Kaarina Kukkonen

Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort.

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 randomized 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.

Long-Term Safety and Impact on Infection Rates of Postnatal Probiotic and Prebiotic (Synbiotic) Treatment: Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVE. Live probiotic bacteria and dietary prebiotic oligosaccharides (together termed synbiotics) increasingly are being used in infancy, but evidence of long-term safety is lacking. In a randomized, placebo-controlled, double-blind trial, we studied the safety and long-term effects of feeding synbiotics to newborn infants. METHODS. Between November 2000 and March 2003, pregnant mothers carrying infants at high risk for allergy were randomly assigned to receive a mixture of 4 probiotic species (Lactobacillus rhamnosus GG and LC705, Bifidobacterium breve Bb99, and Propionibacterium freudenreichii ssp shermanii) or a placebo for 4 weeks before delivery. Their infants received the same probiotics with 0.8 g of galactooligosaccharides, or a placebo, daily for 6 months after birth. Safety data were obtained from clinical examinations and interviews at follow-up visits at ages 3, 6, and 24 months and from questionnaires at ages 3, 6, 12, and 24 months. Growth data were collected at each time point. RESULTS. Of the 1018 eligible infants, 925 completed the 2-year follow-up assessment. Infants in both groups grew normally. We observed no difference in neonatal morbidity, feeding-related behaviors (such as infantile colic), or serious adverse events between the study groups. During the 6-month intervention, antibiotics were prescribed less often in the synbiotic group than in the placebo group (23% vs 28%). Throughout the follow-up period, respiratory infections occurred less frequently in the synbiotic group (geometric mean: 3.7 vs 4.2 infections). CONCLUSION. Feeding synbiotics to newborn infants was safe and seemed to increase resistance to respiratory infections during the first 2 years of life.

Probiotics in infancy induce protective immune profiles that are characteristic for chronic low-grade inflammation

Background Probiotics are widely studied both in the treatment and prevention of allergic diseases, but their mode of action is poorly known.

High intestinal IgA associates with reduced risk of IgE-associated allergic diseases

Kukkonen K, Kuitunen M, Haahtela T, Korpela R, Poussa T, Savilahti E. High intestinal IgA associates with reduced risk of IgE‐associated allergic diseases.
Pediatr Allergy Immunol 2010: 21: 67–73.
© 2009 John Wiley & Sons A/S

Effect of probiotics on vaccine antibody responses in infancy – a randomized placebo-controlled double-blind trial

Probiotics are immunomodulatory and may thus affect vaccine antibody responses. With the accumulating evidence of their health‐promoting effects, probiotics are increasingly administered in allergy‐prone infants. Therefore, we studied the effect of probiotics on antibody responses to diphtheria, tetanus and Haemophilus influenzae type b (Hib) vaccines in 6‐month‐old infants participating in a randomized placebo‐controlled double‐blind allergy‐prevention trial. Mothers of unborn children at increased risk for atopy used a combination of four probiotic strains, or a placebo, for 4 wk before delivery. During 6 months from birth, their infants received the same probiotics and galacto‐oligosaccharides, or a placebo. The infants were immunized with a DTwP (diphtheria, tetanus and whole cell pertussis) at ages 3, 4, and 5 months, and with a Hib polysaccharide conjugate at 4 months. Serum diphtheria, tetanus, and Hib IgG antibodies were measured at 6 months. In the probiotic group, protective Hib antibody concentrations (≥1 μg/ml) occurred more frequently, 16 of 32 (50%) vs. six of 29 (21%) (p = 0.020), and the geometric mean (inter‐quartile range) Hib IgG concentration tended to be higher 0.75 (0.15–2.71) μg/ml than in the placebo group 0.40 (0.15–0.92) μg/ml (p = 0.064). In these respective groups, diphtheria, 0.38 (0.14–0.78) vs. 0.47 (0.19–1.40) IU/ml (p = 0.449), and tetanus, 1.01(0.47–1.49) vs. 0.81 (0.56–1.39) IU/ml (p = 0.310), IgG titers were comparable. In conclusion, in allergy‐prone infants probiotics seem not to impair antibody responses to diphtheria, tetanus, or Hib, but may improve response to Hib immunization.

Increased activation of GATA‐3, IL‐2 and IL‐5 of cord blood mononuclear cells in infants with IgE sensitization

Risk of allergic diseases has been linked to abnormal patterns of fetal immune development, suggesting that priming of the immune system may occur in utero. The aim of the study was to investigate whether the pattern of immune response in cord blood mononuclear cells (CBMC) shows association with allergic diseases and IgE sensitization at 2 yr of age, and to study the effect of maternal probiotic supplementation on CBMC immune responses. CBMC were isolated from 98 neonates in a randomized double‐blinded intervention study. CBMC were stimulated with beta‐lactoglobulin, and phytohemaglutinin (PHA). Secretion of interferon‐gamma (IFN‐γ), interleukin‐5 (IL‐5), and IL‐13 was measured by an ELISA; IL‐2, IL‐4, and IL‐10 by a cytokine bead assay. T‐cell polarization‐associated IL‐4 receptor and IL‐12R expressions, and the respective transcription factors GATA‐3 and T‐bet were analyzed with RT‐PCR. The above responses were compared with the development of allergic diseases and IgE sensitization at 2 yr of age, and with the maternal probiotic or placebo supplementation. PHA‐stimulated GATA‐3 expression and IL‐2 secretion in CBMC were higher in IgE‐sensitized children at an age of 2 yr than in the non‐sensitized, non‐allergic children (p = 0.03 and 0.026). PHA‐induced expression of GATA‐3 correlated with IL‐5 (p = 0.003, r = 0.300) and IL‐13 (p = 0.007, r = 0.278) secretion of CBMC, and IL‐5 secretion of β‐lactoglobulin‐stimulated CBMC was higher in IgE‐sensitized children at 2 yr of age than in the non‐sensitized, non‐allergic children (p = 0.013). Probiotic bacteria had no effect on CBMC immune responses. In CBMC‐enhanced induction of GATA‐3, which activates several Th2 cytokines genes, was a risk factor for IgE sensitization. The immune deviation towards Th2‐type immunity developed already in utero and seemed to modulate the pattern of immune response favoring an IgE response to environmental antigens.

Pro- and prebiotic supplementation induces a transient reduction in hemoglobin concentration in infants.

Objectives: Regarding safety, we investigated the effect of prenatal probiotic and 6 months of pro- and prebiotic supplementation of infants on their hematologic values at 6 months and 2 years and factors affecting these values. Patients and Methods: In a prospective randomized controlled probiotic intervention trial in infants at high risk for allergy, we obtained blood samples consecutively from 98 infants at 6 months and from 658 children at 2 years to measure hematologic values. We collected fecal samples at 3 and 6 months to measure immunologic development by calprotectin, α-1-antitrypsin, tumor necrosis factor-α, and immunoglobulin A. Results: At 6 months, infants in the probiotic group had significantly lower hemoglobin (Hb) values than did the placebo group, mean (SD): 119.8 g/L (6.3) versus 123.3 g/L (8.4), P = 0.025. Adjustment for factors that might affect Hb values (breast-feeding duration, solid-food introduction, and sex), revealed no need for adjustment. A significant negative correlation emerged between Hb values at 6 months and fecal calprotectin at age 3 months r = −0.301, P = 0.009, which was affected neither by breast-feeding, sex, nor study group. At 2 years, hematologic values in both groups became similar. Conclusions: Probiotics cause a gut mucosal inflammation with decreased Hb values during intervention, corrected after halting the supplementation.

Probiotics in the Treatment and Prevention of Allergy in Children

Several fold increase in allergic diseases in developed, high-income countries during recent decades is attributed to environmental changes such as urbanization with improved hygiene. This, together with conquering severe bacterial infections during childhood, has reduced the microbial stimulation of the developing immune system of infants. Studies on the pathogenesis of allergy both in man and experimental animal have shown the importance of commensal bacteria in the gastrointestinal tract in stimulating and directing the immune system. The interest in modulating commensal bacterial flora with probiotics to prevent and treat allergy has multiplied in recent years.In the present review we report results on randomized, controlled studies in which childhood atopic eczema was treated or which aimed to prevent development of allergy during childhood.Nine studies with 639 patients have looked at the effect of probiotics in treatment of eczema. While 3 studied showed no effect, other studies suggested a moderate benefit of the use of probiotics on the severity of eczema. Studies suggested that the effect may be seen particularly in patients with food allergy and/or sensitization.Nine studies have reported on the prevention of allergy on 6 study population with altogether 1989 high risk infants. While the early study reporting the development of allergy at ages 2, 4 and 7 years showed a marked reduction of eczema in 77 treated infants, later studies have failed to show similar success. Two studies showed no effect. In the largest study with more than 900 children at age 2 atopic eczema was reduced by 20%, but at age 5 positive effect was present in only the subgroup of children who had born by cesarean section. None of studies has reported adverse effects of probiotics in infants.Result in both treatment and prevention studies are quite variable, the major reason being the use of different strains of probiotic bacteria and varying types of intervention. Even if the results are encouraging, we need a stronger effect. This may be reached by finding new strains of probiotics affecting stronger stimulation of immune system, together with longer lasting and varying treatment schedules. However, safety issues have to be observed.

Interaction of NPSR1 genotypes and probiotics in the manifestation of atopic eczema in early childhood

BACKGROUND Neuropeptide S Receptor (NPSR1) gene has been associated with multiple allergic phenotypes in several patient populations. OBJECTIVE We analysed the effect of the NPSR1 genotypes in the development of asthma, rhinitis, eczema, or food allergy in children randomly receiving either probiotic or placebo treatment. METHODS 796 children born to families at high risk for allergic diseases were examined by a paediatrician at the age of three months, six months, two years, and five years. Asthma, rhinitis, eczema, and food allergy were diagnosed according to international guidelines. Treatment with probiotics (double-blinded and placebo controlled) was begun with mothers at 35 weeks of gestation age and continued after the birth of infants up to the age of six months. Association and additive inheritance models were used in genetic analyses. RESULTS Distribution of the hopo546333 was suggestive in the group of patients with atopic eczema at two years. The hopo546333_G was found more often in those with eczema in the placebo group (p=0.048, after Bonferroni correction) and the hopo546333_A was found more often in those with eczema and probiotics compared to those with eczema and placebo treatment. None of the NPSR1 tagging SNPs was associated with asthma, IgE-mediated asthma, or sensitisation. Allergic disease in both parents doubled the risk for IgE-mediated allergic disease (OR 2.1). CONCLUSIONS The NPSR1 gene SNP hopo546333 showed a suggestive association for high IgE-associated atopic eczema at two years.

Fucosylated oligosaccharides in mother’s milk alleviate the effects of caesarean birth on infant gut microbiota

One of the most abundant components in human milk is formed by oligosaccharides, which are poorly digested by the infant. The oligosaccharide composition of breast milk varies between mothers, and is dependent on maternal secretor (FUT2) genotype. Secretor mothers produce milk containing α1-2 fucosylated human milk oligosaccharides, which are absent in the milk of non-secretor mothers. Several strains of bacteria in the infant gut have the capacity to utilise human milk oligosaccharides (HMOs). Here we investigate the differences in infant gut microbiota composition between secretor (N = 76) and non-secretor (N = 15) mothers, taking into account birth mode. In the vaginally born infants, maternal secretor status was not associated with microbiota composition. In the caesarean-born, however, many of the caesarean-associated microbiota patterns were more pronounced among the infants of non-secretor mothers compared to those of secretor mothers. Particularly bifidobacteria were strongly depleted and enterococci increased among the caesarean-born infants of non-secretor mothers. Furthermore, Akkermansia was increased in the section-born infants of secretor mothers, supporting the suggestion that this organism may degrade HMOs. The results indicate that maternal secretor status may be particularly influential in infants with compromised microbiota development, and that these infants could benefit from corrective supplementation.