Evidence base for the effectiveness of probiotics in children.
Probiotics are medicines and dietary supplements containing strains of representatives of normal microflora that have a beneficial effect on the body. Probiotic strains of bacteria can also be included in food [1, 2].
Probiotics: history and modernity.
For the first time L. Pasteur spoke about the functional role of bacteria in the process of digestion about 150 years ago. By studying the “diseases of wine”, he found that fermentation is the result of the activity of microorganisms and that the type of fermentation is associated with certain bacteria. This discovery allowed L. Pasteur to suggest that fermentation processes in the intestines of humans and animals are also caused by bacteria .
A serious study of the role of microflora in the human body began at the beginning of the last century at the Pasteur Institute and is associated with the name of the great Russian scientist I.I. Mechnikov, winner of the Nobel Prize for discoveries in the field of immunity. Mechnikov proposed the concept of the relationship between a person and his microflora and expressed the idea that it is possible to modify the intestinal microflora, replacing harmful microbes with useful ones.
He drew attention to the fact that, according to the results of the census in Europe, in Bulgaria, especially in rural areas, the number of centenarians turned out to be much higher than in other countries, and connected this with the peculiarities of the diet, namely with the use of a large amount of the traditional fermented milk product. – “Bulgarian yoghurt” (yoghurt) [1, 3]. In 1905, the Bulgarian doctor S. Grigorov isolated two bacteria that cause fermentation in “Bulgarian sour milk”: rod-shaped (Lactobacillus bulgaricus) and spherical (Streptococcus thermophilus). Based on these bacteria, I.I.
Mechnikov created the first probiotic – the famous “Mechnikovsky curdled milk” – and proposed its use for medicinal purposes .
In the same years, the French pediatrician A. Tissier, who also worked at the Pasteur Institute, discovered a pattern: in children with diarrhea, the number of Y-shaped bacteria (called bifidobacteria) in the stool was reduced, while in healthy children the level of these bacteria was high. It has been suggested that bifidobacteria play a role in protecting against intestinal infections, and it has been proposed to use them for therapeutic purposes in diarrhea [1, 2].
A great contribution to the study of human intestinal microflora was made by the German scientist A. Nissle. It was he who proposed the term “dysbiosis”. In 1917, A. Nissle isolated and began to use for medicinal purposes a non-pathogenic strain of Escherichia coli with antagonistic properties against pathogens of intestinal infections.
At that time, this was of particular relevance, since antibiotics had not yet been discovered .
In 1923, the French microbiologist A. Boulard, working in Indochina, drew attention to the fact that local residents with diarrhea successfully use the peel of a number of tropical fruits. After conducting research, he isolated the yeast of the genus sugar fungi (Saccharomyces boulardii) from the peel of the fruit. Subsequently, the lyophilisate of this yeast began to be used as an agent for the treatment of diarrhea..
Subsequently, scientific interest in human microflora and probiotics decreased for several decades due to the fact that many scientific theories regarding the microflora of the body did not find their practical confirmation, as well as due to the emergence of effective antibacterial agents for the treatment of intestinal infections. However, in the last decade, there has been a significant increase in scientific interest in probiotics . This is clearly evidenced by the analysis of publications in the Medline database (Fig.): If during the period from 1954 to 1997 less than 100 works related to probiotics were published, then only in 2009 their number was 10 times more, with a significant a proportion of randomized controlled trials (RCTs).
According to modern data, probiotics can be divided into four groups: lactobacilli, bifidobacteria, other lactic acid bacteria (enterococci, streptococci, etc.) and various non-fermented milk microorganisms (E. coli, bacilli, yeast, etc.) . Probiotics are able to have a multifactorial effect on the digestive system and the body as a whole through immunological and non-immunological mechanisms (table).
Currently, there is a serious evidence base on the effectiveness of probiotics in the treatment and prevention of infectious diseases of the gastrointestinal tract (GIT) and some allergic diseases in children. In addition, there are separate studies supporting the effectiveness of probiotics in other conditions: respiratory infections, inflammatory bowel diseases, and a number of others. However, the assessment of the effectiveness of probiotic drugs is seriously difficult due to their heterogeneity and the lack of uniform research protocols.
There are significant differences in the effectiveness of individual probiotics, questions about the optimal doses of probiotics, the advisability of using their combinations remain unresolved, which requires further clinical studies..
Probiotics in the treatment and prevention of gastrointestinal diseases in children.
To date, there is substantial evidence of the need to use probiotics in preterm infants for the prevention of necrotizing enterocolitis. A Cochrane systematic review, presented in early 2008, showed that the administration of enteral probiotics reduced the risk of severe necrotizing enterocolitis and mortality in premature infants. However, according to the review, more studies were required to determine the efficacy and safety of probiotics in very low birth weight infants (less than 1500 g) . And already at the end of 2008, the results of a multicenter randomized controlled trial of oral administration of a combined probiotic (B. bifidum and L. acidophilus) in very low birth weight infants for the prevention of necrotizing enterocolitis were presented. The study included 434 babies in 7 neonatal intensive care units in Taiwan.
The results of the study showed that in the group of children receiving the probiotic, enterocolitis was observed 3.5 times less often, and the lethality was 5 times less .
The scientific literature contains a large number of works devoted to the efficacy and safety of using various probiotics as a means for the treatment and prevention of acute intestinal infections. The results of the Cochrane systematic review suggest that in addition to rehydration, it is advisable to prescribe probiotics for infectious diarrhea in children and adults, since their use reduces the risk of diarrhea persistence by the third day of treatment and decreases the duration of diarrhea by 30.5 hours .
According to a meta-analysis of 18 studies, the use of various probiotics leads to a reduction in the duration of acute diarrhea in children under 5 years of age by about a day .
Another meta-analysis included only 9 studies on the use of probiotics of the genus Lactobacillus in children with acute infectious diarrhea. It was found that the use of such probiotics leads to a decrease in the duration of diarrhea by 0.7 days and reduces the number of bowel movements by 1.6 by the second day of treatment. The authors also emphasize the high safety of drugs based on probiotics of the genus Lactobacillus in children .
Thus, there is currently strong evidence of the feasibility of using probiotics as a means for the treatment of acute intestinal infections in children..
The data of the scientific literature of recent years indicate the benefits of including probiotics in the complex therapy of lesions of the digestive system associated with Helicobacter pylori (H. pylori). It has been established that certain species of Lactobacillus and Bifidobacterium have an in vitro bactericidal effect against H. pylori, producing bacteriocins or organic acids, and prevent H. pylori adhesion to epithelial cells. These protective effects of probiotics have been confirmed in experimental animal studies.
The results of clinical studies in children and adults have shown that probiotics, as a rule, do not usually eradicate H. pylori, but reduce the degree of colonization in the stomach and, when used in conjunction with antibiotic therapy, can enhance the eradication of H. pylori. Probiotics, possessing antioxidant and anti-inflammatory properties, can also stabilize the barrier function of the stomach and reduce the severity of inflammatory changes in the mucous membrane.
In the current concept, adopted by the second Maastricht Agreement in 2000, probiotics are considered as a potential treatment for H. pylori infection and associated gastric inflammation. In addition, probiotics are able to reduce the side effects of antibiotic therapy . A multicenter, randomized, double-blind study conducted several years ago in children with gastritis showed that the addition of a dairy product with L. casei to standard triple therapy significantly increased H. pylori eradication: by 27.1% for all patients included in the study (intention to treat – ITT-analysis), and by 30.3% for patients who completed the study according to the protocol (per-protocol – PP-analysis) .
Most scientific studies on the use of probiotics are devoted to their use for the prevention and treatment of antibiotic-associated diarrhea, since one of its causes is the suppression of normal intestinal microflora, which creates favorable conditions for the reproduction of pathogenic and opportunistic microorganisms, and also leads to metabolic disorders. The 2007 Cochrane systematic review focused on the use of probiotics for the prevention of antibiotic-associated diarrhea in children. The results of the review indicate that the use of probiotics is promising
for the prevention of antibiotic-associated diarrhea in children, but further research is needed, since it has not yet been established which probiotics are appropriate for use in children depending on age, and the optimal duration of therapy has not been determined.
The greatest evidence for the effectiveness of preventing antibiotic-associated diarrhea in children is currently available for L. rhamnosus GG, L. sporogens and S. boulardii. It was also found that probiotics are safe for the prevention of antibiotic-associated diarrhea in children .
Probiotics in the treatment and prevention of allergic diseases in children.
One of the possible reasons for the increase in the number of allergic diseases may be a violation of the intestinal microflora. The 2007 Cochrane systematic review focused on the use of probiotics for the prevention of allergic diseases and food hypersensitivity in young children. Based on the results of the analysis, the preventive effect of probiotics for atopic dermatitis was established. The largest number of evidence for efficacy was for Lactobacillus rhamnosus GG.
However, due to the significant heterogeneity of the analyzed studies, further study of this issue is required .
The presented meta-analysis of studies of the use of probiotics for the treatment and prevention of atopic dermatitis in children showed that out of nine randomized placebo-controlled studies with a comprehensive assessment of skin lesions using the SCORAD index, a reliable therapeutic effect of probiotics was established in seven studies. However, in two of them, the effect was observed only in children with IgE-associated atopic dermatitis, and in one, only in children with food allergies. Two of the three randomized, placebo-controlled trials have established a prophylactic effect of probiotics against atopic dermatitis in infants at high risk of atopy .
A meta-analysis of studies in children and adults presented in 2008 showed that probiotics significantly reduce the symptoms of allergic rhinitis and reduce the need for drug therapy. However, more qualitative research on this problem is required .
The effectiveness of various probiotic strains in the correction of dysbiotic disorders in children.
Probiotic strains with proven efficacy to date, primarily in young children, are Bifidobacterium lactis BB-12, Lactobacillus rhamnosus GG and Streptococcus thermophilus .
There is experimental evidence that Bifidobacterium lactis BB-12 has the ability to colonize the intestines of a child from the first days of life . It has also been shown that taking Bifidobacterium lactis ВB-12 significantly increases the level of IgA production in the intestine in young children . And in a double-blind, placebo-controlled, randomized study in premature infants, it was found that the administration of Bifidobacterium lactis BB-12 significantly increased the level of bifidoflora in feces, while reducing the level of bacteria of the intestinal family and clostridia .
In 2009, a laboratory comparative study of four probiotics was carried out: B. lactis ВB-12, Escherichia coli EMO, L. casei and S. boulardii. It has been shown that in vitro only B. lactis BB-12 and L. casei synthesize substances with antimicrobial properties and inhibit the growth of pathogenic bacteria. The hydrophobic properties of the cell wall are inherent in B. lactis BB-12 and E. coli EMO, which is a predictor of adhesive properties and a high ability to colonize the intestine. It was also found that Bifidobacterium lactis BB-12 stimulates the production of secretory IgA in laboratory animals (on a par with E. coli EMO, but to a lesser extent than S. boulardii) . The scientific literature presents the results of a randomized controlled study of oral the use of a combined probiotic (B. infantis, S. thermophilus and B. lactis BB-12) in very low birth weight infants in order to prevent necrotizing enterocolitis.
The results of the study showed that in the group of children receiving the probiotic, enterocolitis developed 4.1 times less frequently, while lethal cases were observed only in the control group .
Breastfeeding with breast milk is the “gold standard” of nutrition for a baby in the first year of life. Natural feeding has a number of fundamental advantages over artificial feeding. In particular, human milk oligosaccharides have a pronounced prebiotic effect – they stimulate the growth of bifidobacteria in the colon, which leads to inhibition of the development of pathogenic and opportunistic flora. Breast milk also contributes to the production of secretory IgA in the baby. These factors play an important role in the fact that babies receiving breast milk are less susceptible to intestinal and respiratory infections.
The most important benefit of breastfeeding is the reduced risk of developing allergies .
However, for various reasons, babies in the first year of life are often bottle-fed. As one of the methods, to a certain extent, reducing the disadvantages of artificial feeding, the addition of probiotics to the milk formula or the additional appointment of probiotics is considered. In the scientific literature, a number of works are presented that have shown the feasibility of using milk formulas for artificial feeding of children with the addition of Bifidobacterium lactis BB-12 (alone or in combination with other probiotics).
So, 15 years ago, in an evidence-based study, it was found that in newborns receiving milk formula with Bifidobacterium lactis BB-12, the number of bifidobacteria corresponds to their level in breastfed children, and is significantly higher than in children receiving standard mix .
In children during the first months of life, who received infant formula only with B. lactis ВB-12 or additionally with S. thermophilus, higher rates of physical development were noted . It has also been shown that long-term use of infant formula with B. lactis BB-12 and S. thermophilus in children during the first two years of life has a high safety profile, and in addition, significantly reduces the incidence of intestinal colic and the need for antibiotics .
In 1994, in a double-blind, placebo-controlled, randomized trial, one of the first evidence-based studies on probiotics, it was shown that the use of infant formula supplemented with B. lactis BB-12 and S. thermophilus in the diet of hospitalized children aged 5 to 24 months reduces the risk of diarrhea (from 31% to 7%) and the frequency of shedding rotavirus (from 39% to 10%) . Later, in a multicenter, double-blind, placebo-controlled, randomized study in formula-fed children under 8 months of age (from the age of less than 2 months), it was shown that the use of infant formula with B. lactis BB-12 significantly reduced the number of episodes of diarrhea and somewhat reduces its duration . Also, in a double-blind, placebo-controlled, randomized study, the effect of the prophylactic use of milk formulas with probiotics L. reuteri and B. lactis BB-12 in healthy children aged 4 to 10 months, who were, according to the parents’ decision, artificially fed and attending kindergarten, was examined. It was found that the frequency of episodes of diarrhea and their duration, as well as the frequency of episodes of fever for various reasons were significantly lower in the groups receiving probiotics compared with the placebo group.
The same authors in a subsequent study showed a high safety profile of milk formulas with these probiotics [29, 30].
In a double-blind, placebo-controlled, randomized study in formula-fed infants (from the age of less than 2 months), a significant positive effect of the appointment of a combined probiotic containing B. lactis BB-12 and L. rhamnosus GG on the incidence of respiratory infections was found. In the group of children who received milk formula with a probiotic, acute otitis media developed more than 2 times less often, antibiotics were required almost 3 times less often, and repeated respiratory infections were observed. Earlier, the same authors found that against the background of the use of this probiotic, the formation of the immune system in children is accelerated [31, 32].
There is evidence in the scientific literature that probiotics containing Bifidobacterium lactis BB-12 reduce the likelihood of developing antibiotic-associated diarrhea. According to a meta-analysis of 6 evidence-based studies, the use of probiotics prevents the development of antibiotic-associated diarrhea in 1 in 7 children. Probiotics based on L. rhamnosus GG, S. boulardii, as well as a combined probiotic containing B. lactis BB-12 and S. thermophilus have the greatest effect .
In a double-blind, placebo-controlled, randomized study, it was shown that the use of a mixture based on whey protein hydrolysates with the addition of B. lactis BB-12 or L. rhamnosus GG in children in the first months of life leads to a significantly more pronounced effect on the SCORAD index compared to the use of a mixture based on whey protein hydrolysates without probiotics . Another evidence-based study found that against the background of the use of Bifidobacterium lactis BB-12 in children of the first months of life, the manifestations of atopic dermatitis decrease . And in a recent double-blind, placebo-controlled, randomized study, it was shown that the use of a combined probiotic containing L. acidophilus and B. lactis BB-12 in children with hay fever leads to a slight decrease in the severity and duration of rhinitis symptoms, and also significantly reduces the number of eosinophils in the mucosa. nasal membrane .
Thus, today in the scientific literature there is the greatest amount of evidence on the effectiveness of probiotic strains B. lactis BB-12, S. thermophilus and L. rhamnosus GG in various diseases of the gastrointestinal tract, allergic diseases and a number of other conditions in children, especially young children..
In 2009, a new biologically active food supplement was registered on the domestic pharmaceutical market for the prevention and treatment of intestinal dysbiosis in children from the first days of life – Bifiform Baby (Ferrosan A / S (Denmark), certificate of state registration Bifiform Baby No. RU .77.99.11.003.E.000122.08.10 dated 02.08.2010). The composition of 1 dose includes: Bifidobacterium lactis BB-12 10 9 CFU, Streptococcus thermophilus TH-4 10 8 CFU. The daily dose is 0.5 g of the drug in the form of a suspension.
An important feature of this drug is that it is approved for use in children from birth and is available in liquid form in bottles with a dispensing pipette. It should be noted that today this is the only drug approved for use in children from such an early age, with a special release form.
The available scientific data allow us to recommend the probiotic Bifiform Baby for newborns and infants, including those with a burdened perinatal history, prematurity, as well as for children who are bottle-fed, for the prevention of the development of intestinal microbiocenosis disorders and their correction [37, 38].
In 2010, a medicine for children 3–12 years old was registered in Russia containing L. rhamnosus GG 10 9 CFU, B. lactis BB-12 10 9 CFU and B vitamins, called Bifiform Kids (Ferrosan A / C (Denmark), registration certificate No. LSR-009020/10 dated 31.08.2010). The drug is available in the form of chewable tablets with an orange-raspberry flavor, especially for children.
Taking into account the available scientific data on the effectiveness of probiotic strains included in the Bifiform Kids preparation, it is indicated for children over 3 years old for the treatment of acute intestinal infections of an established and unknown etiology, including viral diarrhea, for the prevention and treatment of dysbacteriosis of various etiologies, including those accompanied by suppression of the immune systems, as well as in the complex therapy of food allergies.