding
None.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
This section is not applicable.
Consent for publication
This section is not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Data Availability Statement
No datasets were generated or analysed during the current study.