Divergent maturational patterns of the infant bacterial and fungal gut microbiome in the first year of life are associated with inter-kingdom community dynamics and infant nutrition.

BACKGROUND: The gut microbiome undergoes primary ecological succession over the course of early life before achieving ecosystem stability around 3 years of age. These maturational patterns have been well-characterized for bacteria, but limited descriptions exist for other microbiota members, such as fungi. Further, our current understanding of the prevalence of different patterns of bacterial and fungal microbiome maturation and how inter-kingdom dynamics influence early-life microbiome establishment is limited. RESULTS: We examined individual shifts in bacterial and fungal alpha diversity from 3 to 12 months of age in 100 infants from the CHILD Cohort Study. We identified divergent patterns of gut bacterial or fungal microbiome maturation in over 40% of infants, which were characterized by differences in community composition, inter-kingdom dynamics, and microbe-derived metabolites in urine, suggestive of alterations in the timing of ecosystem transitions. Known microbiome-modifying factors, such as formula feeding and delivery by C-section, were associated with atypical bacterial, but not fungal, microbiome maturation patterns. Instead, fungal microbiome maturation was influenced by prenatal exposure to artificially sweetened beverages and the bacterial microbiome, emphasizing the importance of inter-kingdom dynamics in early-life colonization patterns. CONCLUSIONS: These findings highlight the ecological and environmental factors underlying atypical patterns of microbiome maturation in infants, and the need to incorporate multi-kingdom and individual-level perspectives in microbiome research to improve our understandings of gut microbiome maturation patterns in early life and how they relate to host health. Video Abstract.

Delayed gut microbiota maturation in the first year of life is a hallmark of pediatric allergic disease.

Allergic diseases affect millions of people worldwide. An increase in their prevalence has been associated with alterations in the gut microbiome, i.e., the microorganisms and their genes within the gastrointestinal tract. Maturation of the infant immune system and gut microbiota occur in parallel; thus, the conformation of the microbiome may determine if tolerant immune programming arises within the infant. Here we show, using deeply phenotyped participants in the CHILD birth cohort (n = 1115), that there are early-life influences and microbiome features which are uniformly associated with four distinct allergic diagnoses at 5 years: atopic dermatitis (AD, n = 367), asthma (As, n = 165), food allergy (FA, n = 136), and allergic rhinitis (AR, n = 187). In a subset with shotgun metagenomic and metabolomic profiling (n = 589), we discover that impaired 1-year microbiota maturation may be universal to pediatric allergies (AD p = 0.000014; As p = 0.0073; FA p = 0.00083; and AR p = 0.0021). Extending this, we find a core set of functional and metabolic imbalances characterized by compromised mucous integrity, elevated oxidative activity, decreased secondary fermentation, and elevated trace amines, to be a significant mediator between microbiota maturation at age 1 year and allergic diagnoses at age 5 years (ßindirect = -2.28; p = 0.0020). Microbiota maturation thus provides a focal point to identify deviations from normative development to predict and prevent allergic disease.

Maturational patterns of the infant gut mycobiome are associated with early-life body mass index.

Unlike the bacterial microbiome, the role of early-life gut fungi in host metabolism and childhood obesity development remains poorly characterized. To address this, we investigate the relationship between the gut mycobiome of 100 infants from the Canadian Healthy Infant Longitudinal Development (CHILD) Cohort Study and body mass index Z scores (BMIz) in the first 5 years of life. An increase in fungal richness during the first year of life is linked to parental and infant BMI. The relationship between richness pattern and early-life BMIz is modified by maternal BMI, maternal diet, infant antibiotic exposure, and bacterial beta diversity. Further, the abundances of Saccharomyces, Rhodotorula, and Malassezia are differentially associated with early-life BMIz. Using structural equation modeling, we determine that the mycobiome's contribution to BMIz is likely mediated by the bacterial microbiome. This demonstrates that mycobiome maturation and infant growth trajectories are distinctly linked, advocating for inclusion of fungi in larger pediatric microbiome studies.

Breastfeeding enrichment of B. longum subsp. infantis mitigates the effect of antibiotics on the microbiota and childhood asthma risk.

BACKGROUND: Early antibiotic exposure is linked to persistent disruption of the infant gut microbiome and subsequent elevated pediatric asthma risk. Breastfeeding acts as a primary modulator of the gut microbiome during early life, but its effect on asthma development has remained unclear. METHODS: We harnessed the CHILD cohort to interrogate the influence of breastfeeding on antibiotic-associated asthma risk in a subset of children (n = 2,521). We then profiled the infant microbiomes in a subset of these children (n = 1,338) using shotgun metagenomic sequencing and compared human milk oligosaccharide and fatty acid composition from paired maternal human milk samples for 561 of these infants. FINDINGS: Children who took antibiotics without breastfeeding had 3-fold higher asthma odds, whereas there was no such association in children who received antibiotics while breastfeeding. This benefit was associated with widespread "re-balancing" of taxonomic and functional components of the infant microbiome. Functional changes associated with asthma protection were linked to enriched Bifidobacterium longum subsp. infantis colonization. Network analysis identified a selection of fucosylated human milk oligosaccharides in paired maternal samples that were positively associated with B. infantis and these broader functional changes. CONCLUSIONS: Our data suggest that breastfeeding and antibiotics have opposing effects on the infant microbiome and that breastfeeding enrichment of B. infantis is associated with reduced antibiotic-associated asthma risk. FUNDING: This work was supported in part by the Canadian Institutes of Health Research; the Allergy, Genes and Environment Network of Centres of Excellence; Genome Canada; and Genome British Columbia.

Development of a Symptom-Based Tool for Screening of Children at High Risk of Preschool Asthma.

Importance: Despite advances in asthma therapeutics, the burden remains highest in preschool children; therefore, it is critical to identify primary care tools that distinguish preschool children at high risk for burdensome disease for further evaluation. Current asthma prediction tools, such as the modified Asthma Predictive Index (mAPI), require invasive tests, limiting their applicability in primary care and low-resource settings. Objective: To develop and evaluate the use of a symptom-based screening tool to detect children at high risk of asthma, persistent wheeze symptoms, and health care burden. Design, Setting, and Participants: The cohort for this diagnostic study included participants from the CHILD Study (n = 2511) from January 1, 2008, to December 31, 2012, the Raine Study from January 1, 1989, to December 31, 2012 (n = 2185), and the Canadian Asthma Primary Prevention Study (CAPPS) from January 1, 1989, to December 31, 1995 (n = 349), with active follow-up to date. Data analysis was performed from November 1, 2019, to May 31, 2022. Exposures: The CHILDhood Asthma Risk Tool (CHART) identified factors associated with asthma in patients at 3 years of age (timing and number of wheeze or cough episodes, use of asthma medications, and emergency department visits or hospitalizations for asthma or wheeze) to identify children with asthma or persistent symptoms at 5 years of age. Main Outcomes and Measures: Within the CHILD Study cohort, CHART was evaluated against specialist clinician diagnosis and the mAPI. External validation was performed in both a general population cohort (Raine Study [Australia]) and a high-risk cohort (CAPPS [Canada]). Predictive accuracy was measured by sensitivity, specificity, area under the receiver operating characteristic curve (AUROC), and positive and negative predicted values. Results: Among 2511 children (mean [SD] age at 3-year clinic visit, 3.08 [0.17] years; 1324 [52.7%] male; 1608 of 2476 [64.9%] White) with sufficient questionnaire data to apply CHART at 3 years of age, 2354 (93.7%) had available outcome data at 5 years of age. CHART applied in the CHILD Study at 3 years of age outperformed physician assessments and the mAPI in predicting persistent wheeze (AUROC, 0.94; 95% CI, 0.90-0.97), asthma diagnosis (AUROC, 0.73; 95% CI, 0.69-0.77), and health care use (emergency department visits or hospitalization for wheeze or asthma) (AUROC, 0.70; 95% CI, 0.61-0.78). CHART had a similar predictive performance for persistent wheeze in the Raine Study (N = 2185) in children at 5 years of age (AUROC, 0.82; 95% CI, 0.79-0.86) and CAPPS (N = 349) at 7 years of age (AUROC, 0.87; 95% CI, 0.80-0.94). Conclusions and Relevance: In this diagnostic study, CHART was able to identify children at high risk of asthma at as early as 3 years of age. CHART could be easily incorporated as a routine screening tool in primary care to identify children who need monitoring, timely symptom control, and introduction of preventive therapies.

From Prescription Drugs to Natural Health Products: Medication Use in Canadian Infants.

Limited data exist on pharmaceutical product use by infants, although available data suggests higher prevalence of use among children under 12 months of age. We conducted a descriptive study of 3050 infants recruited in the CHILD Cohort Study, a prospective, multicenter, longitudinal cohort following children from pregnancy through childhood. Parents were surveyed for use of prescription and over-the-counter drugs, and natural health products (NHPs, including homeopathic products and vitamins) at 3, 6, and 12 months after delivery. By one year of age, 96.0% of children had taken at least one pharmaceutical product. Among 307 reported products, 32 were given to at least 1% of cohort infants. Vitamin D, acetaminophen, ibuprofen, topical hydrocortisone, amoxicillin, and nystatin were the most common medications and natural health products (NHPs) received, with 8/32 of the most frequently used products being NHPs. Overall, 14.7% of pharmaceutical products administered to children were off-label and 35.8% were NHPs or products without a Drug Identification Number (DIN). The use of over-the-counter medications and NHPs is common and off-label use of drugs is frequent, even in the first year of life. This study highlights the importance of conducting studies on medication use in infants, and of infant medication use monitoring by healthcare providers.

Longitudinal Associations Between Sleep Habits, Screen Time and Overweight, Obesity in Preschool Children.

Introduction: Decreased sleep duration and increased screen time as early as preschool age may contribute to overweight and obesity. The effects of bedtime together with nocturnal sleep duration remain unclear with a paucity of data evaluating these associations longitudinally. We aim to evaluate the independent and joint effects of sleep duration, sleep bedtime, and screen time at 3 years of age on BMI status, particularly overweight and obesity by age 5 years. Methods: Data from 2185 participants of the CHILD Cohort Study were analyzed longitudinally using generalized estimating equations (GEE). Models included changes in overweight/obesity status from 3 to 5 years of age as outcome, and nocturnal sleep duration, bedtime, and daily screen time at 3 years of age as explanatory variables. The joint effects of nocturnal sleep time and excess screen time, late bedtime on overweight/obesity were subsequently analyzed. Results: The median nocturnal sleep time at 3 and 5 years of age was 11.0 hours/night [IQR 10.5, 11.5]. A total of 14.5% children went to bed after 9PM at 3 years and 7.2% at 5 years. Median screen time was 1.0 hr/day [IQR 1.0, 2.0] at both ages. Longitudinal analyses showed that sleeping less than 10.5 hours at age 3 years was associated with 46% greater odds of overweight/obesity by age 5 years (OR 1.46, 95% CI 1.07, 2.00). The risk was higher when coupled with late bedtime after 9pm (OR 1.60, 95% CI 1.12, 2.31). Children with both short nocturnal sleep duration and excess screen time (>1hr/day) had twice the associated risk of overweight/obesity by age 5 years (OR 1.96, 95% CI 1.34, 2.88). Conclusion: Nocturnal sleep duration and screen time are modifiable risk factors in young children, which may have important implications for obesity prevention as early as infancy.

Longitudinal body mass index trajectories at preschool age: children with rapid growth have differential composition of the gut microbiota in the first year of life.

BACKGROUND/OBJECTIVE: The steep rise in childhood obesity has emerged as a worldwide public health problem. The first 4 years of life are a critical window where long-term developmental patterns of body mass index (BMI) are established and a critical period for microbiota maturation. Understanding how the early-life microbiota relate to preschool growth may be useful for identifying preventive interventions for childhood obesity. We aim to investigate whether longitudinal shifts within the bacterial community between 3 months and 1 year of life are associated with preschool BMI z-score trajectories. METHODS: BMI trajectories from birth to 5 years of age were identified using group-based trajectory modeling in 3059 children. Their association with familial and environmental factors were analyzed. Infant gut microbiota at 3 months and 1 year was defined by 16S RNA sequencing and changes in diversity and composition within each BMIz trajectory were analyzed. RESULTS: Four BMIz trajectories were identified: low stable, normative, high stable, and rapid growth. Infants in the rapid growth trajectory were less likely to have been breastfed, and gained less microbiota diversity in the first year of life. Relative abundance of Akkermansia increased with age in children with stable growth, but decreased in those with rapid growth, abundance of Ruminococcus and Clostridium at 1 year were elevated in children with rapid growth. Children who were breastfed at 6 months had increased levels of Sutterella, and decreased levels of Ruminococcus and Clostridium. CONCLUSION: This study provides new insights into the relationship between the gut microbiota in infancy and patterns of growth in a cohort of preschool Canadian children. We highlight that rapid growth since birth is associated with bacteria shown in animal models to have a causative role in weight gain. Our findings support a novel avenue of research targeted on tangible interventions to reduce childhood obesity.

Wheeze trajectories: Determinants and outcomes in the CHILD Cohort Study.

BACKGROUND: Wheezing in early life is associated with asthma in adulthood; however, the determinants of wheezing trajectories and their associations with asthma and lung function in childhood remain poorly understood. OBJECTIVE: In the CHILD Cohort Study, we aimed to identify wheezing trajectories and examine the associations between these trajectories, risk factors, and clinical outcomes at age 5 years. METHODS: Wheeze data were collected at 8 time points from 3 months to 5 years of age. We used group-based trajectory models to derive wheeze trajectories among 3154 children. Associations with risk factors and clinical outcomes were analyzed by weighted regression models. RESULTS: We identified 4 trajectories: a never/infrequent trajectory, transient wheeze, intermediate-onset (preschool) wheeze, and persistent wheeze. Higher body mass index was a common risk factor for all wheeze trajectories compared with that in the never/infrequent group. The unique predictors for specific wheeze trajectories included male sex, lower respiratory tract infections, and day care attendance for transient wheeze; paternal history of asthma, atopic sensitization, and child genetic risk score of asthma for intermediate wheeze; and maternal asthma for persistent wheeze. Blood eosinophil counts were higher in children with the intermediate wheeze trajectory than in those children with the other trajectories at the ages of 1 and 5 years. All wheeze trajectories were associated with decreased lung function and increased risk of asthma at age 5 years. CONCLUSIONS: We identified 4 distinct trajectories in children from 3 months to 5 years of age, reflecting different phenotypes of early childhood wheeze. These trajectories were characterized by different biologic and physiologic traits and risk factors.

Early-life cytomegalovirus infection is associated with gut microbiota perturbations and increased risk of atopy.

BACKGROUND: The "old friends" hypothesis posits that reduced exposure to previously ubiquitous microorganisms is one factor involved in the increased rates of allergic diseases. Cytomegalovirus (CMV) may be one of the "old friends" hypothesized to help prevent allergic diseases. We sought to elucidate whether early-life CMV infection is associated with childhood atopy via perturbations of the gut microbiota. METHODS: Participants were recruited from a population-based birth cohort (CHILD study) and followed prospectively until age 5 years in four Canadian cities. A total of 928 participants provided stool microbiome data, urine for CMV testing, skin prick tests, and questionnaire-based detailed environmental exposures. Cytomegalovirus infection was assessed in the first year of life while the main outcome was defined by persistent sensitization to any allergen at ages 1, 3, and 5 years. RESULTS: Early CMV infection was associated with increased beta and decreased alpha diversity of the gut microbiota. Both changes in diversity measures and early CMV infection were associated with persistent allergic sensitization at age 5 years (aOR = 2.08; 95% CI: 1, 4.33). Mediation analysis demonstrated that perturbation of gut microbial composition explains 30% of the association. CONCLUSIONS: Early-life CMV infection is associated with an alteration in the intestinal microbiota, which mediates the effect of the infection on childhood atopy. This work indicates that preventing CMV infection would not put children at increased risk of developing atopy. Rather, a CMV vaccine, in addition to preventing CMV-associated morbidity and mortality, might reduce the risk of childhood allergic diseases.

Assessing secondhand and thirdhand tobacco smoke exposure in Canadian infants using questionnaires, biomarkers, and machine learning.

BACKGROUND: As smoking prevalence has decreased in Canada, particularly during pregnancy and around children, and technological improvements have lowered detection limits, the use of traditional tobacco smoke biomarkers in infant populations requires re-evaluation. OBJECTIVE: We evaluated concentrations of urinary nicotine biomarkers, cotinine and trans-3'-hydroxycotinine (3HC), and questionnaire responses. We used machine learning and prediction modeling to understand sources of tobacco smoke exposure for infants from the CHILD Cohort Study. METHODS: Multivariable linear regression models, chosen through a combination of conceptual and data-driven strategies including random forest regression, assessed the ability of questionnaires to predict variation in urinary cotinine and 3HC concentrations of 2017 3-month-old infants. RESULTS: Although only 2% of mothers reported smoking prior to and throughout their pregnancy, cotinine and 3HC were detected in 76 and 89% of the infants' urine (n = 2017). Questionnaire-based models explained 31 and 41% of the variance in cotinine and 3HC levels, respectively. Observed concentrations suggest 0.25 and 0.50 ng/mL as cut-points in cotinine and 3HC to characterize SHS exposure. This cut-point suggests that 23.5% of infants had moderate or regular smoke exposure. SIGNIFICANCE: Though most people make efforts to reduce exposure to their infants, parents do not appear to consider the pervasiveness and persistence of secondhand and thirdhand smoke. More than half of the variation in urinary cotinine and 3HC in infants could not be predicted with modeling. The pervasiveness of thirdhand smoke, the potential for dermal and oral routes of nicotine exposure, along with changes in public perceptions of smoking exposure and risk warrant further exploration.

Lung clearance index predicts persistence of preschool wheeze.

BACKGROUND: The lung clearance index (LCI) is a measure of pulmonary function. Variable feasibility (50->80%) in preschool children has been reported. There are limited studies exploring its relationship to respiratory symptoms and how it predicts persistent wheeze. We aimed to assess the association with respiratory symptoms in preschool-aged children with LCI and determine its utility in predicting persistent wheeze. METHODS: LCI was measured in a subcohort of the CHILD Cohort Study at age 3 years using SF6  multiple breath washout test mass spectrometry. Respiratory symptom phenotypes at age 3 were derived from children's respiratory symptoms reported by their parents. Responses were used to categorize children into 4 symptom groups: recurrent wheeze (3RW), recurrent cough (3RC), infrequent symptoms (IS), and no current symptoms (NCS). At age 5 years, these children were seen by a specialist clinician and assessed for persistent wheeze (PW). RESULTS: At age 3 years, 69% (234/340) had feasible LCI. Excluding two children with missing data, 232 participants were categorized as follows: 33 (14%) 3RW; 28 (12%) 3RC; 17 (7%) IS; and 154 (66%) NCS. LCI z-score at age 3 years was highest in children with 3RW compared to 3RC (mean (SD): 1.14 (1.56) vs. 0.09 (0.95), p < .01), IS (mean (SD): -0.14 (0.59), p < .01), and NCS (mean (SD): -0.08 (1.06), p < .01). LCI z-score at age 3 was predictive of persistent wheeze at age 5 (PW) (AUROC: 0.87). CONCLUSIONS: LCI at age 3 was strongly associated with recurrent wheeze at age 3, and predictive of its persistence to age 5.

Factors associated with breast-feeding initiation and continuation in Canadian-born and non-Canadian-born women: a multi-centre study.

OBJECTIVE: To identify factors associated with breast-feeding initiation and continuation in Canadian-born and non-Canadian-born women. DESIGN: Prospective cohort of mothers and infants born from 2008 to 2012: the Canadian Healthy Infant Longitudinal Development (CHILD) Cohort Study. SETTING: General community setting in four Canadian provinces. PARTICIPANTS: In total, 3455 pregnant women from Vancouver, Edmonton, Winnipeg and Toronto between 2008 and 2012. RESULTS: Of 3010 participants included in the current study, the majority were Canadian-born (75·5 %). Breast-feeding initiation rates were high in both non-Canadian-born (95·5 %) and Canadian-born participants (92·7 %). The median breast-feeding duration was 10 months in Canadian-born participants and 11 months in non-Canadian-born participants. Among Canadian-born participants, factors associated with breast-feeding initiation and continuation were older maternal age, higher maternal education, living with their partner and recruitment site. Rooming-in during the hospital stay was also associated with higher rates of breast-feeding initiation, but not continuation at 6-month postpartum. Factors associated with non-initiation of breast-feeding and cessation at 6-month postpartum were maternal smoking, living with a current smoker, caesarean birth and early-term birth. Among non-Canadian-born participants, maternal smoking during pregnancy was associated with lower odds of breast-feeding initiation and lower odds of breast-feeding continuation at 6 months, and older maternal age and recruitment site were associated with breast-feeding continuation at 6 months. CONCLUSIONS: Although Canadian-born and non-Canadian-born women in the CHILD cohort have similar breast-feeding initiation rates, breast-feeding initiation and continuation are more strongly associated with socio-demographic characteristics in Canadian-born participants. Recruitment site was strongly associated with breast-feeding continuation in both groups and may indicate geographic disparities in breast-feeding rates nationally.

World Health Organization growth standards: How do Canadian children measure up?

BACKGROUND: World Health Organization (WHO) growth standards for children aged 0 to 5 years describe growth under optimal conditions and were adopted for use in Canada in 2012. We are seeking to validate these charts in a well-characterized, longitudinal cohort of healthy, Canadian youngsters, assess tracking over time, and evaluate the prognostic implications of early growth. METHODS: Data from 2,795 mother-infant dyads from the CHILD birth cohort were classified by feeding modality at 6 months as exclusively breastfed, partially breastfed, or formula-fed. WHO z-scores (z) were calculated at birth, 3 months, 1 year, and 3 years. Receiver operator characteristics (ROC) assessed the predictive performance of early weight (WT), weight-for-length (WfL), or body mass index (BMI) z-scores for overweight/obesity at 3 years. RESULTS: Compared to WHO standards, Canadian children at birth had lower median WfLz (-0.73) and BMIz (-0.29), with more positive scores by 3 years (WfLz=BMIz=0.58). At both 1 and 3 years, formula feeding was associated with higher scores than breastfeeding, even after regression adjustment for covariates. Head circumference z-score was typically positive at all times and regardless of feeding modality. At 1 year, ROC area under the curve was 0.79 for WTz, WfLz, and BMIz, and BMIz>0.88 identified children with increased risk of overweight/obesity (BMIz >2) at age 3 years (20.3% versus 3.0%, P<0.001). CONCLUSIONS: Compared to WHO growth charts, Canadian children at 3 years show an upward shift in BMIz and WfLz, particularly when formula-fed. Infant growth parameters may identify infants with increased risk of overweight/obesity at age 3 years; early recognition may allow targeting infants at higher risk.

Breastfeeding in the First Days of Life Is Associated With Lower Blood Pressure at 3 Years of Age.

Background Breastfeeding in infancy is associated with lower cardiovascular disease risk in adulthood; however, the amount of breastfeeding required to achieve this benefit is unknown. Methods and Results In the CHILD (Canadian Healthy Infant Longitudinal Development) Cohort Study, we analyzed 2382 children with complete data on early life feeding and blood pressure. Infant feeding was documented from hospital records in the first few days of life and reported by mothers throughout infancy. Blood pressure was measured at 3 years of age. Analyses controlled for birth weight, gestational age, socioeconomic status, maternal body mass index, and other potential confounders. We found that nearly all children (2333/2382; 97.9%) were ever breastfed, of whom 98 (4.2%) only briefly received breast milk during their birth hospitalization ("early limited breastfeeding"). At 3 years of age, blood pressure was higher in children who were never breastfed (mean systolic/diastolic 103/60 mm Hg) compared with those who were ever breastfed (99/58 mm Hg), including those who received only early limited breastfeeding (99/57 mm Hg). These differences in systolic blood pressure persisted in adjusted models (ever breastfed: -3.47 mm Hg, 95% CI, -6.14 to -0.80; early limited breastfeeding: -4.24 mm Hg, 95% CI, -7.45 to -1.04). Among breastfed children, there was no significant dose-response association according to the duration or exclusivity of breastfeeding. Associations were not mediated by child body mass index. Conclusions Although the benefits of sustained and exclusive breastfeeding are indisputable, this study indicates any breastfeeding, regardless of duration or exclusivity, is associated with lower blood pressure at 3 years of age. Further research examining the bioactive components of early breast milk, underlying mechanisms, and long-term associations is warranted.

A rich meconium metabolome in human infants is associated with early-life gut microbiota composition and reduced allergic sensitization.

Microbiota maturation and immune development occur in parallel with, and are implicated in, allergic diseases, and research has begun to demonstrate the importance of prenatal influencers on both. Here, we investigate the meconium metabolome, a critical link between prenatal exposures and both early microbiota and immune development, to identify components of the neonatal gut niche that contribute to allergic sensitization. Our analysis reveals that newborns who develop immunoglobulin E (IgE)-mediated allergic sensitization (atopy) by 1 year of age have a less-diverse gut metabolome at birth, and specific metabolic clusters are associated with both protection against atopy and the abundance of key taxa driving microbiota maturation. These metabolic signatures, when coupled with early-life microbiota and clinical factors, increase our ability to accurately predict whether or not infants will develop atopy. Thus, the trajectory of both microbiota colonization and immune development are significantly affected by metabolites present in the neonatal gut at birth.

Bacteroides-dominant gut microbiome of late infancy is associated with enhanced neurodevelopment.

Dysbiosis of gut microbiota has been retrospectively linked to autism spectrum disorders but the temporal association between gut microbiota and early neurodevelopment in healthy infants is largely unknown. We undertook this study to determine associations between gut microbiota at two critical periods during infancy and neurodevelopment in a general population birth cohort.Here, we analyzed data from 405 infants (199 females) from the CHILD (Canadian Healthy Infant Longitudinal Development) Cohort Study. Neurodevelopmental outcomes were objectively assessed using the Bayley Scale of Infant Development (BSID-III) at 1 and 2 years of age. Microbiota profiling with 16S rRNA gene sequencing was conducted on fecal samples obtained at a mean age of 4 and 12 months.Using clustering methods, we identified three groups of infants based on relative abundance of gut microbiota at 12 months: Proteobacteria-dominant cluster (22.4% higher abundance at 12 months), Firmicutes-dominant cluster (46.0% higher abundance at 12 months) and Bacteroidetes-dominant cluster (31.6% higher abundance at 12 months). Relative to the Proteobacteria-dominant cluster, the Bacteroidetes-dominant cluster was associated with higher scores for cognitive (4.8 points; FDRp = .02), language (4.2 points; FDRp≤0.001), and motor (3.1 points; FDRp = .03) development at age 2 in models adjusted for covariates. When stratified by sex, only male infants with a Bacteroidetes-dominant microbiota had more favorable cognitive (5.9 points, FDRp = .06) and language (7.9 points; FDRp≤0.001) development. Genus Bacteroides abundance in gut microbiota was positively correlated with cognitive and language scores at age 2. Fully adjusted linear mixed model analysis revealed a positive association between Bacteroidetes-dominant cluster and change in cognitive and language performance from 1 to 2 years, predominantly among males. No associations were evident between 4-month microbiota clusters and BSID-II scores. Noteworthy is that enhanced sphingolipid synthesis and metabolism, and antagonism or competition between Bacteroides and Streptococcus were characteristic of a Bacteroidetes-dominant gut microbiota.This study found strong evidence of positive associations between Bacteroidetes gut microbiota in late infancy and subsequent neurodevelopment, most prominently among males but not females.

Composition and Associations of the Infant Gut Fungal Microbiota with Environmental Factors and Childhood Allergic Outcomes.

Although often neglected in gut microbiota studies, recent evidence suggests that imbalanced, or dysbiotic, gut mycobiota (fungal microbiota) communities in infancy coassociate with states of bacterial dysbiosis linked to inflammatory diseases such as asthma. In the present study, we (i) characterized the infant gut mycobiota at 3 months and 1 year of age in 343 infants from the CHILD Cohort Study, (ii) defined associations among gut mycobiota community composition and environmental factors for the development of inhalant allergic sensitization (atopy) at age 5 years, and (iii) built a predictive model for inhalant atopy status at age 5 years using these data. We show that in Canadian infants, fungal communities shift dramatically in composition over the first year of life. Early-life environmental factors known to affect gut bacterial communities were also associated with differences in gut fungal community alpha diversity, beta diversity, and/or the relative abundance of specific fungal taxa. Moreover, these metrics differed among healthy infants and those who developed inhalant allergic sensitization (atopy) by age 5 years. Using a rationally selected set of early-life environmental factors in combination with fungal community composition at 1 year of age, we developed a machine learning logistic regression model that predicted inhalant atopy status at 5 years of age with 81% accuracy. Together, these data suggest an important role for the infant gut mycobiota in early-life immune development and indicate that early-life behavioral or therapeutic interventions have the potential to modify infant gut fungal communities, with implications for an infant's long-term health. IMPORTANCE Recent evidence suggests an immunomodulatory role for commensal fungi (mycobiota) in the gut, yet little is known about the composition and dynamics of early-life gut fungal communities. In this work, we show for the first time that the composition of the gut mycobiota of Canadian infants changes dramatically over the course of the first year of life, is associated with environmental factors such as geographical location, diet, and season of birth, and can be used in conjunction with knowledge of a small number of key early-life factors to predict inhalant atopy status at age 5 years. Our study highlights the importance of considering fungal communities as indicators or inciters of immune dysfunction preceding the onset of allergic disease and can serve as a benchmark for future studies aiming to examine infant gut fungal communities across birth cohorts.