Long-term changes in milk component immunoglobulins reflect milk oral immunotherapy outcomes in Finnish children.

BACKGROUND: Milk oral immunotherapy (OIT) may increase the amount of milk protein that can be ingested without triggering an allergic reaction. It is important to understand why some patients benefit from the treatment while others do not. OBJECTIVE: The aim was to define the differences in the milk allergen component-specific (casein, α-lactalbumin, ß-lactoglobulin) immunoglobulin (sIg [sIgE, sIgG4, and sIgA]) levels relative to the long-term outcomes of milk OIT. METHODS: In this long-term, open-label follow-up study, 286 children started milk OIT between 2005 and 2015. Follow-up data were collected at two points: the post-buildup phase and long term (range 1-11 years, median 6 years). Comparisons of sIg levels were made among three outcome groups of self-reported long-term milk consumption (high-milk dose, low-milk dose, and avoidance). RESULTS: A total of 168 (59%) of the 286 patients on OIT participated. Most patients (57%) were in the high-dose group; here, 80% of these patients had a baseline casein sIgE value less than 28 kUA/L, they had the lowest casein sIgE levels at all time (p < .001), their casein sIgG4/IgE levels increased, and long-term casein sIgA was highest compared with the low-dose and avoidance groups (p = .02). Low-milk dose group had the highest casein sIgG4/IgE levels in long term (p = .002). CONCLUSION: The baseline Ig profiles and responses to milk OIT differed depending on long-term milk consumption. Lower casein sIgE levels were associated with better outcome. Milk casein sIgA differed in the long term among high-milk consumers.

Early-life environment and the risk of eczema at 2 years-Meta-analyses of six Finnish birth cohorts.

BACKGROUND: Urban-related nature exposures are suggested to contribute to the rising prevalence of allergic diseases despite little supporting evidence. Our aim was to evaluate the impact of 12 land cover classes and two greenness indices around homes at birth on the development of doctor-diagnosed eczema by the age of 2 years, and the influence of birth season. METHODS: Data from 5085 children were obtained from six Finnish birth cohorts. Exposures were provided by the Coordination of Information on the Environment in three predefined grid sizes. Adjusted logistic regression was run in each cohort, and pooled effects across cohorts were estimated using fixed or random effect meta-analyses. RESULTS: In meta-analyses, neither greenness indices (NDVI or VCDI, 250 m × 250 m grid size) nor residential or industrial/commercial areas were associated with eczema by age of 2 years. Coniferous forest (adjusted odds ratio 1.19; 95% confidence interval 1.01-1.39 for the middle and 1.16; 0.98-1.28 for the highest vs. lowest tertile) and mixed forest (1.21; 1.02-1.42 middle vs. lowest tertile) were associated with elevated eczema risk. Higher coverage with agricultural areas tended to associate with elevated eczema risk (1.20; 0.98-1.48 vs. none). In contrast, transport infrastructure was inversely associated with eczema (0.77; 0.65-0.91 highest vs. lowest tertile). CONCLUSION: Greenness around the home during early childhood does not seem to protect from eczema. In contrast, nearby coniferous and mixed forests may increase eczema risk, as well as being born in spring close to forest or high-green areas.

Perinatal Probiotic Mixture and Development of Allergic Sensitization up to 13 Years of Age.

BACKGROUND: Probiotics have shown promising results in primary prevention of allergies in early years, but the long-term effects on allergic sensitization need more evaluation. OBJECTIVES: We conducted a randomized double-blind placebo-controlled study to determine whether the use of a mixture of pre- and probiotics perinatally affects the prevalence of immunoglobulin E (IgE) sensitization up to 13 years in high-risk children. METHODS: One thousand two hundred twenty-three pregnant women were randomized to receiving probiotics or placebo from 36 gestational weeks until delivery, and their infants received pre- and probiotics or placebo from birth until 6 months. At 2, 5, and 13 years, blood samples were taken to determine specific IgE levels against common foods, pollen, and animal antigens. RESULTS: The prevalence of IgE sensitization to any allergen was high and increased with age. No significant difference in the prevalence of IgE sensitization to any particular one of the tested allergens was found between the groups. At 2, 5, and 13 years these prevalence rates of IgE sensitization to any allergen were 31.1 and 34.1%, 50.1 and 45.6%, and 61.4 and 56.8% in the probiotic and placebo groups, respectively. At 13 years, IgE sensitization to cat/dog dander was more frequent in the probiotic group compared to the placebo group (40.2 vs. 31.0%, p = 0.03). CONCLUSIONS: In high-risk children, perinatal use of a mixture of probiotics did not affect the prevalence of sensitization to any one of the tested allergens, but it was associated with more frequent IgE sensitization to cat/dog dander at 13 years.

Perinatal probiotic intervention prevented allergic disease in a Caesarean-delivered subgroup at 13-year follow-up.

BACKGROUND: The long-term effects of probiotic intervention for primary prevention of allergic diseases are not well known. We previously reported less eczema until 10 years in our probiotic intervention trial. OBJECTIVE: To investigate the effect of early probiotic intervention on the prevalence of allergic diseases up to 13 years of age. METHODS: Pregnant women (n = 1223) carrying a child at a high risk of allergy (at least one parent with allergic disease) were randomized to receive a mixture of probiotics (Lactobacillus rhamnosusGG and LC705, Bifidobacterium breve Bb99 and Propionibacterium freudenreichii) or placebo in a double-blind manner from 36 weeks of gestation until birth. Their infants received the same product for the first six months (registration number NCT00298337). At 13-year follow-up, the participants were requested to return a questionnaire and to provide a blood sample. RESULTS: A questionnaire was returned by 642 participants (63.1% of intention-to-treat infants), and 459 provided a blood sample. In the whole cohort, there were no statistically significant differences in doctor-diagnosed allergic disease (55.2% and 59.0%, probiotic and placebo group, respectively) or allergic disease (47.9% and 51.6%) based on the ISAAC questionnaire data. Inhalant-specific IgE sensitization (>0.7 kU/L) was 59.3% in the probiotic group and 49.8% in the placebo group (P = 0.040). In a post hoc analysis made in Caesarean-delivered subgroup, allergy was reported in 41.5% of the probiotic group and 67.9% of the placebo group (P = 0.006), and eczema in 18.9% and 37.5%, respectively (P = 0.031). In the whole cohort, 8.5% of the probiotic group had suffered from wheezing attacks during the previous 12 months vs 14.7% in the placebo group (P = 0.013). There were no statistically significant differences discovered between the characteristics of the participating group and the dropout group. CONCLUSIONS: Probiotic intervention protected Caesarean-delivered subgroup from allergic disease and eczema, but not the total cohort.

Outcome of oral immunotherapy for persistent cow's milk allergy from 11 years of experience in Finland.

BACKGROUND: The safety and efficacy of long-term milk oral immunotherapy (OIT) in Finnish children with persistent cow's milk allergy (CMA) were evaluated in an open-label, non-randomized study. METHODS: During the 11-year study, 296 children aged 5 years or older with immunoglobulin E (IgE)-mediated CMA started milk OIT. Follow-up data were collected at three time points: the post-buildup phase, 1 year thereafter, and at the cross-sectional long-term follow-up between January 2016 and December 2017. Patients were divided according to baseline milk-specific IgE (sIgE) level and by the amount of milk consumption at the long-term follow-up. The high-dose group consumed ≥2 dL of milk daily, while the failure group consumed <2 dL of milk or were on a milk-avoidance diet. RESULTS: Out of the initial study group, 244/296 (83%) patients participated in the long-term follow-up. Among these patients, 136/244 (56%) consumed ≥2 dL of milk daily. The median follow-up time was 6.5 years. Of the recorded markers and clinical factors, the baseline milk sIgE level was most associated with maintaining milk OIT (P < 0.001). Respiratory symptoms in the post-buildup phase increased the risk of treatment failure (OR 3.5, 95% CI: 1.5-8.1, P = 0.003) and anaphylaxis (OR 14.3, 95% CI: 1.8-114, P = 0.01). CONCLUSION: More than half of the patients were able to maintain the targeted milk dose in their daily diet. Baseline milk sIgE level and reactivity during the early treatment stage strongly predicted the long-term outcome and safety of milk OIT.

Gal d 1-specific IgE predicts allergy to heated egg in Finnish children.

BACKGROUND: Allergen-specific IgE levels can be useful in predicting outcomes of oral food challenges, but optimal cutoff levels vary in different populations. The aim was to determine cutoff values for egg white- and Gal d 1-, Gal d 2-, Gal d 3-, and Gal d 4-specific IgE (sIgE) predicting positive oral heated egg challenges in 185 Finnish children and adolescents. METHODS: A total of 185 egg-sensitized patients (age: 1-19 years, median: 6.3, mean: 7.0 years) with suspected egg allergy underwent double-blind, placebo-controlled (n = 78), or open (n = 107) oral food challenges with heated egg white. Specific IgE levels to egg white, Gal d 1 (ovomucoid), Gal d 2 (ovalbumin), Gal d 3 (conalbumin), and Gal d 4 (lysozyme) were measured by ImmunoCAP and compared with challenge outcomes. RESULTS: Of the 185 challenges, 124 (67%) were positive. Gal d 1 sIgE levels were significantly higher in the challenge-positive (median 13.5 kU/L, mean 33.2 kU/L) than in the challenge-negative group (median 0.2 kU/L, mean 1.2 kU/L), P < 0.0001. The diagnostic capacity of sIgE to egg white and Gal d 2, 3, and 4 was clearly weaker. In ROC analysis, the AUC for egg white was 0.86, Gal d 2 0.84, Gal d 3 0.79, and Gal d 4 0.77. Sensitization to Gal d 1 with a cutoff of value of >3.7 kU/L predicted a positive challenge with a specificity of 95% and sensitivity of 78%. The likelihood ratio was 15.9. In ROC analysis, the area under the curve was 0.94 (95% CI, 0.91-0.97). With a cutoff value of >14 kU/L, all challenges were positive, and with a cutoff of <0.9 kU/L, 95% of the challenges were negative. In the children aged 1-5 years (n = 88), the cutoff for Gal d 1 was >3.8 kU/L, and in the children above 6 years of age (n = 97), it was >3.5 kU/L. CONCLUSION: Gal d 1-specific IgE is useful in distinguishing egg-sensitized patients with clinically reactive egg allergy from those tolerant of heated egg. The optimal cutoff point in a Finnish population of 185 children and adolescents was 3.7 kU/L with no significant difference between the younger and older age groups.

Component-resolved diagnosis in selecting patients for yellowjacket venom immunotherapy.

BACKGROUND: Venom immunotherapy is effective in preventing systemic allergic reactions (SARs), but the diagnosis of venom allergy is problematic. OBJECTIVE: To compare the performance of component-resolved diagnosis and conventional tests in patients referred for venom immunotherapy. METHODS: We measured serum-specific immunoglobulin E to yellowjacket and honeybee venoms (Ves v 1 and Ves v 5 and Api m 1), cross-reactive carbohydrate determinants, serum basal tryptase (ImmunoCAP, ThermoFisher Scientific, Uppsala, Sweden), and skin prick test reactions in 84 patients referred to receive venom immunotherapy. History of SAR and its severity were evaluated. RESULTS: Of the 78 patients with suspected yellowjacket venom (YJV) allergy, a history of SAR was confirmed in 47 (60%) and 31 (40%) had a non-SAR reaction. The most accurate tests to confirm venom allergy after a SAR were serum-specific immunoglobulin E to yellowjacket whole-venom extract spiked with Ves v 5 (area under the curve 0.87, 95% confidence interval 0.77-0.97, P < .001) and Ves v 5 (area under the curve 0.86, 95% confidence interval 0.76-0.96, P < .001). Sensitization to Ves v 1 was infrequent and its area under the curve was low (0.62, 95% confidence interval 0.47-0.76, P = .106). Sensitivity of the YJV skin prick test was 86%, but its specificity was low at 54%. Double sensitization to yellowjacket and honeybee occurred frequently in skin prick tests. Of the patients without a SAR, 26% showed a positive reaction to YJV in any serum test and 46% showed a positive reaction in skin tests. CONCLUSION: Specific immunoglobulin E to the YJV spiked with Ves v 5 confirmed the allergy after a SAR. A history of SAR should be confirmed before testing, because venom sensitization is frequent in other types of reactions.

Celiac Disease by the Age of 13 Years Is Not Associated With Probiotics Administration in Infancy.

Probiotics are theoretically promising in primary prevention of celiac disease (CD), but research evidence on the topic is scarce. We used the data and material of a clinical double-blind randomized placebo-controlled trial on primary allergy prevention (n = 1223) to investigate in an exploratory study whether administration of a mix of pro- and prebiotics during late pregnancy and first 6 months of life was associated with prevalence of CD during 13-year follow-up. Children who fulfilled diagnostic criteria for CD (n = 11) and subjects with a serum sample available for analyzing CD antibodies (n = 867) were included. CD or elevated tissue transglutaminase IgA antibodies were not associated with probiotics or placebo. Nor were there any associations with the mode of delivery, the duration of exclusive or total breast-feeding, or respiratory infections during the first 2 years of life. Allergic diseases or sensitization by the age of 2 or 5 years were not clearly associated with the development of CD.

FUT2-dependent breast milk oligosaccharides and allergy at 2 and 5 years of age in infants with high hereditary allergy risk.

PURPOSE: Manifestation of allergic disease depends on genetic predisposition, diet and commensal microbiota. Genetic polymorphism of mothers determines their breast milk glycan composition. One major determinant is the fucosyltransferase 2 (FUT2, secretor gene) that was shown to be linked to commensal microbiota establishment. We studied whether FUT2-dependent breast milk oligosaccharides are associated with allergic disease in breast-fed infants later in life. METHODS: We analyzed FUT2-dependent oligosaccharides in breast milk samples of mothers (n = 266) from the placebo group of a randomized placebo-controlled trial of prebiotics and probiotics as preventive against allergic disease in infants with high allergy risk (trial registry number: NCT00298337). Using logistic regression models, we studied associations between FUT2-dependent breast milk oligosaccharides and incidence of allergic disease at 2 and 5 years of age. RESULTS: At 2 years, but not at 5 years of age, we observed a presumed lower incidence (p < 0.1) for IgE-associated eczema manifestation in C-section-born infants who were fed breast milk containing FUT2-dependent oligosaccharides. By logistic regression, we observed a similar relation (p < 0.1) between presence of FUT2-dependent breast milk oligosaccharides and IgE-associated disease and IgE-associated eczema in C-section-born infants only. When testing with the levels of breast milk oligosaccharide 2'-fucosyllactose as proxy for FUT2 activity, we observed significant (p < 0.05) associations in the C-section-born infants with 'any allergic disease,' IgE-associated disease, eczema and IgE-associated eczema. CONCLUSION: The data indicate that infants born by C-section and having a high hereditary risk for allergies might have a lower risk to manifest IgE-associated eczema at 2 years, but not 5 years of age, when fed breast milk with FUT2-dependent milk oligosaccharides. Further studies with larger cohorts and especially randomized controlled intervention trials are required to build on these preliminary observations.

Double-blind placebo-controlled challenge showed that peanut oral immunotherapy was effective for severe allergy without negative effects on airway inflammation.

AIM: This study examined the efficacy and the safety of peanut oral immunotherapy (OIT). METHODS: We recruited 60 patients aged six years to 18 years who had a moderate-to-severe reaction to a double-blind placebo-controlled peanut challenge: 39 received OIT during an eight-month build-up phase and maintenance phase and 21 controls avoided peanuts. We measured specific immunoglobulin E and G4 (IgE and IgG4) to peanuts and to Ara h 1, 2, 3, 8 and 9 and monitored adverse events, bronchial hyper-responsiveness (BHR) to methacholine and fractional concentrations of exhaled nitric oxide (FeNO). The median follow-up period was 30 months. RESULTS: Most (85%) of the OIT patients passed the build-up phase and 67% tolerated 5 g of peanuts during the post-treatment challenge. No controls were desensitised, with a risk ratio of 29 and 95% confidence interval of 1.9-455. During OIT, IgE to peanut, Ara h 1, 2 and 3 decreased and IgG4 increased. Consuming peanuts had no harmful effects on BHR or FeNO. The annual incidence rate of emergency visits during the follow-up period was 11% or 3.0 per 10 000 patient-days. CONCLUSION: Peanut OIT was efficacious in severe allergies without negative effects on airway inflammation, but unpredictable long-term reactions might occur.

Serum 25-Hydroxyvitamin D in Early Childhood Is Nonlinearly Associated with Allergy.

BACKGROUND: Vitamin D has several immunological functions. Data on the relation of vitamin D status and allergy are controversial. METHODS: We investigated the association between serum concentrations of 25-hydroxyvitamin D (25-OHD) and allergy in childhood. The study population (n = 819) was part of a randomized, double-blind, placebo-controlled trial where the mothers of offspring with a high risk for allergy received a mixture of probiotics (or placebo) for the last 4 weeks of pregnancy, and the child received this from birth to 6 months. Study subjects were followed for the emergence of sensitization and allergic symptoms for a period of 5 years, with medical examinations at the ages of 3 and 6 months, 2 and 5 years and also in the event of allergic symptoms. Levels of 25-OHD were measured in umbilical cord blood (UCB) samples (n = 724) and serum samples drawn at the age of 2 years (n = 369); the data were categorized into tertiles (T1-T3) and quartiles (Q1-Q4). The relation between 25-OHD levels and sensitization and allergy was analyzed with multivariable logistic regression analysis. RESULTS: 25-OHD levels in T2 in UCB were associated with a higher risk for sensitization by the age of 2 years and allergic disorders by the age of 5 years. In the serum samples, at the age of 2 years, 25-OHD levels in Q3 were associated with a higher risk of sensitization and IgE-mediated allergies by the age of 5 years. CONCLUSIONS: The 25-OHD levels in early childhood are associated with the emergence of allergy, but the association appears to be nonlinear.

Early-life gut microbiota associates with allergic rhinitis during 13-year follow-up in a Finnish probiotic intervention cohort.

Perinatal and early-life factors reported to affect risk of allergic diseases may be mediated by changes in the gut microbiota. Here, we explored the associations between the infant gut microbiota and allergic morbidity in childhood until 13 years of age in a subgroup of the FLORA probiotic intervention cohort. A mixture of four probiotic strains with galacto-oligosaccharides was administrated to the mothers from the 36th week of the pregnancy and later to their infants until 6 months of age. The infants were monitored for the manifestations of atopic eczema, food allergy, allergic rhinitis, and asthma by a pediatrician at 2 and 5 years of age; the allergic status was subsequently verified by a questionnaire at 10 and 13 years of age. The fecal microbiota at 3 months was profiled by 16S rRNA amplicon sequencing targeting the V3-V4 region, with and without adjusting for potentially important early-life factors. Overall, the positive diagnosis for allergic rhinitis between 2 and 13 years was associated with microbiota composition both in non-adjusted and adjusted models. This association was more pronounced in children born to one parent with confirmed atopic diseases compared to those who had two atopic parents and was characterized by a lower relative abundance of Bifidobacterium and Escherichia/Shigella spp. and a higher proportion of Bacteroides. While the probiotic and galacto-oligosaccharides intervention in the entire cohort was previously shown to reduce the prevalence of eczema to a certain extent, no associations were found between the 3-month gut microbiota and childhood eczema in the studied sub-cohort.IMPORTANCEAllergic diseases have increased in prevalence during the past decades globally. Although probiotics have been considered a promising strategy for preventing certain allergy related symptoms, studies connecting the infant gut microbiota and later life allergic morbidity in various populations remain limited. The present study supports an association between the infant microbiota and allergic morbidity after first years of life, which has been rarely examined.CLINICAL TRIALSRegistered at ClinicalTrials.gov (NCT00298337).

[Nut allergy - a difficult problem for the clinician]. / Pähkinäaallergia - vaikea ongelma kliinikolle.

Nuts belong to the most significant causes of food anaphylaxis in Finland. Diagnosis of nut allergy is complicated by the fact that for those having birch allergy, skin prick tests and serum tests yield a positive reaction for peanut and hazelnut without the nut causing the allergy reactions. For fear of anaphylaxis, avoidance of nuts on the basis of conventional tests measuring allergic sensitization leads to an unnecessary therapeutic diet. Attempts must be made to recognize patients for whom the ingestion of even minute doses of nuts may be life-threatening. For patients having severe symptoms, guidance counseling and first-aid medication are offered as a precaution for accidental exposure.

Impact of maternal allergy and use of probiotics during pregnancy on breast milk cytokines and food antibodies and development of allergy in children until 5 years.

BACKGROUND: Whether breast milk (BM) can protect against allergy has been studied extensively, with conflicting results. Variations in mothers' BM composition may explain some of the conflicting results. Our aim was to assess the impact of maternal allergy and probiotic intervention on BM food antibodies, transforming growth factor (TGF)-ß(2) and interleukin (IL)-10 and their impact on allergy development in children until the ages of 2 and 5. METHODS: We measured total IgA, IgA antibodies to cow's milk (CM), casein, ß-lactoglobulin and ovalbumin (OVA), TGF-ß(2) and IL-10 in 364 colostrum samples and 321 BM samples taken at 3 months from mothers participating in a prospective study evaluating the allergy-preventive effect of probiotics in a cohort with an increased risk for allergy. RESULTS: CM, casein and OVA antibodies, TGF-ß(2) and IL-10 were detectable in most samples. Maternal allergy was associated with raised levels of IgA to casein (p = 0.04) and lower levels of TGF-ß(2) (p = 0.006) in mature BM. Probiotic supplementation was associated with increased IL-10 (p = 0.046) and decreased casein IgA antibodies (p = 0.027) in mature BM. High OVA IgA antibodies in colostrum were associated with the development of atopy by the age of 2, while low levels in mature BM were a significant risk factor for the development of eczema by the age of 2. TGF-ß(2) levels in BM constituted a risk for development of allergy by the age of 2. CONCLUSIONS: The immunologic composition of BM was only slightly affected by maternal atopy and could be altered by probiotic supplementation. Small effects of BM components on allergy development in children were evident.

Protective and risk factors for allergic diseases in high-risk children at the ages of two and five years.

BACKGROUND: Environmental and lifestyle factors such as breast-feeding and pets seem to affect atopic disease prevalence. We identified risk factors for allergic diseases. METHODS: We prospectively followed until the age of 5 years a cohort of 1,223 children born into allergic families, who participated in a randomized placebo-controlled trial of probiotics as preventive against allergic disease. We evaluated the cumulative incidence of allergic diseases with questionnaires and examined all children at the ages of 2 and 5 years. RESULTS: Compared to allergy in one parent only, allergy in both parents conferred an increased risk of allergic disease at the ages of 2 (OR 1.64; 95% CI 1.11-2.42, p = 0.013) and 5 (OR 1.83; 95% CI 1.24-2.70, p = 0.002) and at the age of 2 for eczema (OR 1.74; 95% CI 1.17-2.58, p = 0.006). Exclusive breast-feeding over 2 months elevated the risk of eczema at the ages of 2 (OR 1.73; 95% CI 1.15-2.61, p = 0.009) and 5 (OR 1.51; 95% CI 1.03-2.23, p = 0.036). Cat or dog exposure at 0-2 years and at 0-5 years protected against IgE sensitization until 5 years of age (OR 0.60; 95% CI 0.37-1.00, p = 0.048, and OR 0.61; 95% CI 0.39-0.96, p = 0.033), and exposure at the ages of 0-5 years protected against allergic rhinitis until the age of 5 (OR 0.46; 95% CI 0.25-0.85, p = 0.013) in the probiotic group. CONCLUSIONS: Allergy in both parents is an independent predictor of eczema and of allergic disease until the ages of 2 and 5. Long, exclusive breast-feeding was associated with increased eczema at the ages of 2 and 5, and cat or dog exposure was associated with decreased IgE sensitization and allergic rhinitis in the probiotic group.

Gut microbiota develop towards an adult profile in a sex-specific manner during puberty.

Accumulating evidence indicates that gut microbiota may regulate sex-hormone levels in the host, with effects on reproductive health. Very little is known about the development of intestinal microbiota during puberty in humans. To assess the connection between pubertal timing and fecal microbiota, and to assess how fecal microbiota develop during puberty in comparison with adult microbiota, we utilized a Finnish allergy-prevention-trial cohort (Flora). Data collected at 13-year follow-up were compared with adult data from a different Finnish cohort. Among the 13-year-old participants we collected questionnaire information, growth data from school-health-system records and fecal samples from 148 participants. Reference adult fecal samples were received from the Health and Early Life Microbiota (HELMi) cohort (n = 840). Fecal microbiota were analyzed using 16S rRNA gene amplicon sequencing; the data were correlated with pubertal timing and compared with data on adult microbiota. Probiotic intervention in the allergy-prevention-trial cohort was considered as a confounding factor only. The main outcome was composition of the microbiota in relation to pubertal timing (time to/from peak growth velocity) in both sexes separately, and similarity to adult microbiota. In girls, fecal microbiota became more adult-like with pubertal progression (p = 0.009). No such development was observed in boys (p = 0.9). Both sexes showed a trend towards increasing relative abundance of estrogen-metabolizing Clostridia and decreasing Bacteroidia with pubertal development, but this was statistically significant in girls only (p = 0.03). In girls, pubertal timing was associated positively with exposure to cephalosporins prior to the age of 10. Our data support the hypothesis that gut microbiota, particularly members of Ruminococcaceae, may affect pubertal timing, possibly via regulating host sex-hormone levels.Trial registration The registration number for the allergy-prevention-trial cohort: ClinicalTrials.gov, NCT00298337, registered 1 March 2006-Retrospectively registered, https://clinicaltrials.gov/show/NCT00298337 . The adult-comparison cohort (HELMi) is NCT03996304.