Introduction

Malnutrition in children is still a major public health issue across the world, particularly in developing countries. According to the 2011 WHO Report, 27% of children under 5 years old are underweight [1].

In Iran as a developing country, 15.7% of children are underweight and 18.9% are stunted [2]. Under nutrition is a major risk factor of mortality and morbidity among the children under 5 years [3]. Failure to thrive (FTT) patients may deal with recurrent gastrointestinal and respiratory tract infections, cognitive defects, developmental delay, and emotional and socioeconomic problems [4]. So, it can cause a heavy economic burden on the health system [5].

Adequate nutrition is important for optimal growth and development [6]. Insufficient caloric intake and nutrient absorption are the common causes of FTT [7]. Macronutrient and micronutrients deficiencies through different ways such as poor nutrition and infectious disorders are the major cause of under nutrition [3, 8]. So prevention and treatment of this problem may be of value. Therefore, finding an effective, safe, and available treatment for weight gain in children with malnutrition is important.

Nowadays, there is a trend in consumption of probiotics for weight gain because of their beneficial effects on micronutrient and macronutrient absorption [9]. It is shown that widespread ingestion of probiotics may promote weight gain by changing the intestinal flora [10].

The other beneficial effects of probiotics is on infectious diarrhea and dysentery [11, 12], antibiotic associated diarrhea [13], upper respiratory infections [14, 15], necrotizing enterocolitis in very low birth weight infants [16,17,18], irritable bowel syndrome (IBS) [19], childhood atopy [20], colic [21], anemia [22] and children growth pattern [23].

Probiotics are live microorganisms that when administered in sufficient amounts may cause a health benefit on the host [24]. They work by regulating the immune system, inhibiting the pathogen adherent to gut epithelium, and improving nutrient absorption [9].

Prebiotics are nondigestible substances that provide a beneficial physiological effect for the host by selectively stimulating the favorable growth or activity of a limited number of indigenous bacteria. Prebiotics increase the absorption of minerals and trace elements [25].

The combination of probiotics and prebiotics named synbiotics exerts a beneficial effect beyond their own effect [26].

Because of the beneficial effects of synbiotics on nutrient absorption and immune system, different studies have evaluated the effects of synbiotic supplementation on growth parameters that the results were conflicting, so this study was established to evaluate the growth of undernourished children consuming a synbiotics or placebo sachet with weight, height, and BMI as the primary outcomes. As secondary outcomes, the study evaluated infectious episodes and gastrointestinal (GI) problems as well as the appetite improvement.

Materials and Methods

This study was a triple-blind, placebo-controlled, randomized nutritional intervention study conducted in Khatamolanbia Clinic, Shahid Sadoughi University of Medical Sciences, Yazd, Iran, from 2016 to 2017. Eighty children of age 24 to 59 months with mild to moderate undernourishment who were normal on the other parts of physical were recruited. The severity of malnutrition was determined according to the Gomez classification that mild, moderate, and severe status has been equivalent to 75–90%, 60–74%, and less than 60% of standard weight, respectively [27]. From a total of 80 children with mild to moderate FTT, 11 were excluded that the patients according to the exclusion criteria (6), loss of follow-up (3), and poor compliance (2).

Exclusion criteria were antibiotic consumption 2 weeks prior the study, diarrhea at the time of study, any congenital abnormality or chromosomal disorder, ICU admission more than 3 days, birth weight under 2500 g, and gestational age under 37 weeks.

The study protocol was approved by the research and ethical committee of Shahid Sadoughi University of Medical Sciences. Written informed consent was obtained from the patients’ parents or guardians.

The patients were randomly divided in two groups: synbiotic and control, using a random table numbers. The patients in the two groups were matched by age, sex, and weight. The case group was given a synbiotic sachet (Kidilact) which contained 109 colony-forming unit (CFU) of 7 effective strains including Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus bulgaricus, Lactobacillus casei, Bifidobacterium infantis, Bifidobacterium breve, and Streptococcus thermophilus, as probiotics, and a prebiotic Fructooligosaccharides 1 g daily for 30 days. The children in the control group were given a placebo sachet daily which had a similar taste, smell, and appearance with synbiotic sachet and were supplied by the same company. The sachets were in the form of a powder reconstituted by parents with 5–10 ml of water and administered orally as a suspension. Products were manufactured according to current good manufacturing practices, and were packaged and coded at the Zist Takhmir Company. The pediatrician, parents, pharmacy, and statistical analyzer were not aware of the codes of synbiotic or placebo. The parents received the sachets at first visit by clinic pharmacy.

All patients were visited by a pediatrician at first. Physical examination and anthropometric measurements were recorded at first by the pediatrician as well as after 30 days of intervention by the same pediatrician. The children were weighed (measured with a Seca [Unicap, Australia] digital scale with an accuracy of 0.1 kg) and height measured (measured with a Somatometer [Stanley Mabo, Depose, France] with an accuracy of 0.1 cm) in light clothing without shoes using a digital standing scale by the same physician. Body mass index (BMI) was calculated as weight (kilograms) divided by height (meters) squared. In this study, we measured average of weight gain and other growth parameters in two groups of case and control to compare weight gain velocity (weight gain as gr/month), height increment velocity (height increment as cm/month), and BMI velocity (BMI difference as kg/m2/month) during the study.

Compliance of intake was assessed by pediatric assistant every week by telephone call. Furthermore, the parents were asked to return the empty boxes of sachets for assuring the compliance.

Moreover, numbers of upper respiratory disorders, gastrointestinal problems, antibiotic consumption, and appetite improvement and any adverse reaction to the medication were assessed weekly by telephone call.

Considering confidence level of 95% and a power of 80%, the sample size was estimated as minimum of 31 patients in each group. Results were reported as mean ± standard deviation (SD) for the quantitative variables. The groups were compared using the Student’s t test and the chi-square test (or Fisher’s exact test if required) for the categorical variables.

All the statistical analyses were performed using SPSS version 19.0 (SPSS Inc., Chicago, IL, USA). A P value < 0.05 was considered as statistically significant.

After finishing the statistical analysis, breaking the codes were done.

Results

Of 80 FTT children, 69 patients met the inclusion criteria and completed the study.

Forty one (59%) were females and 28 (41%) were males. Of these, 37 patients (24 girls, 13 boys) were in the synbiotic group and 32 patients (17 girls, 15 boys) were in the placebo group.

Age range was between 24 and 59 months with a median of 43 months old. Fifty six of 69 patients (81%) were mild under nutrition and 13 (19%) were moderate under nutrition.

The demographic characteristics of the 69 patients who completed the study are presented in Table 1. There was no significant difference in the weight, age, gender, and mode of delivery distribution among the two groups.

Table 1 Demographic data of children in the case and control group
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The mean initial children weight was 12.41 ± 1.59 kg (range 8.5–16 kg). While mean initial weight and follow-up weight, in the synbiotic group, were 12.05 ± 1.63 kg and 12.65 ± 1.66 kg, respectively. The mean weight of children in placebo group at the first and at the end of intervention was 12.53 ± 1.63 kg and 12.60 ± 1.51 kg respectively.

The average weight velocity after treatment was found to be significantly higher in the case group as compared to the control group (600 g vs. 74 g) (P 0.000) (Table 2). On further analysis, it was found that the effect of synbiotics on weight gain was not confined to a particular age group or malnutrition subgroups.

Table 2 Effect of synbiotic supplementation on anthropometric parameters among FTT children 2 to 5 years old after treatment
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BMI in the case group at the first and at the end of this study was 13.68 ± .94 and 14.12 ± 1.11 respectively and in the control group was 13.82 ± .74 and 13.89 ± .63 respectively. BMI changes in the case group were statistically significant than the control group (P 0.045).

The mean height in the case group before and after treatment was 94.89 ± 5.95 and 95.30 ± 5.02 cm and in the control group was 95.28 ± 6.40 and 95.65 ± 5.97 respectively. The mean height increment in the synbiotic and control group was not statistically different (0.41 vs. 0.37 cm, P 0.761).

No difference on infectious disease episodes was seen in the two groups after 30 days of synbiotic intervention, whereas infection episodes in synbiotic and placebo group were 7 (20%) and 8 (27.58%) respectively (P 0.845).

GI problems occurred in the synbiotic and placebo group in 3 (9.37%) and 5 (13.51%) children respectively (P 0.575).

No statistical significance was observed between the synbiotic and placebo groups in antibiotic consumption (4 vs. 6 respectively) (P 0.52) (Table 3).

Table 3 Effect of synbiotic supplementation on infection episodes and diarrhea among 2- to 5-year-old FTT children
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Sixteen patients (24.51%) reported appetite improvement, whereas 7 (20.91%) were in the synbiotic group and 9(28.12%) were in the control group. The differences among the two groups were not statistically significant (P 0.211) (Table 3).

Discussion

The present study evaluated the efficacy of 30-days administration of synbiotic supplementation on growth parameters in mild to moderate FTT children. We found that synbiotics can be beneficial in terms of weight and BMI gain, particularly in children who are under-nourished after 30 days of intervention, with a similar efficacy to other clinical studies. [15, 22, 28] However, synbiotic did not have a significant effect on frequency of infection and GI problems.

The product used in this study was Kidilact sachet which contained Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus bulgaricus, Lactobacillus casei, Bifidobacterium infantis, Bifidobacterium breve, and Streptococcus thermophilus, as probiotics, and Fructooligosaccharides as a prebiotic. The reasons we chose this product were that it was well tolerated in children and also because of probiotic Bifidobacterium and Lactobacillus major benefits. As in a study by Million et al. [29], they concluded that different Lactobacillus species are associated with different effects on weight that are host-specific. They showed that Lactobacillus acidophilus administration causes a significant weight gain in human and in animal, while Lactobacillus gasseri was associated with weight loss both in obese humans and in animals. Also in our study, the synbiotic sachet consisted of Lactobacillus acidophilus but not Lactobacillus gasseri.

The effect of synbiotic supplementation on weight, height, and BMI that are important anthropometric parameters for child growth was reported in different studies. In various studies, it is shown that probiotics may promote weight gain [15, 28], while in the other studies, weight loss [30, 31] was observed as a result of synbiotic consumption. On the other hand, some other studies failed to show efficacy of probiotics and synbiotics on weight [38,39,40.] The results of these studies were different based on obesity or malnutrition of the cases. Hence, in a study by Ipar [32], they concluded that synbiotic can help obese children to lose weight. Also, age of the participants has an important role in the effectiveness of probiotics, while in a study by Dror et al. [23], synbiotics caused weight loss in adults and weight gain in children. The different effects of synbiotics in the studies may be due to variation in the dose and strains of probiotics, duration of intervention, characteristics of participants, statistical analyses, and different geographic regions.

It is proven that the gut senses alterations in nutrient availability and subsequently modulates the nutrient absorption. [33, 34] Also, the different effect of probiotics on obese and undernourished children may be due to gut microbiota differences between overweight and lean children [35]. Furthermore, the different gut microbiota may influence caloric intake, intestinal absorption, and energy balance [34].

In this study, we reported the positive effect of synbiotic on weight and BMI which was in accordance with the studies conducted by He [15], Famouri [28], Kerac [36], and Saran [37] on undernourished children and contrary to the studies by Gil-Compos [38], Gibson [39], and Scalabrin [40] that reported no effect of synbiotic consumption on weight gain in well-nourished children [41, 42].

It seems that different gut microbiota composition in undernourished and well-nourished children and also living in developed or developing countries may play an important role on the effects that synbiotic may have [43, 44].

In developed countries, synbiotic supplementation had no effect on weight gain [38,39,40,41,42, 45]. However, it had a significant effect on weight promotion in children living in developing countries [15, 22, 28, 37, 46].

Moreover, the composition of gut microbiota may vary due patient’s age [47], while in the studies that the subjects were infants or individuals younger than 7 months old, the effect of synbiotics on weight gain has not been established [38,39,40,41,42, 45]. But in the studies conducted on children with 1–5 years of age, the synbiotics supplementation had a significant effect on weight improvement [15, 22, 28, 37, 46].

Our study was done in Iran as a developing country and was conducted on undernourished children aged 2–5 years, so the results of our study were in accordance with the other studies that were done on undernourished children in developing countries.

In our study, we did not find any effect of synbiotics on height, while in studies by He [15], Saran [37], and Silva [48], they found a significant difference in height of the children. In He et al. [15], the children in the probiotic group had a change in height-for-age z score at 9 months of supplementation, and in Saran et al., the children in the probiotic group grew more in length compared to the control group, after 6 months. In Silva et al.’s study, height increment was shown after 101 days of probiotics consumption. In our study we just used 30 days of synbiotic, so short duration of synbiotic may not conclude the effectiveness of synbiotic on height.

Although it is described that lactobacillus/Bifidobacterium improved protection against rotavirus diarrhea and infection in pediatrics [49], in this study we have not seen any effect of synbiotic on prevention of infection episodes and GI problems.

The limitation of our study was exclusion of sever malnourished children, since they need additional treatments. The other limitation of this study was that we did not assess dietary intake of participants along the study and were therefore unable to control for this variable.

Conclusion

In conclusion, this study provides evidence that short course of synbiotic supplementation may cause weight and BMI gain in mild to moderate undernourished children.

Further studies are needed to better understand the mechanisms of synbiotics’ effects. It is recommended to evaluate gut microbiota and also the levels of micronutrient and macronutrient in plasma before and after the treatment.