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The Microbiome and Probiotics in Childhood Michael Harrison Hsieh, MD, PhD1
Stanford University, Stanford, California Semin Reprod Med 2014;32:23–27
Abstract
Keywords
► probiotics ► children ► microbiome
Address for correspondence Michael Harrison Hsieh, MD, PhD, Department of Urology, Stanford University School of Medicine, Stanford University, 300 Pasteur Drive, S-287, Stanford, CA 9305 (e-mail: [email protected]).
Infants, from the moment of birth, are colonized by large numbers of microbes. This colonization continues throughout childhood and from preliminary studies seems to be a highly dynamic process, even during the usual physiologic state we refer to as health. In this context, the persistence of bacterial and fungal species in and on the human body likely confers various benefits to the host. One specific approach to modulate such beneficial effects is the administration of probiotics, also known as beneficial microbes. Herein, we outline the highest level evidence in regard to the evolution of the microbiome during childhood and its manipulation by probiotics for genitourinary, enteric, and allergic and atopic disorders. Thus, probiotic approaches are promising alternatives and adjuvants to traditional vaccines and antibiotics. This may usher in a new age in which vaccine and antibiotic side effects and antibiotic resistance are minimal issues in the setting of maintaining children’s health and prevention of disease.
The Human Microbiome Project and other microbial genomics initiatives have primarily focused on the adult human microbiome. If the microbial landscape we call the microbiome is relatively unmapped in adults, by comparison the microbiome of children is almost completely unknown. Moreover, it is highly likely that the microbiome of children is particularly dynamic, given that the rapid growth and physiological changes which occur throughout childhood may influence the pediatric microbiome. In general, children also rebound more quickly from many illnesses compared with adults, another biological feature which may modulate the microbiome during childhood. Considering that probiotics, “live microorganisms which when administered in adequate amounts confer a health benefit on the host,”1 may mediate most of their effects through perturbations of the microbiome, it is probable that outcomes of microbial therapy will be heavily predicated on the age and developmental status of a given child. Herein, we review in detail the known literature regarding interactions among the microbiome, probiotics, and children’s health, with a goal of highlighting the highest quality findings.
The Known Pediatric Microbiome Before the quality of evidence for therapeutic microbiology (e.g., probiotics) in children can be weighed, we must first
Issue Theme The Microbiome and Reproduction; Guest Editors, James H. Segars, MD, and Kjersti M. Aagaard, MD, PhD
outline what is known regarding the microbial communities in and on children’s bodies in the baseline state we refer to as health. It has been estimated that 100 trillion microbes live within each individual human being.2,3 The continuous interactions among our bodies and these microbes partially determine whether individuals stay healthy or develop diseases such as infections and immune-mediated disorders. For instance, commensal bacteria in the gut can facilitate metabolism of bile acids and bile acid proteins, vitamin absorption and production, inhibition of pathogen overgrowth, and fermentation of dietary carbohydrates.4 Moreover, pathogens may have unexpected roles in diverse diseases including autoimmune disorders,5 cancer,6 inflammatory bowel disease (IBD),7 and chronic pain states.8,9 However, before the human microbiota modulates health and disease, natural birth, as the infant passes through the birth canal, is typically the first encounter with environmental microbes. These microbes include the endogenous microbiota of the mother’s vagina (except in cases of cesarean delivery) and distal enteric tract,10 but are modulated by maternal administration of antibiotics, such as treatment for Group B streptococcus to prevent transmission to the infant. Indeed, birth by cesarean section and neonatal antibiotic utilization delay infant gut colonization.11 Hospitalization, diet, and mode of feeding likely also influence the infant microbiota.12 Palmer et al
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DOI http://dx.doi.org/ 10.1055/s-0033-1361819. ISSN 1526-8004.
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1 Department of Urology, Stanford University School of Medicine,
Microbiome and Probiotics in Childhood
Hsieh
reported that the composition and temporal patterns of enteric microbiota varied broadly among infants, with complex communities existing by 1 week of age and yet demonstrating stability for months at a time.11 Dizygotic twins featured parallel temporal patterns suggestive of environmental effects. At the end of the first year of life, each infant’s enteric microbiome achieves relative equilibrium and adult-like complexity. Interestingly, some have speculated that the composition of the intestinal microbiota is linked to brain development (reviewed by Douglas-Escobar et al13). This body of work, as well as other microbiome studies, has led to the concepts of eubiosis versus dysbiosis, normal versus abnormal microbiota, as key determinants of health and disease (reviewed by Buccigrossi et al14). The kinetics of bacterial colonization in the newborn gut are further complicated by passage of commensal bacteria (i.e., Bifidobacterium) from maternal blood to breast milk, and eventually the infant enteric tract.15 Bacterial components may translocate from mother to infant through maternal leukocytes, which in turn may train the developing infant immune system to appropriately respond to commensal and pathogenic bacteria. Certainly, more data are needed to explain the patterns of microbial colonization and their effects on the development of childhood immunity.
Probiotics for Pediatric Atopic/Allergic Disorders Probiotics may modulate host immune responses and thereby alleviate pediatric immune-mediated disorders. The immunomodulatory effects of commensal-derived probiotics have implications for the hygiene hypothesis. This hypothesis asserts that the increased incidence of chronic inflammatory diseases (e.g., asthma, allergic disorders, IBDs) is partly attributable to decreased early life exposure to commensal microbes and other organisms that have been tightly associated with humans throughout evolution.16 These organisms, including saprophytic mycobacteria and worms, may be viewed by the innate immune system as harmless commensals which induce immunoregulatory mechanisms. Indeed, contact with cows, straw, and consumption of unprocessed cow’s milk may provide protection against asthma (reviewed by Wlasiuk and Vercelli17). Many studies have been conducted to elucidate the role of probiotics in atopic diseases and allergies. These studies are too numerous to analyze individually herein, but one systematic review suggested that Lactobacillus rhamnosus GG may be effective in long-term prevention of development of atopic dermatitis.18 Another meta-analysis reported that probiotics reduced the incidence of atopic dermatitis regardless of whether use was during pregnancy, early life, or taken by either mother and/or child (relative risk [RR], 0.79; 95% confidence interval [CI], 0.71–0.88]).19 Interestingly, a third meta-analysis found that Lactobacillus-only probiotics given during pregnancy reduced risk of atopic eczema in children, but multistrain probiotics did not, even if they contained lactobacilli.20 Thus, several systematic reviews and metaanalyses suggest that probiotics, and perhaps lactobacilli in particular, may reduce risk of atopic dermatitis. Seminars in Reproductive Medicine
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Probiotics for Enteric Health and Disease The use of probiotics in infant formula is another unresolved application of probiotics. Braegger et al have declared that although probiotic-supplemented formula does not appear to adversely affect infant growth or result in apparent ill effects, they caution that there is still insufficient data to recommend the widespread use of probiotic-supplemented formula.21 Mugambi et al likewise agree that weight gain is unaltered by use of probiotic-supplemented formula, but that the number of stools per day increased significantly with the use of supplemented formula.22 In addition, probiotic-supplemented formula did not decrease the incidence of infant gastroesophageal reflux, crying, restlessness, vomiting, or diarrhea.23 In premature infants, supplementation with Bifidobacterium lactis had no effect on the risk of necrotizing enterocolitis stage or 2 (RR, 0.53; 95% CI, 0.16–1.83), risk of sepsis (RR, 0.6; 95% CI, 0.07–5.2), or need for antibiotics (RR, 0.67; 95% CI, 0.28–1.62). A lack of power of these studies, however, does not allow for a clear statement regarding effects on risk of necrotizing enterocolitis. Interestingly, B. lactis supplementation did have some effects on anthropometric measures. No adverse events associated with B. lactis supplementation were observed.24 In a broader meta-analysis encompassing numerous probiotic supplements, formula supplementation was associated with a decreased risk of necrotizing enterocolitis in preterm very low-birth-weight infants (RR, 0.33; 95% CI, 0.24–0.46). Risk of death was also reduced in the probiotic supplementation group (RR, 0.56; 95% CI, 0.43–0.73). However, there was no difference in the risk of sepsis between the probiotic and placebo groups (RR, 0.90; 95% CI, 0.71–1.15).25 Very similar findings were reported by a Cochrane Review by Alfaleh et al,26 and Downard et al27 in another Cochrane Review likewise advocated the use of prophylactic probiotics in preterm infants (< 2,500 g) to reduce the incidence of necrotizing enterocolitis. Thus, probiotic supplementation of formula in general may be useful for prevention of necrotizing enterocolitis and reducing risk of death in premature infants. Probiotics have also been tested in the setting of other enteric diseases, namely, Helicobacter pylori infection. One trial of children infected with H. pylori demonstrated that L. casei DN-114 001 supplementation of triple therapy (omeprazole, amoxicillin, and clarithromycin) yielded greater H. pylori clearance rates.28 One meta-analysis showed that Saccharomyces boulardii supplementation of triple therapy enhanced the eradication rate (RR, 11.13; 95% CI, 1.05–1.21) and reduced the risk of therapy-related adverse effects (RR, 0.46; 95% CI, 0.3–0.7), especially diarrhea (RR, 0.47; 95% CI, 0.32–0.69).29 Thus, both Lactobacillus and S. boulardii supplementation of triple therapy may augment its anti-H. pylori effects. Another gastrointestinal disease that has been treated with probiotics is antibiotic-associated diarrhea. Johnston et al concluded, in a Cochrane Review, that despite heterogeneous probiotic strains, doses, duration, and study quality, there may be a protective effect of probiotics against the
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development of antibiotic-associated diarrhea, but that the quality of the positive evidence was poor.30 A specific form of antibiotic-associated diarrhea with relevance to probiotics and children is C. difficile-associated infections. A systematic review and meta-analysis of the literature demonstrated that probiotics reduced the incidence of C. difficile-associated diarrhea by 66% (pooled RR, 0.34 [95% CI, 0.24–0.49]). Among probiotic-treated patients, 9.3% experienced adverse events, compared with 12.6% of control patients (RR, 0.82 [95% CI, 0.65–1.05]).31 However, in a subsequent systematic review and meta-analysis of the effects of probiotics on the risk of C. difficile-associated, antibiotic-induced diarrhea in adults and children, there was no difference in incidence rates of infection among the probiotics, placebo, or no treatment control groups (RR, 0.89; 95% CI, 0.64–1.24). A pooled analysis of adverse events indicated that probiotics reduce the risk of adverse events by 20% (RR, 0.80; 95% CI, 0.68–0.95).32 Thus, the “jury is still out” for the efficacy of probiotics in C. difficile-associated, antibiotic-induced diarrhea in children. In other forms of diarrhea, namely infectious, S. boulardii has been specifically noted as being effective.33 For example, S. boulardii reduced the duration of diarrhea by 1 day and hospitalization by 20 hours. Lactobacillus rhamnosus GG also seems to reduce rates of diarrhea (RR, 0.37; 95% CI, 0.23–0.59) and symptomatic rotavirus gastroenteritis (RR, 0.49; 95% CI, 0.28–0.86). However, there was no significant difference between the probiotic and placebo groups in duration of hospitalization or diarrhea. Lactobacillus rhamnosus GG was not associated with harm in any of the trials.34 Ostensibly noninfectious pediatric gastrointestinal disorders, specifically abdominal pain, have also been explored as therapeutic targets of probiotics. One meta-analysis noted that L. rhamnosus GG supplementation was correlated with a significantly higher rate of treatment responses (e.g., decrease in pain intensity or no pain) in the overall population with abdominal pain-related functional enteric disorders (RR, 1.31; 95% CI, 1.08–1.59 and 4–22) and in the irritable bowel syndrome subgroup (RR, 1.70; 95% CI, 1.27–2.27 and 3–8).35 Thus, Lactobacillus-based probiotics may have a beneficial role in these enteric diseases. In contrast, the utility of probiotics in pediatric IBD (i.e., Crohn disease or ulcerative colitis) is unclear at best. A metaanalysis indicated that IBD patients receiving lactobacilli featured essentially equivalent rates of clinical or endoscopic relapse, even among children.36 This was true whether patients received L. rhamnosus strain GG or Lactobacillus johnsonii.36
The Microbiome and Pediatric Obesity: A Potential Role for Probiotics The enteric microbiota may modulate the host not only locally within the gut; commensal microbes may also confer systemic effects and profoundly influence host metabolism. For example, one article suggested that the sizes of gut populations of Bacteroides and Firmicutes bacteria (including their ratios) may be associated with pediatric obesity.37 In another
Hsieh
publication, the relative size of Enterobacteriaceae, Desulfovibrio, and Akkermansia muciniphila-like bacteria was also related to risk of obesity in children.38 These differences in the gut microbiome of lean and obese children suggest that probiotic manipulation could influence metabolism. However, Kaplan and Walker have correctly pointed out that establishing causality between the composition of enteric microbial communities and obesity is difficult.39 Conversely, the microbiome may be important in states of chronic starvation in children such as kwashiorkor. Smith et al studied Malawian twin pairs discordant for nutritional state (i.e., one twin remain nourished, whereas the other malnourished).40 Both children in discordant twin pairs were given a peanut-based, ready-to-use therapeutic food (RUTF). Metagenomic studies showed that RUTF induced a transient maturation of metabolic functions in kwashiorkor-associated enteric microbiomes that regressed upon cessation of RUTF. Moreover, transplantation of feces from kwashiorkor patients on a Malawian diet into gnotobiotic mice resulted in weight loss and perturbations in metabolism that were only transiently rescued by RUTF. Thus, the gut microbiome may be a key causal parameter in pediatric starvation states such as kwashiorkor.40
Probiotics for Urogenital Health and Disease In the 1970s, workers ascertained that most uropathogens in girls originate in the gut, traverse the perineum to the vagina, and then infect the bladder. Some investigators have examined the microbiology of indigenous lactobacilli found in high numbers in the vaginas of women with no history of urinary tract infections (UTI), and how the absence of these commensal microbes may be associated with susceptibility to recurrent UTI.41 As a consequence of this observation, other workers have postulated that it may be possible to favorably manipulate the vaginal microbiome through orally administered probiotics. In one clinical trial, 585 premature infants (< 33 weeks or < 1,500 g) were fed milk supplemented with 6 109 colony-forming unit (CFU) of L. rhamnosus GG or placebo milk once per day from the initial feed until discharge (mean 48 days).42 The frequency of UTI episodes was diminished (3.4 vs. 5.8%), but the difference was not statistically significant. A randomized clinical trial compared oral L. acidophilus ATCC 4356 to trimethoprim/sulfamethoxazole as prophylaxis for UTI in 120 children with vesicoureteral reflux.43 The two treatment arms did not differ significantly with regard to UTI prevention with incidences of 18.3% in the probiotic arm and 21.6% in the antibiotic arm. However, these results indicate that probiotics could be used as alternatives to antibiotics with a possible reduction of complications due to antibiotics. A more complex question beyond the scope of this review is whether and in what settings antibiotic prophylaxis is efficacious for children with reflux. Regardless, more studies are needed to confirm these findings. In summary, there is little data on probiotic applications to prevent pediatric UTI. An intriguing but unexplored Seminars in Reproductive Medicine
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Microbiome and Probiotics in Childhood
Microbiome and Probiotics in Childhood
Hsieh
possibility is combining antibiotics with probiotics. If combinations of antibiotics and probiotics are efficacious, these agents may help prevent or cure UTI with less antibiotic resistance and fewer antibiotic-associated side effects.
Probiotics-Induced Sepsis Although probiotics seem to be promising approaches for prevention or treatment of a variety of pediatric diseases and are mostly well-tolerated, several reports of probioticsassociated bacteremia and sepsis in children have been published.44,45 Some of these studies included infants who are susceptible to infections due to immature immune systems and underdeveloped mucosal barriers. Caution with regard to selection of probiotics strains (such as focusing on commensalderived probiotics), and clinical study design, particularly in infants, is warranted. Given the large numbers of commercially available probiotic products that are poorly or mislabeled,46–56 we advise that patients and their health care providers only consider products which document not only specific bacterial species but full strain names, CFU, nonprobiotic ingredients, manufacturing standards, and high quality, peer-reviewed scientific studies of the probiotic strains in question.
1 Guidelines for the Evaluation of Probiotics in Food. Geneva,
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Summary Advances in the science of probiotics for children in the 21st century will be accelerated by pediatric microbiome research and functional genomics of beneficial microbes in children. These commensal microbes or “Old Friends” mediate development of robust immune responses, digestion, absorption of vitamins, and suppression of pathogens. Two major pipelines will fuel the development of new probiotics in pediatric medicine. First, the delineation of genes responsible for crucial probiotic functions will facilitate derivation of genetically modified organisms, also known as “designer strains,” that will represent optimized, engineered alternatives to natural probiotic strains for specific pediatric applications. Second, candidate probiotic strains isolated from natural sources (human, animal, or food) can be compared systematically by functional genomics and systems biology. The best natural probiotics can then be selected for specific pediatric uses. Many more clinical and laboratory investigations must be performed to elucidate mechanisms of probiosis and matching of specific probiotics with particular disease phenotypes in children. In summary, humans have used beneficial bacteria via the diet throughout human history. Investigator-initiated research and “big science,” as exemplified by the Human Microbiome Project, will drive accelerated development of probiotics for the prevention and treatment of many pediatric disorders.
Acknowledgment M.H.H. has research support from the National Institutes of Health (NIH) (NIDDK K08 DK087895).
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Microbiome and Probiotics in Childhood
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The Microbiome and Probiotics in Childhood Michael Harrison Hsieh, MD, PhD1
Stanford University, Stanford, California Semin Reprod Med 2014;32:23–27
Abstract
Keywords
► probiotics ► children ► microbiome
Address for correspondence Michael Harrison Hsieh, MD, PhD, Department of Urology, Stanford University School of Medicine, Stanford University, 300 Pasteur Drive, S-287, Stanford, CA 9305 (e-mail: [email protected]).
Infants, from the moment of birth, are colonized by large numbers of microbes. This colonization continues throughout childhood and from preliminary studies seems to be a highly dynamic process, even during the usual physiologic state we refer to as health. In this context, the persistence of bacterial and fungal species in and on the human body likely confers various benefits to the host. One specific approach to modulate such beneficial effects is the administration of probiotics, also known as beneficial microbes. Herein, we outline the highest level evidence in regard to the evolution of the microbiome during childhood and its manipulation by probiotics for genitourinary, enteric, and allergic and atopic disorders. Thus, probiotic approaches are promising alternatives and adjuvants to traditional vaccines and antibiotics. This may usher in a new age in which vaccine and antibiotic side effects and antibiotic resistance are minimal issues in the setting of maintaining children’s health and prevention of disease.
The Human Microbiome Project and other microbial genomics initiatives have primarily focused on the adult human microbiome. If the microbial landscape we call the microbiome is relatively unmapped in adults, by comparison the microbiome of children is almost completely unknown. Moreover, it is highly likely that the microbiome of children is particularly dynamic, given that the rapid growth and physiological changes which occur throughout childhood may influence the pediatric microbiome. In general, children also rebound more quickly from many illnesses compared with adults, another biological feature which may modulate the microbiome during childhood. Considering that probiotics, “live microorganisms which when administered in adequate amounts confer a health benefit on the host,”1 may mediate most of their effects through perturbations of the microbiome, it is probable that outcomes of microbial therapy will be heavily predicated on the age and developmental status of a given child. Herein, we review in detail the known literature regarding interactions among the microbiome, probiotics, and children’s health, with a goal of highlighting the highest quality findings.
The Known Pediatric Microbiome Before the quality of evidence for therapeutic microbiology (e.g., probiotics) in children can be weighed, we must first
Issue Theme The Microbiome and Reproduction; Guest Editors, James H. Segars, MD, and Kjersti M. Aagaard, MD, PhD
outline what is known regarding the microbial communities in and on children’s bodies in the baseline state we refer to as health. It has been estimated that 100 trillion microbes live within each individual human being.2,3 The continuous interactions among our bodies and these microbes partially determine whether individuals stay healthy or develop diseases such as infections and immune-mediated disorders. For instance, commensal bacteria in the gut can facilitate metabolism of bile acids and bile acid proteins, vitamin absorption and production, inhibition of pathogen overgrowth, and fermentation of dietary carbohydrates.4 Moreover, pathogens may have unexpected roles in diverse diseases including autoimmune disorders,5 cancer,6 inflammatory bowel disease (IBD),7 and chronic pain states.8,9 However, before the human microbiota modulates health and disease, natural birth, as the infant passes through the birth canal, is typically the first encounter with environmental microbes. These microbes include the endogenous microbiota of the mother’s vagina (except in cases of cesarean delivery) and distal enteric tract,10 but are modulated by maternal administration of antibiotics, such as treatment for Group B streptococcus to prevent transmission to the infant. Indeed, birth by cesarean section and neonatal antibiotic utilization delay infant gut colonization.11 Hospitalization, diet, and mode of feeding likely also influence the infant microbiota.12 Palmer et al
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DOI http://dx.doi.org/ 10.1055/s-0033-1361819. ISSN 1526-8004.
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1 Department of Urology, Stanford University School of Medicine,
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reported that the composition and temporal patterns of enteric microbiota varied broadly among infants, with complex communities existing by 1 week of age and yet demonstrating stability for months at a time.11 Dizygotic twins featured parallel temporal patterns suggestive of environmental effects. At the end of the first year of life, each infant’s enteric microbiome achieves relative equilibrium and adult-like complexity. Interestingly, some have speculated that the composition of the intestinal microbiota is linked to brain development (reviewed by Douglas-Escobar et al13). This body of work, as well as other microbiome studies, has led to the concepts of eubiosis versus dysbiosis, normal versus abnormal microbiota, as key determinants of health and disease (reviewed by Buccigrossi et al14). The kinetics of bacterial colonization in the newborn gut are further complicated by passage of commensal bacteria (i.e., Bifidobacterium) from maternal blood to breast milk, and eventually the infant enteric tract.15 Bacterial components may translocate from mother to infant through maternal leukocytes, which in turn may train the developing infant immune system to appropriately respond to commensal and pathogenic bacteria. Certainly, more data are needed to explain the patterns of microbial colonization and their effects on the development of childhood immunity.
Probiotics for Pediatric Atopic/Allergic Disorders Probiotics may modulate host immune responses and thereby alleviate pediatric immune-mediated disorders. The immunomodulatory effects of commensal-derived probiotics have implications for the hygiene hypothesis. This hypothesis asserts that the increased incidence of chronic inflammatory diseases (e.g., asthma, allergic disorders, IBDs) is partly attributable to decreased early life exposure to commensal microbes and other organisms that have been tightly associated with humans throughout evolution.16 These organisms, including saprophytic mycobacteria and worms, may be viewed by the innate immune system as harmless commensals which induce immunoregulatory mechanisms. Indeed, contact with cows, straw, and consumption of unprocessed cow’s milk may provide protection against asthma (reviewed by Wlasiuk and Vercelli17). Many studies have been conducted to elucidate the role of probiotics in atopic diseases and allergies. These studies are too numerous to analyze individually herein, but one systematic review suggested that Lactobacillus rhamnosus GG may be effective in long-term prevention of development of atopic dermatitis.18 Another meta-analysis reported that probiotics reduced the incidence of atopic dermatitis regardless of whether use was during pregnancy, early life, or taken by either mother and/or child (relative risk [RR], 0.79; 95% confidence interval [CI], 0.71–0.88]).19 Interestingly, a third meta-analysis found that Lactobacillus-only probiotics given during pregnancy reduced risk of atopic eczema in children, but multistrain probiotics did not, even if they contained lactobacilli.20 Thus, several systematic reviews and metaanalyses suggest that probiotics, and perhaps lactobacilli in particular, may reduce risk of atopic dermatitis. Seminars in Reproductive Medicine
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Probiotics for Enteric Health and Disease The use of probiotics in infant formula is another unresolved application of probiotics. Braegger et al have declared that although probiotic-supplemented formula does not appear to adversely affect infant growth or result in apparent ill effects, they caution that there is still insufficient data to recommend the widespread use of probiotic-supplemented formula.21 Mugambi et al likewise agree that weight gain is unaltered by use of probiotic-supplemented formula, but that the number of stools per day increased significantly with the use of supplemented formula.22 In addition, probiotic-supplemented formula did not decrease the incidence of infant gastroesophageal reflux, crying, restlessness, vomiting, or diarrhea.23 In premature infants, supplementation with Bifidobacterium lactis had no effect on the risk of necrotizing enterocolitis stage or 2 (RR, 0.53; 95% CI, 0.16–1.83), risk of sepsis (RR, 0.6; 95% CI, 0.07–5.2), or need for antibiotics (RR, 0.67; 95% CI, 0.28–1.62). A lack of power of these studies, however, does not allow for a clear statement regarding effects on risk of necrotizing enterocolitis. Interestingly, B. lactis supplementation did have some effects on anthropometric measures. No adverse events associated with B. lactis supplementation were observed.24 In a broader meta-analysis encompassing numerous probiotic supplements, formula supplementation was associated with a decreased risk of necrotizing enterocolitis in preterm very low-birth-weight infants (RR, 0.33; 95% CI, 0.24–0.46). Risk of death was also reduced in the probiotic supplementation group (RR, 0.56; 95% CI, 0.43–0.73). However, there was no difference in the risk of sepsis between the probiotic and placebo groups (RR, 0.90; 95% CI, 0.71–1.15).25 Very similar findings were reported by a Cochrane Review by Alfaleh et al,26 and Downard et al27 in another Cochrane Review likewise advocated the use of prophylactic probiotics in preterm infants (< 2,500 g) to reduce the incidence of necrotizing enterocolitis. Thus, probiotic supplementation of formula in general may be useful for prevention of necrotizing enterocolitis and reducing risk of death in premature infants. Probiotics have also been tested in the setting of other enteric diseases, namely, Helicobacter pylori infection. One trial of children infected with H. pylori demonstrated that L. casei DN-114 001 supplementation of triple therapy (omeprazole, amoxicillin, and clarithromycin) yielded greater H. pylori clearance rates.28 One meta-analysis showed that Saccharomyces boulardii supplementation of triple therapy enhanced the eradication rate (RR, 11.13; 95% CI, 1.05–1.21) and reduced the risk of therapy-related adverse effects (RR, 0.46; 95% CI, 0.3–0.7), especially diarrhea (RR, 0.47; 95% CI, 0.32–0.69).29 Thus, both Lactobacillus and S. boulardii supplementation of triple therapy may augment its anti-H. pylori effects. Another gastrointestinal disease that has been treated with probiotics is antibiotic-associated diarrhea. Johnston et al concluded, in a Cochrane Review, that despite heterogeneous probiotic strains, doses, duration, and study quality, there may be a protective effect of probiotics against the
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development of antibiotic-associated diarrhea, but that the quality of the positive evidence was poor.30 A specific form of antibiotic-associated diarrhea with relevance to probiotics and children is C. difficile-associated infections. A systematic review and meta-analysis of the literature demonstrated that probiotics reduced the incidence of C. difficile-associated diarrhea by 66% (pooled RR, 0.34 [95% CI, 0.24–0.49]). Among probiotic-treated patients, 9.3% experienced adverse events, compared with 12.6% of control patients (RR, 0.82 [95% CI, 0.65–1.05]).31 However, in a subsequent systematic review and meta-analysis of the effects of probiotics on the risk of C. difficile-associated, antibiotic-induced diarrhea in adults and children, there was no difference in incidence rates of infection among the probiotics, placebo, or no treatment control groups (RR, 0.89; 95% CI, 0.64–1.24). A pooled analysis of adverse events indicated that probiotics reduce the risk of adverse events by 20% (RR, 0.80; 95% CI, 0.68–0.95).32 Thus, the “jury is still out” for the efficacy of probiotics in C. difficile-associated, antibiotic-induced diarrhea in children. In other forms of diarrhea, namely infectious, S. boulardii has been specifically noted as being effective.33 For example, S. boulardii reduced the duration of diarrhea by 1 day and hospitalization by 20 hours. Lactobacillus rhamnosus GG also seems to reduce rates of diarrhea (RR, 0.37; 95% CI, 0.23–0.59) and symptomatic rotavirus gastroenteritis (RR, 0.49; 95% CI, 0.28–0.86). However, there was no significant difference between the probiotic and placebo groups in duration of hospitalization or diarrhea. Lactobacillus rhamnosus GG was not associated with harm in any of the trials.34 Ostensibly noninfectious pediatric gastrointestinal disorders, specifically abdominal pain, have also been explored as therapeutic targets of probiotics. One meta-analysis noted that L. rhamnosus GG supplementation was correlated with a significantly higher rate of treatment responses (e.g., decrease in pain intensity or no pain) in the overall population with abdominal pain-related functional enteric disorders (RR, 1.31; 95% CI, 1.08–1.59 and 4–22) and in the irritable bowel syndrome subgroup (RR, 1.70; 95% CI, 1.27–2.27 and 3–8).35 Thus, Lactobacillus-based probiotics may have a beneficial role in these enteric diseases. In contrast, the utility of probiotics in pediatric IBD (i.e., Crohn disease or ulcerative colitis) is unclear at best. A metaanalysis indicated that IBD patients receiving lactobacilli featured essentially equivalent rates of clinical or endoscopic relapse, even among children.36 This was true whether patients received L. rhamnosus strain GG or Lactobacillus johnsonii.36
The Microbiome and Pediatric Obesity: A Potential Role for Probiotics The enteric microbiota may modulate the host not only locally within the gut; commensal microbes may also confer systemic effects and profoundly influence host metabolism. For example, one article suggested that the sizes of gut populations of Bacteroides and Firmicutes bacteria (including their ratios) may be associated with pediatric obesity.37 In another
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publication, the relative size of Enterobacteriaceae, Desulfovibrio, and Akkermansia muciniphila-like bacteria was also related to risk of obesity in children.38 These differences in the gut microbiome of lean and obese children suggest that probiotic manipulation could influence metabolism. However, Kaplan and Walker have correctly pointed out that establishing causality between the composition of enteric microbial communities and obesity is difficult.39 Conversely, the microbiome may be important in states of chronic starvation in children such as kwashiorkor. Smith et al studied Malawian twin pairs discordant for nutritional state (i.e., one twin remain nourished, whereas the other malnourished).40 Both children in discordant twin pairs were given a peanut-based, ready-to-use therapeutic food (RUTF). Metagenomic studies showed that RUTF induced a transient maturation of metabolic functions in kwashiorkor-associated enteric microbiomes that regressed upon cessation of RUTF. Moreover, transplantation of feces from kwashiorkor patients on a Malawian diet into gnotobiotic mice resulted in weight loss and perturbations in metabolism that were only transiently rescued by RUTF. Thus, the gut microbiome may be a key causal parameter in pediatric starvation states such as kwashiorkor.40
Probiotics for Urogenital Health and Disease In the 1970s, workers ascertained that most uropathogens in girls originate in the gut, traverse the perineum to the vagina, and then infect the bladder. Some investigators have examined the microbiology of indigenous lactobacilli found in high numbers in the vaginas of women with no history of urinary tract infections (UTI), and how the absence of these commensal microbes may be associated with susceptibility to recurrent UTI.41 As a consequence of this observation, other workers have postulated that it may be possible to favorably manipulate the vaginal microbiome through orally administered probiotics. In one clinical trial, 585 premature infants (< 33 weeks or < 1,500 g) were fed milk supplemented with 6 109 colony-forming unit (CFU) of L. rhamnosus GG or placebo milk once per day from the initial feed until discharge (mean 48 days).42 The frequency of UTI episodes was diminished (3.4 vs. 5.8%), but the difference was not statistically significant. A randomized clinical trial compared oral L. acidophilus ATCC 4356 to trimethoprim/sulfamethoxazole as prophylaxis for UTI in 120 children with vesicoureteral reflux.43 The two treatment arms did not differ significantly with regard to UTI prevention with incidences of 18.3% in the probiotic arm and 21.6% in the antibiotic arm. However, these results indicate that probiotics could be used as alternatives to antibiotics with a possible reduction of complications due to antibiotics. A more complex question beyond the scope of this review is whether and in what settings antibiotic prophylaxis is efficacious for children with reflux. Regardless, more studies are needed to confirm these findings. In summary, there is little data on probiotic applications to prevent pediatric UTI. An intriguing but unexplored Seminars in Reproductive Medicine
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possibility is combining antibiotics with probiotics. If combinations of antibiotics and probiotics are efficacious, these agents may help prevent or cure UTI with less antibiotic resistance and fewer antibiotic-associated side effects.
Probiotics-Induced Sepsis Although probiotics seem to be promising approaches for prevention or treatment of a variety of pediatric diseases and are mostly well-tolerated, several reports of probioticsassociated bacteremia and sepsis in children have been published.44,45 Some of these studies included infants who are susceptible to infections due to immature immune systems and underdeveloped mucosal barriers. Caution with regard to selection of probiotics strains (such as focusing on commensalderived probiotics), and clinical study design, particularly in infants, is warranted. Given the large numbers of commercially available probiotic products that are poorly or mislabeled,46–56 we advise that patients and their health care providers only consider products which document not only specific bacterial species but full strain names, CFU, nonprobiotic ingredients, manufacturing standards, and high quality, peer-reviewed scientific studies of the probiotic strains in question.
1 Guidelines for the Evaluation of Probiotics in Food. Geneva,
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Summary Advances in the science of probiotics for children in the 21st century will be accelerated by pediatric microbiome research and functional genomics of beneficial microbes in children. These commensal microbes or “Old Friends” mediate development of robust immune responses, digestion, absorption of vitamins, and suppression of pathogens. Two major pipelines will fuel the development of new probiotics in pediatric medicine. First, the delineation of genes responsible for crucial probiotic functions will facilitate derivation of genetically modified organisms, also known as “designer strains,” that will represent optimized, engineered alternatives to natural probiotic strains for specific pediatric applications. Second, candidate probiotic strains isolated from natural sources (human, animal, or food) can be compared systematically by functional genomics and systems biology. The best natural probiotics can then be selected for specific pediatric uses. Many more clinical and laboratory investigations must be performed to elucidate mechanisms of probiosis and matching of specific probiotics with particular disease phenotypes in children. In summary, humans have used beneficial bacteria via the diet throughout human history. Investigator-initiated research and “big science,” as exemplified by the Human Microbiome Project, will drive accelerated development of probiotics for the prevention and treatment of many pediatric disorders.
Acknowledgment M.H.H. has research support from the National Institutes of Health (NIH) (NIDDK K08 DK087895).
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