title: Assessment of the safety, tolerance, and protective effect against diarrhea of infant formulas containing mixtures of probiotics or probiotics and prebiotics in a randomized controlled trial. Low diversity of the gut microbiota in infants with atopic eczema. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Probiotics during weaning reduce the incidence of eczema. A protective effect of Lactobacillus rhamnosus HN001 against eczema in the first 2 years of life persists to age 4 years A Th1/Th2‐associated chemokine imbalance during infancy in children developing eczema, wheeze and sensitization Effects of feeding probiotics during weaning on infections and antibody responses to diphtheria, tetanus and Hib vaccines. Effect of Formula Composition on the Development of Infant Gut Microbiota A differential effect of 2 probiotics in the prevention of eczema and atopy: a double-blind, randomized, placebo-controlled trial. Dietary supplementation with lactobacilli and bifidobacteria is well tolerated and not associated with adverse events during late pregnancy and early infancy. Human Milk Probiotic Lactobacillus fermentum CECT5716 Reduces the Incidence of Gastrointestinal and Upper Respiratory Tract Infections in Infants Clinical evaluation of a new starter formula for infants containing live Bifidobacterium longum BL999 and prebiotics. Synbiotics prevent asthma‐like symptoms in infants with atopic dermatitis Early supplementation with Lactobacillus rhamnosus HN001 reduces eczema prevalence to 6 years: does it also reduce atopic sensitization? Airway inflammation in probiotic-treated children at 5 years. Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: a randomized, double-blind, placebo-controlled trial. The acquisition of tolerance toward cow's milk through probiotic supplementation: a randomized, controlled trial. Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort.
abstract: BACKGROUND Probiotics and prebiotics are considered to be beneficial to the gastrointestinal health of infants . OBJECTIVE The objective was to evaluate infant formulas containing probiotics and synbiotics ( combinations of probiotics and prebiotics ) for safety and tolerance . DESIGN In a prospect i ve , controlled , double-blind , r and omized trial , healthy full-term infants were exclusively fed a control formula or study formulas containing Bifidobacterium longum BL999 ( BL999 ) + Lactobacillus rhamnosus LPR ( LPR ) , BL999 + LPR + 4 g/L of 90 % galactooligosaccharide/10 % short-chain fructooligosaccharide ( GOS/SCFOS ) , or BL999 + Lactobacillus paracasei ST11 ( ST11 ) + 4 g/L GOS/SCFOS from < or = 2 to 16 wk of age ( treatment period ) . Safety and tolerance were assessed based on weight gain during the treatment period ( primary outcome ) as well as recumbent length , head circumference , digestive tolerance , and adverse events ( secondary outcomes ) , which were evaluated at 2 , 4 , 8 , 12 , 16 , and 52 wk of age . RESULTS Two hundred eighty-four infants were enrolled . During the treatment period , difference in mean weight gain between control and study formula groups in both the intention-to-treat and per- protocol population s were within the predefined equivalence boundaries of + /-3.9 g/d , indicating equivalent weight gain . Secondary outcomes did not show significant differences between groups during the treatment period . CONCLUSION Infants fed formulas containing probiotics or synbiotics show a similar rate in weight gain compared with those fed a control formula and tolerate these formulas well BACKGROUND It is debated whether a low total diversity of the gut microbiota in early childhood is more important than an altered prevalence of particular bacterial species for the increasing incidence of allergic disease . The advent of powerful , cultivation-free molecular methods makes it possible to characterize the total microbiome down to the genus level in large cohorts . OBJECTIVE We sought to assess microbial diversity and characterize the dominant bacteria in stool during the first year of life in relation to atopic eczema development . METHODS Microbial diversity and composition were analyzed with barcoded 16S rDNA 454-pyrosequencing in stool sample s at 1 week , 1 month , and 12 months of age in 20 infants with IgE-associated eczema and 20 infants without any allergic manifestation until 2 years of age ( Clinical Trials.gov ID NCT01285830 ) . RESULTS Infants with IgE-associated eczema had a lower diversity of the total microbiota at 1 month ( P = .004 ) and a lower diversity of the bacterial phylum Bacteroidetes and the genus Bacteroides at 1 month ( P = .02 and P = .01 ) and the phylum Proteobacteria at 12 months of age ( P = .02 ) . The microbiota was less uniform at 1 month than at 12 months of age , with a high interindividual variability . At 12 months , when the microbiota had stabilized , Proteobacteria , comprising gram-negative organisms , were more abundant in infants without allergic manifestation ( Empirical Analysis of Digital Gene Expression in R [ edgeR ] test : P = .008 , q = 0.02 ) . CONCLUSION Low intestinal microbial diversity during the first month of life was associated with subsequent atopic eczema Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more A reduced microbial load early in life has been suggested to be linked to the increasing prevalence of allergic diseases in the industrialized world . Some studies have indicated that probiotics may be effective in the prevention of eczema . In vitro studies indicate that probiotics have immunomodulatory effects . In the present study , we evaluated the effects of feeding Lactobacillus F19 during weaning on the incidence of eczema and Th1/Th2 balance . In a double-blind , placebo-controlled r and omized intervention trial , infants were fed cereals with ( n = 89 ) or without Lactobacillus F19 ( n = 90 ) from 4 to 13 months of age . We assessed the cumulative incidence of eczema at 13 months of age . The ratio of interferon-gamma ( IFN-gamma ) to interleukin 4 ( IL4 ) mRNA expression levels in polyclonally stimulated peripheral blood T cells was used as a proxy for immune balance . Total and specific IgE serum levels were also assessed . The cumulative incidence of eczema at 13 months was 11 % ( 4 - 17 % , 95 % CI ) and 22 % ( 13 - 31 % , 95 % CI ) in the probiotic and placebo groups , respectively ( p < 0.05 ) . The number needed to treat was 9 ( 6.5 - 11.5 , 95 % CI ) . At 13 months of age , the IFN-gamma/IL4 mRNA ratio was higher in the probiotic compared with the placebo group ( p < 0.05 ) . In contrast , there were no differences between groups in serum concentrations of IgE. In summary , feeding Lactobacillus F19 during weaning could be an effective tool in the prevention of early manifestation of allergy , e.g. , eczema . The higher Th1/Th2 ratio in the probiotic compared with the placebo group suggests enhancing effects of Lactobacillus F19 on the T cell-mediated immune response Using a double blind r and omized placebo‐controlled trial ( Australian New Zeal and Clinical Trials Registry : ACTRN12607000518460 ) , we have shown that in a high risk birth cohort , maternal supplementation from 35 weeks gestation until 6 months if breastfeeding and infant supplementation until 2 years with Lactobacillus rhamnosus HN001 ( HN001 ) ( 6 × 109 cfu/day ) halved the cumulative prevalence of eczema by age 2 years . Bifidobacterium animalis subsp lactis HN019 ( HN019 ) ( 9 × 109 cfu/day ) had no effect Background Analyses of circulating chemokines offer novel tools to investigate the T helper (Th)1/Th2 imbalance in allergic disease in vivo Microbial exposure is necessary for the development of normal immune function , which has driven the idea of using probiotics for treatment and prevention of  immune-mediated diseases in infancy and childhood . Mounting evidence indicates that probiotics have immunomodulatory effects . However , the mechanisms are still poorly understood . Specific antibody response is a valuable proxy for immune system maturation status in infancy . We aim ed at determining the impact of Lactobacillus F19 ( LF19 ) during weaning on infections and IgG antibody responses to routine vaccines . In a double-blind , placebo-controlled r and omized intervention trial , infants were fed cereals with ( n = 89 ) or without LF19 ( n = 90 ) from 4 to 13 months of age . Infants were immunized with DTaP ( diphtheria and tetanus toxoid and acellular pertussis ) , polio and Hib-conjugate vaccines at ( 3 ) , 5(1/2 ) and 12 months of age . We assessed the number of days with infections , antibiotic prescriptions and antibody concentrations to Hib capsular polysaccharide ( HibPS ) , diphtheria toxin ( D ) and tetanus toxoid ( T ) before and after the second and third doses . Days with infectious symptoms did not differ between the groups . Days with antibiotic prescriptions were fewer in the LF19 group ( p = 0.044 ) . LF19 enhanced anti-D concentrations when adjusting for breastfeeding duration and colonization with LF19 ( p = 0.024 ) . There was an interaction of the intervention and colonization with LF19 on anti-T concentrations during the course of vaccination ( p = 0.035 ) . The anti-HibPS concentrations were higher after the first and second dose of Hib vaccine in infants breastfed < 6 months compared with those breastfed > or = 6 months ( p < 0.05 ) , with no effect by LF19 . In conclusion , feeding LF19 did not prevent infections , but increased the capacity to raise immune responses to protein antigens , with more pronounced effects in infants breastfed < 6 months Objectives : Breast-feeding induces a gut microbiota rich in bifidobacteria , whereas formula-fed babies have a more diverse colonization . This ecosystem contributes to the development of the immune response and the lower incidence of diarrhea and allergy in breast-fed infants . This r and omized double-blind controlled trial aim ed to evaluate the bifidogenic effect of a mainly whey protein study formula low in phosphate and protein , allowing a composition closer to that of human milk . Patients and Methods : One hundred ninety healthy infants exclusively received study formula with or without Bifidobacterium longum ( BL999 ) , or a control formula for up to 4 months . Breast-fed infants served as a reference population . Stool sample s collected at 2 months of age were analyzed for bacterial counts ( log colony-forming unit [CFU]/g ) . Results : Bifidobacteria counts were significantly higher in infants receiving the study formula alone ( 10.0[0.8 ] , P < 0.0001 , median [ interquartile range ] ) or with BL999 ( 9.8[1.4 ] , P < 0.01 ) than control ( 9.2[3.5 ] ) , and were similar to breast-fed infants ( 10.1[0.4 ] , P > 0.05 ) . The difference between the 2 study groups was 0.16 log CFU/g ( 90 % confidence interval [ CI ] [ 0–0.4 ] ) , within the predefined equivalence margin . Microbiota profile , as a percentage of total bacteria counts , showed about 50 % Bifidobacteria , 8 % Enterobacteria , and < 10 % Clostridia in study formulae and breast-fed infants versus 22 % , 13 % , and 19 % in controls , respectively . There were no significant differences in growth measurements , digestive tolerance , and adverse events between groups . Conclusions : This study showed that infant formula closer resembling human milk was more bifidogenic than the control formula and led to a microbiota profile similar to that for breast-fed infants BACKGROUND The role of probiotics in prevention of allergic disease is still not clearly established , although early reports suggested Lactobacillus GG halved the risk of eczema at 2 years . OBJECTIVE To determine whether probiotic supplementation in early life could prevent development of eczema and atopy at 2 years . METHODS Double-blind , r and omized placebo-controlled trial of infants at risk of allergic disease . Pregnant women were r and omized to take Lactobacillus rhamnosus HN001 ( L rhamnosus ) , Bifidobacterium animalis subsp lactis strain HN019 or placebo daily from 35 weeks gestation until 6 months if breast-feeding , and their infants were r and omized to receive the same treatment from birth to 2 years ( n = 474 ) . The infant 's cumulative prevalence of eczema and point prevalence of atopy , using skin prick tests to common allergens , was assessed at 2 years . RESULTS Infants receiving L rhamnosus had a significantly ( P = .01 ) reduced risk of eczema ( hazard ratio [ HR ] , 0.51 ; 95 % CI , 0.30 - 0.85 ) compared with placebo , but this was not the case for B animalis subsp lactis ( HR , 0.90 ; 95 % CI , 0.58 - 1.41 ) . There was no significant effect of L rhamnosus ( HR , 0.74 ; 95 % CI , 0.46 - 1.18 ) or B animalis subsp lactis ( HR , 0.82 ; 95 % CI , 0.52 - 1.28 ) on atopy . L rhamnosus ( 71.5 % ) was more likely than B animalis subsp lactis ( 22.6 % ) to be present in the feces at 3 months , although detection rates were similar by 24 months . CONCLUSION We found that supplementation with L rhamnosus , but not B animalis subsp lactis , substantially reduced the cumulative prevalence of eczema , but not atopy , by 2 years . Underst and ing how Lactobacilli act to prevent eczema requires further investigation Lactic acid bacteria and bifidobacteria are increasingly being administered to pregnant women and infants with the intention of improving health . Although these organisms have a long record of safe use , it is important to identify any adverse effects in potentially vulnerable population s. In a r and omized , double-blinded , placebo-controlled trial , we evaluated the safety of a bacterial dietary supplement for the prevention of atopy in infants .  Two strains of lactobacilli ( Lactobacillus salivarius CUL61 and Lactobacillus paracasei CUL08 ) and bifidobacteria ( Bifidobacterium animalis subsp . lactis CUL34 and Bifidobacterium bifidum CUL20 ) with a total of 1 x 10(10 ) colony-forming units were administered daily to women during the last month of pregnancy and to infants aged 0 - 6 mo .  Adverse events ( AE ) were classified according to WHO International Statistical Classification of Diseases criteria . Common symptoms were recorded by regular question naires . Baseline characteristics of 220 mother-infant dyads in the treatment and 234 in the placebo group were similar . Compliance with the trial interventions , loss to follow-up , symptoms , drug usage , infant growth , method of feeding , visits to the doctor , and mothers ' assessment of infant health were similar in the 2 groups . Fifteen ( 6.8 % ) mothers and 73 ( 33.2 % ) infants in the treatment group and 21 ( 9.0 % ) mothers and 75 ( 32.1 % ) infants in the placebo group reported AE ( P = 0.49 and P = 0.84 , respectively ) . Severe AE occurred in 18 mothers and 63 infants with a similar frequency in each group . None of the AE were attributed to the intervention . Our findings support the safe use of this consortium of organisms during pregnancy and early infancy Objectives : The aim of the study was to examine the effects of a follow-on formula containing Lactobacillus fermentum CECT5716 ( L fermentum ) on the incidence of infections in infants between the ages of 6 and 12 months . Patients and Methods : A r and omized double-blinded controlled study including infants at the age of 6 months was conducted . Infants were assigned r and omly to either follow-on formula supplemented with L fermentum plus galactooligosaccharide ( experimental group , EG ) , or the same formula supplemented with only galactooligosaccharide ( control group , CG ) . The main outcome was the incidence of infections for the 6-month duration of the study . Results : The EG showed a significant 46 % reduction in the incidence rate ( IR ) of gastrointestinal infections ( EG : 0.196 ± 0.51 , CG : 0.363 ± 0.53 , IR ratio 0.54 , 95 % confidence interval [ CI ] 0.307–0.950 , P = 0.032 ) , 27 % reduction in the incidence of upper respiratory tract infections ( EG : 0.969 ± 0.96 , CG : 1.330 ± 1.23 , IR ratio 0.729 , 95 % CI 0.46–1.38 , P = 0.026 ) , and 30 % reduction in the total number of infections ( EG : 1.464 ± 1.15 , CG : 2.077 ± 1.59 , IR ratio 0.70 , 95 % CI 0.46–1.38 , P = 0.003 ) , at the end of the study period compared with CG . Conclusions : Administration of a follow-on formula with L fermentum CECT5716 may be useful for the prevention of community-acquired gastrointestinal and upper respiratory infections OBJECTIVES The larger number of bifidobacteria in the intestine of breast-fed infants has been associated with their better health compared with formula-fed infants . We assessed the safety and tolerability of an experimental formula containing 2 x 10(7 ) colony-forming units of Bifidobacterium longum BL999 and 4 g/L of a prebiotic mixture containing 90 % galacto-oligosaccharides and 10 % fructo-oligosaccharides . METHODS A 7-mo prospect i ve , r and omized , reference-controlled , double-blinded trial was performed in infants who were not breast fed after the 14th day of birth . One hundred thirty-eight infants were enrolled and assigned to receive the control or experimental formula until they were 112 d old .  Mean weight gain ( primary outcome ) and recumbent length , head circumference , tolerability ( gastrointestinal symptoms ) , and overall morbidity ( secondary outcomes ) were measured at 14 , 28 , 56 , 84 , and 112 d of age . RESULTS Equivalence in mean weight gain between the two groups was shown . The treatment difference in the intention-to-treat and per- protocol population s were within the predefined equivalence boundaries of + /-3.9 g/d . No statistically significant difference in recumbent length , head circumference , or incidence of adverse events was found between the two groups . Infants in the experimental group had fewer incidences of constipation and had stool characteristics that suggest that the experimental formula was tolerated well . Furthermore , these infants showed a trend toward fewer respiratory tract infections . CONCLUSIONS The starter formula containing BL999 and galacto-oligosaccharides/fructo-oligosaccharides is safe and well-tolerated To cite this article : van der Aa LB , van Aalderen WMC , Heymans HSA , Henk Sillevis Smitt J , Nauta AJ , Knippels LMJ , Ben Amor K , Sprikkelman AB , the Synbad Study Group . Synbiotics prevent asthma‐like symptoms in infants with atopic dermatitis . Allergy 2011 ; 66 : 170–177 The role of probiotics in prevention of  allergic disease  is still not clear ; efficacy may depend on the timing , dose , duration , and specific probiotic used . Using a double‐blind r and omized placebo‐controlled trial ( Australian New Zeal and Clinical Trials Registry : ACTRN12607000518460 ) , we have shown that in a high‐risk birth cohort , maternal supplementation from 35 weeks gestation until 6 months if breastfeeding and infant supplementation from birth until 2 years with Lactobacillus rhamnosus HN001 ( HN001 ) ( 6 × 109 cfu/day ) halved the cumulative prevalence of eczema at 2 and 4 years . Bifidobacterium animalis subsp lactis HN019 ( HN019 ) ( 9 × 109 cfu/day ) had no significant effect Early treatment of new-born high-risk children with certain probiotic strains has reduced the risk of atopic eczema . Whether probiotics reduce risk for airway inflammation in long term is not known . We aim ed at study ing the effect of probiotic treatment during the six first months of life on airway inflammation at age 5 yr . In a r and omized double-blind allergy prevention trial between 2000 and 2007 in Helsinki , Finl and , we gave a probiotic combination , plus pre-biotics , or placebo , to 1018 children during 6 months from birth . At age 5 , we measured exhaled nitric oxide ( FE(NO ) ) in a r and omized sub- population of 160 children . Allergic diseases and IgE-sensitization  were assessed in all infants .  FE(NO ) did not differ between probiotic and placebo groups , median ( interquartile range , IQR ) 5.45 ( 4.3 - 7.3 ) vs. 5.70 ( 3.9 - 6.8 ) ppb , p = 0.22 . FE(NO ) was elevated among those suffering from asthma during the first 5 yr than in healthy non-sensitized children ( p = 0.009 ) . FE(NO ) correlated positively with serum total and allergen-specific IgE concentrations . Early intervention with probiotics and pre-biotics does not affect airway inflammation later in childhood BACKGROUND The increase in allergic diseases is attributed to a relative lack of microbial stimulation of the infantile gut immune system . Probiotics , live health-promoting microbes , might offer such stimulation . OBJECTIVE We studied the effect of a mixture of 4 probiotic bacterial strains along with prebiotic galacto-oligosaccharides in preventing allergic diseases . METHODS We r and omized 1223 pregnant women carrying high-risk children to use a probiotic preparation or a placebo for 2 to 4 weeks before delivery . Their infants received the same probiotics plus galacto-oligosaccharides ( n = 461 ) or a placebo ( n = 464 ) for 6 months . At 2 years , we evaluated the cumulative incidence of allergic diseases ( food allergy , eczema , asthma , and allergic rhinitis ) and IgE sensitization ( positive skin prick test response or serum antigen-specific IgE level > 0.7 kU/L ) . Fecal bacteria were analyzed during treatment and at age 2 years . RESULTS Probiotic treatment compared with placebo showed no effect on the cumulative incidence of allergic diseases but tended to reduce IgE-associated ( atopic ) diseases ( odds ratio [ OR ] , 0.71 ; 95 % CI , 0.50 - 1.00 ; P = .052 ) . Probiotic treatment reduced eczema ( OR , 0.74 ; 95 % CI , 0.55 - 0.98 ; P = .035 ) and atopic eczema ( OR , 0.66 ; 95 % CI , 0.46 - 0.95 ; P = .025 ) . Lactobacilli and bifidobacteria more frequently ( P < .001 ) colonized the guts of supplemented infants . CONCLUSION Probiotic treatment showed no effect on the incidence of all allergic diseases by age 2 years but significantly prevented eczema and especially atopic eczema . The results suggest an inverse association between atopic diseases and colonization of the gut by probiotics . CLINICAL IMPLICATION S The prevention of atopic eczema in high-risk infants is possible by modulating the infant 's gut microbiota with probiotics and prebiotics BACKGROUND Cow 's milk allergy ( CMA ) is the most frequently diagnosed food allergy in infancy . In general , patients have a good prognosis because the majority acquire tolerance within the first years . Interventions have been proposed to accelerate tolerance and reduce morbidity . Probiotic supplementation could be effective through modulation of the immune system . OBJECTIVE We sought to determine whether supplementation with a combination of probiotics ( Lactobacillus casei CRL431 and Bifidobacterium lactis Bb-12 ) accelerates tolerance to cow 's milk ( CM ) in infants with CMA . METHODS We performed a double-blind , r and omized , placebo-controlled trial in 119 infants with CMA . Infants received CRL431 and Bb-12 supplemented to their st and ard treatment of extensively hydrolyzed formula for 12 months . Primary outcome was clinical tolerance to CM at 6 and 12 months of treatment . Furthermore , we analyzed T- and B-lymphocyte subsets ( CD3(+ ) , CD3(+)CD4(+ ) , CD3(+)CD8(+ ) , and CD20(+ ) ) in peripheral blood at r and omization and at 12 months with flow cytometry and examined the presence of viable probiotic strains in fecal sample s. RESULTS The cumulative percentage of tolerance to CM at 6 and 12 months was similar in both groups : 56 ( 77 % ) in the probiotics group versus 54 ( 81 % ) in the placebo group . Infants in the placebo group had higher percentages of CD3(+ ) and CD3(+)CD4(+ ) lymphocytes compared with those seen in probiotic-treated infants . Probiotic intake was confirmed because probiotics were isolated from feces more often in treated infants than in the placebo group . CONCLUSION Supplementation of CRL431 and Bb-12 to extensively hydrolyzed formula does not accelerate CM tolerance in infants with CMA BACKGROUND Less microbial exposure in early childhood is associated with more allergic disease later . Allergic children have a different fecal microflora , with less lactobacilli and bifidobacteria . Beneficial effects regarding the development of allergy have been suggested to come through probiotic supplementation . OBJECTIVE We sought to study the effect of probiotic and prebiotic supplementation in preventing allergies . METHODS In a double-blinded , placebo-controlled study we r and omized 1223 mothers with infants at high risk for allergy to receive a probiotic mixture ( 2 lactobacilli , bifidobacteria , and propionibacteria ) or placebo during the last month of pregnancy and their infants to receive it from birth until age 6 months . Infants also received a prebiotic galacto-oligosaccharide or placebo . At 5 years , we evaluated the cumulative incidence of allergic diseases ( eczema , food allergy , allergic rhinitis , and asthma ) and IgE sensitization . RESULTS Of the 1018 intent-to-treat infants , 891 ( 88 % ) attended the 5-year visit .  Frequencies of allergic and IgE-associated allergic disease and sensitization in the probiotic and placebo groups were similar : 52.6 % versus 54.9 % and 29.5 % versus 26.6 % , respectively , and 41.3 % in both . No significant difference appeared in frequencies of eczema ( 39.3 % vs 43.3 % ) , atopic eczema ( 24.0 % vs 25.1 % ) , allergic rhinitis ( 20.7 % vs 19.1 % ) , or asthma ( 13.0 % vs 14.1 % ) between groups . However , less IgE-associated allergic disease occurred in cesarean-delivered children receiving probiotics ( 24.3 % vs 40.5 % ; odds ratio , 0.47 ; 95 % CI , 0.23 % to 0.96 % ; P = .035 ) . CONCLUSIONS No allergy-preventive effect that extended to age 5 years was achieved with perinatal supplementation of probiotic bacteria to high-risk mothers and children . It conferred protection only to cesarean-delivered children
target: We found no evidence to support a protective association between perinatal use of probiotics and doctor diagnosed asthma or childhood wheeze .
  R and omised controlled trials to date have not yielded sufficient evidence to recommend probiotics for the primary prevention of these disorders .
background: OBJECTIVE To evaluate the association of probiotic supplementation during pregnancy or infancy with  childhood asthma and wheeze .