The potential importance of the built-environment microbiome and its impact on human health.

There is increasing evidence that interactions between microbes and their hosts not only play a role in determining health and disease but also in emotions, thought, and behavior. Built environments greatly influence microbiome exposures because of their built-in highly specific microbiomes coproduced with myriad metaorganisms including humans, pets, plants, rodents, and insects. Seemingly static built structures host complex ecologies of microorganisms that are only starting to be mapped. These microbial ecologies of built environments are directly and interdependently affected by social, spatial, and technological norms. Advances in technology have made these organisms visible and forced the scientific community and architects to rethink gene-environment and microbe interactions respectively. Thus, built environment design must consider the microbiome, and research involving host-microbiome interaction must consider the built-environment. This paradigm shift becomes increasingly important as evidence grows that contemporary built environments are steadily reducing the microbial diversity essential for human health, well-being, and resilience while accelerating the symptoms of human chronic diseases including environmental allergies, and other more life-altering diseases. New models of design are required to balance maximizing exposure to microbial diversity while minimizing exposure to human-associated diseases. Sustained trans-disciplinary research across time (evolutionary, historical, and generational) and space (cultural and geographical) is needed to develop experimental design protocols that address multigenerational multispecies health and health equity in built environments.

Antibiotics within first year are linked to infant gut microbiome disruption and elevated atopic dermatitis risk.

BACKGROUND: Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in both pediatric and adult populations. The development of AD has been linked to antibiotic usage, which causes perturbation of the microbiome and has been associated with abnormal immune system function. However, imbalances in the gut microbiome itself associated with antibiotic usage have been inconsistently linked to AD. OBJECTIVE: This study aimed to elucidate the timing and specific factors mediating the relationship between systemic (oral or intravenous) antibiotic usage and AD. METHODS: We used statistical modelling and differential analysis to link CHILD participants' history of antibiotic usage and early-life gut microbiome alterations to atopic dermatitis. RESULTS: Here we report that systemic antibiotics during the first year of life, as compared to later, are associated with AD risk (adjusted odds ratio (aOR) = 1.81 [95% CI = 1.28 - 2.57], p < 0.001), with an increased number of antibiotic courses corresponding to a dose-response-like increased risk of AD risk (1 course: aOR = 1.67 [95% CI = 1.17 - 2.38]; 2 or more courses: aOR = 2.16 [95% CI = 1.30 - 3.59]). Further, we demonstrate that microbiome alterations associated with both AD and systemic antibiotic usage fully mediate the effect of antibiotic usage on the development of AD (ßindirect = 0.072, p < 0.001). Alterations in the 1-year infant gut microbiome of participants who would later develop AD included increased Tyzzerella nexilis, increased monosaccharide utilization, and parallel decreased Bifidobacterium, Eubacterium spp., and fermentative pathways. CONCLUSION: Our findings indicate that early-life antibiotic usage, especially in the first year of life, modulates key gut microbiome components that may be used as markers to predict and possibly prevent the development of AD.

The use of prescription medications and non-prescription medications during lactation in a prospective Canadian cohort study.

BACKGROUND: A lack of safety data on postpartum medication use presents a potential barrier to breastfeeding and may result in infant exposure to medications in breastmilk. The type and extent of medication use by lactating women requires investigation. METHODS: Data were collected from the CHILD Cohort Study which enrolled pregnant women across Canada between 2008 and 2012. Participants completed questionnaires regarding medications and non-prescription medications used and breastfeeding status at 3, 6 and 12 months postpartum. Medications, along with self-reported reasons for medication use, were categorized by ontologies [hierarchical controlled vocabulary] as part of a large-scale curation effort to enable more robust investigations of reasons for medication use. RESULTS: A total of 3542 mother-infant dyads were recruited to the CHILD study. Breastfeeding rates were 87.4%, 75.3%, 45.5% at 3, 6 and 12 months respectively. About 40% of women who were breastfeeding at 3 months used at least one prescription medication during the first three months postpartum; this proportion decreased over time to 29.5% % at 6 months and 32.8% at 12 months. The most commonly used prescription medication by breastfeeding women was domperidone at 3 months (9.0%, n = 229/2540) and 6 months (5.6%, n = 109/1948), and norethisterone at 12 months (4.1%, n = 48/1180). The vast majority of domperidone use by breastfeeding women (97.3%) was for lactation purposes which is off-label (signifying unapproved use of an approved medication). Non-prescription medications were more often used among breastfeeding than non-breastfeeding women (67.6% versus 48.9% at 3 months, p < 0.0001), The most commonly used non-prescription medications were multivitamins and Vitamin D at 3, 6 and 12 months postpartum. CONCLUSIONS: In Canada, medication use is common postpartum; 40% of breastfeeding women use prescription medications in the first 3 months postpartum. A diverse range of medications were used, with many women taking more than one prescription and non-prescription medicines. The most commonly used prescription medication by breastfeeding women were domperidone for off-label lactation support, signalling a need for more data on the efficacy of domperidone for this indication. This data should inform research priorities and communication strategies developed to optimize care during lactation.

Association of Human Milk Fatty Acid Composition with Maternal Cardiometabolic Diseases: An Exploratory Prospective Cohort Study.

Background: Human milk fatty acids derive from maternal diet, body stores, and mammary synthesis and may reflect women's underlying cardiometabolic health. We explored whether human milk fatty acid composition was associated with maternal cardiometabolic disease (CMD) during pregnancy and up to 5 years postpartum. Materials and Methods: We analyzed data from the prospective CHILD Cohort Study on 1,018 women with no preexisting CMD who provided breast milk samples at 3-4 months postpartum. Milk fatty acid composition was measured using gas-liquid chromatography. Maternal CMD (diabetes or hypertension) was classified using questionnaires and birth records as no CMD (reference outcome group; 81.1%), perinatal CMD (developed and resolved during the perinatal period; 14.9%), persistent CMD (developed during, and persisted beyond, the perinatal period; 2.9%), and incident CMD (developed after the perinatal period; 1.1%). Multinomial logistic regression was used to model associations between milk fatty acid composition (individual, summary, ratios, and patterns identified using principal component analysis) and maternal CMD, adjusting for pre-pregnancy anthropometry and race/ethnicity. Results: Medium-chain saturated fatty acids (MC-SFA), lauric (C12:0; odds ratio [OR] = 0.73, 95% confidence interval [CI] = 0.60-0.89) and myristic acid (C14:0; OR = 0.80, 95% CI = 0.66-0.97), and the high MC-SFA principal component pattern (OR = 0.86, 95% CI = 0.76-0.96) were inversely associated with perinatal CMD. Long-chain polyunsaturated fatty acids adrenic acid (C22:4n-6) was positively associated with perinatal (OR = 1.21, 95% CI = 1.01-1.44) and persistent CMD (OR = 1.56, 95% CI = 1.08-2.25). The arachidonic (C20:4n-6)-to-docosahexaenoic acid (C22:6n-3) ratio was inversely associated with incident CMD (OR = 0.52, 95% CI = 0.28-0.96). Conclusions: These exploratory findings highlight a potential novel utility of breast milk for understanding women's cardiometabolic health.

Comprehensive whole-genome sequence analyses provide insights into the genomic architecture of cerebral palsy.

We performed whole-genome sequencing (WGS) in 327 children with cerebral palsy (CP) and their biological parents. We classified 37 of 327 (11.3%) children as having pathogenic/likely pathogenic (P/LP) variants and 58 of 327 (17.7%) as having variants of uncertain significance. Multiple classes of P/LP variants included single-nucleotide variants (SNVs)/indels (6.7%), copy number variations (3.4%) and mitochondrial mutations (1.5%). The COL4A1 gene had the most P/LP SNVs. We also analyzed two pediatric control cohorts (n = 203 trios and n = 89 sib-pair families) to provide a baseline for de novo mutation rates and genetic burden analyses, the latter of which demonstrated associations between de novo deleterious variants and genes related to the nervous system. An enrichment analysis revealed previously undescribed plausible candidate CP genes (SMOC1, KDM5B, BCL11A and CYP51A1). A multifactorial CP risk profile and substantial presence of P/LP variants combine to support WGS in the diagnostic work-up across all CP and related phenotypes.

Examining psychosocial pathways to explain the link between breastfeeding practices and child behaviour in a longitudinal cohort.

OBJECTIVE: Breastfeeding is associated with reduced postpartum depression, stronger parent-child relationships, and fewer behavioral disorders in early childhood. We tested the mediating roles of postpartum depression and parent-child relationship in the association between breastfeeding practices and child behavior. STUDY DESIGN: We used standardized questionnaire data from a subset of the CHILD Cohort Study (n = 1,573) to measure postpartum depression at 6 months, 1 year and 2 years, parent-child relationship 1 year and 2 years, and child behavior at 5 years using the Child Behavior Checklist (range 0-100). Breastfeeding practices were measured at 3 months (none, partial, some expressed, all direct at the breast), 6 months (none, partial, exclusive), 12 months, and 24 months (no, yes). Confounders included birth factors, maternal characteristics, and socioeconomic status. RESULTS: Breast milk feeding at 3 or 6 months was associated with - 1.13 (95% CI: -2.19-0.07) to -2.14 (95% CI: -3.46, -0.81) lower (better) child behavior scores. Reduced postpartum depression at 6 months mediated between 11.5% and 16.6% of the relationship between exclusive breast milk feeding at 3 months and better child behavior scores. Together, reduced postpartum depression at 1 year and reduced parent-child dysfunction at 2 years mediated between 21.9% and 32.1% of the relationship between breastfeeding at 12 months and better child behavior scores. CONCLUSION: Postpartum depression and parent-child relationship quality partially mediate the relationship between breastfeeding practices and child behavior. Breastfeeding, as well as efforts to support parental mental health and parent-child relationships, may help to improve child behavior.

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.

Genome-wide enhancer-associated tandem repeats are expanded in cardiomyopathy.

BACKGROUND: Cardiomyopathy is a clinically and genetically heterogeneous heart condition that can lead to heart failure and sudden cardiac death in childhood. While it has a strong genetic basis, the genetic aetiology for over 50% of cardiomyopathy cases remains unknown. METHODS: In this study, we analyse the characteristics of tandem repeats from genome sequence data of unrelated individuals diagnosed with cardiomyopathy from Canada and the United Kingdom (n = 1216) and compare them to those found in the general population. We perform burden analysis to identify genomic and epigenomic features that are impacted by rare tandem repeat expansions (TREs), and enrichment analysis to identify functional pathways that are involved in the TRE-associated genes in cardiomyopathy. We use Oxford Nanopore targeted long-read sequencing to validate repeat size and methylation status of one of the most recurrent TREs. We also compare the TRE-associated genes to those that are dysregulated in the heart tissues of individuals with cardiomyopathy. FINDINGS: We demonstrate that tandem repeats that are rarely expanded in the general population are predominantly expanded in cardiomyopathy. We find that rare TREs are disproportionately present in constrained genes near transcriptional start sites, have high GC content, and frequently overlap active enhancer H3K27ac marks, where expansion-related DNA methylation may reduce gene expression. We demonstrate the gene silencing effect of expanded CGG tandem repeats in DIP2B through promoter hypermethylation. We show that the enhancer-associated loci are found in genes that are highly expressed in human cardiomyocytes and are differentially expressed in the left ventricle of the heart in individuals with cardiomyopathy. INTERPRETATION: Our findings highlight the underrecognized contribution of rare tandem repeat expansions to the risk of cardiomyopathy and suggest that rare TREs contribute to ∼4% of cardiomyopathy risk. FUNDING: Government of Ontario (RKCY), The Canadian Institutes of Health Research PJT 175329 (RKCY), The Azrieli Foundation (RKCY), SickKids Catalyst Scholar in Genetics (RKCY), The University of Toronto McLaughlin Centre (RKCY, SM), Ted Rogers Centre for Heart Research (SM), Data Sciences Institute at the University of Toronto (SM), The Canadian Institutes of Health Research PJT 175034 (SM), The Canadian Institutes of Health Research ENP 161429 under the frame of ERA PerMed (SM, RL), Heart and Stroke Foundation of Ontario & Robert M Freedom Chair in Cardiovascular Science (SM), Bitove Family Professorship of Adult Congenital Heart Disease (EO), Canada Foundation for Innovation (SWS, JR), Canada Research Chair (PS), Genome Canada (PS, JR), The Canadian Institutes of Health Research (PS).

Multimodal machine learning for modeling infant head circumference, mothers' milk composition, and their shared environment.

Links between human milk (HM) and infant development are poorly understood and often focus on individual HM components. Here we apply multi-modal predictive machine learning to study HM and head circumference (a proxy for brain development) among 1022 mother-infant dyads of the CHILD Cohort. We integrated HM data (19 oligosaccharides, 28 fatty acids, 3 hormones, 28 chemokines) with maternal and infant demographic, health, dietary and home environment data. Head circumference was significantly predictable at 3 and 12 months. Two of the most associated features were HM n3-polyunsaturated fatty acid C22:6n3 (docosahexaenoic acid, DHA; p = 9.6e-05) and maternal intake of fish (p = 4.1e-03), a key dietary source of DHA with established relationships to brain function. Thus, using a systems biology approach, we identified meaningful relationships between HM and brain development, which validates our statistical approach, gives credence to the novel associations we observed, and sets the foundation for further research with additional cohorts and HM analytes.

Early prediction of pediatric asthma in the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort using machine learning.

BACKGROUND: Early identification of children at risk of asthma can have significant clinical implications for effective intervention and treatment. This study aims to disentangle the relative timing and importance of early markers of asthma. METHODS: Using the CHILD Cohort Study, 132 variables measured in 1754 multi-ethnic children were included in the analysis for asthma prediction. Data up to 4 years of age was used in multiple machine learning models to predict physician-diagnosed asthma at age 5 years. Both predictive performance and variable importance was assessed in these models. RESULTS: Early-life data (≤1 year) has limited predictive ability for physician-diagnosed asthma at age 5 years (area under the precision-recall curve (AUPRC) < 0.35). The earliest reliable prediction of asthma is achieved at age 3 years, (area under the receiver-operator curve (AUROC) > 0.90) and (AUPRC > 0.80). Maternal asthma, antibiotic exposure, and lower respiratory tract infections remained highly predictive throughout childhood. Wheezing status and atopy are the most important predictors of early childhood asthma from among the factors included in this study. CONCLUSIONS: Childhood asthma is predictable from non-biological measurements from the age of 3 years, primarily using parental asthma and patient history of wheezing, atopy, antibiotic exposure, and lower respiratory tract infections. IMPACT: Machine learning models can predict physician-diagnosed asthma in early childhood (AUROC > 0.90 and AUPRC > 0.80) using ≥3 years of non-biological and non-genetic information, whereas prediction with the same patient information available before 1 year of age is challenging. Wheezing, atopy, antibiotic exposure, lower respiratory tract infections, and the child's mother having asthma were the strongest early markers of 5-year asthma diagnosis, suggesting an opportunity for earlier diagnosis and intervention and focused assessment of patients at risk for asthma, with an evolving risk stratification over time.

Human Milk Micronutrients and Child Growth and Body Composition in the First 2 years: A Systematic Review.

Human milk (HM) provides a plethora of nutritional and non-nutritional compounds that support infant development. For many compounds, concentrations vary substantially among mothers and across lactation, and their impact on infant growth is poorly understood. We systematically searched MEDLINE, Embase, the Cochrane Library, Scopus, and Web of Science to synthesize evidence published between 1980 and 2022 on HM components and anthropometry through 2 y of age among term-born infants. Outcomes included weight-for-length, length-for-age, weight-for-age, body mass index (in kg/m2)-for-age, and growth velocity. From 9992 abstracts screened, 144 articles were included and categorized based on their reporting of HM micronutrients, macronutrients, or bioactive components. Micronutrients (vitamins and minerals) are reported here, based on 28 articles involving 2526 mother-infant dyads. Studies varied markedly in their designs, sampling times, geographic and socioeconomic settings, reporting practices, and the HM analytes and infant anthropometrics measured. Meta-analysis was not possible because data were sparse for most micronutrients. The most-studied minerals were zinc (15 articles, 1423 dyads) and calcium (7 articles, 714 dyads). HM iodine, manganese, calcium, and zinc concentrations were positively associated with several outcomes (each in ≥2 studies), whereas magnesium (in a single study) was negatively associated with linear growth during early lactation. However, few studies measured HM intake, adjusted for confounders, provided adequate information about complementary and formula feeding, or adequately described HM collection protocols. Only 4 studies (17%) had high overall quality scores. The biological functions of individual HM micronutrients are likely influenced by other HM components; yet, only 1 study analyzed data from multiple micronutrients simultaneously, and few addressed other HM components. Thus, available evidence on this topic is largely inconclusive and fails to address the complex composition of HM. High-quality research employing chronobiology and systems biology approaches is required to understand how HM components work independently and together to influence infant growth and to identify new avenues for future maternal, newborn, or infant nutritional interventions.

Human Milk Macronutrients and Child Growth and Body Composition in the First Two Years: A Systematic Review.

Among exclusively breastfed infants, human milk (HM) provides complete nutrition in the first mo of life and remains an important energy source as long as breastfeeding continues. Consisting of digestible carbohydrates, proteins, and amino acids, as well as fats and fatty acids, macronutrients in human milk have been well studied; however, many aspects related to their relationship to growth in early life are still not well understood. We systematically searched Medline, EMBASE, the Cochrane Library, Scopus, and Web of Science to synthesize evidence published between 1980 and 2022 on HM components and anthropometry through 2 y of age among term-born healthy infants. From 9992 abstracts screened, 57 articles reporting observations from 5979 dyads were included and categorized based on their reporting of HM macronutrients and infant growth. There was substantial heterogeneity in anthropometric outcome measurement, milk collection timelines, and HM sampling strategies; thus, meta-analysis was not possible. In general, digestible carbohydrates were positively associated with infant weight outcomes. Protein was positively associated with infant length, but no associations were reported for infant weight. Finally, HM fat was not consistently associated with any infant growth metrics, though various associations were reported in single studies. Fatty acid intakes were generally positively associated with head circumference, except for docosahexaenoic acid. Our synthesis of the literature was limited by differences in milk collection strategies, heterogeneity in anthropometric outcomes and analytical methodologies, and by insufficient reporting of results. Moving forward, HM researchers should accurately record and account for breastfeeding exclusivity, use consistent sampling protocols that account for the temporal variation in HM macronutrients, and use reliable, sensitive, and accurate techniques for HM macronutrient analysis.

Human Milk Bioactive Components and Child Growth and Body Composition in the First 2 Years: A Systematic Review.

Human milk (HM) contains macronutrients, micronutrients, and a multitude of other bioactive factors, which can have a long-term impact on infant growth and development. We systematically searched MEDLINE, EMBASE, Cochrane Library, Scopus, and Web of Science to synthesize evidence published between 1980 and 2022 on HM components and anthropometry through 2 y of age among term-born infants. From 9992 abstracts screened, 141 articles were included and categorized based on their reporting of HM micronutrients, macronutrients, or bioactive components. Bioactives including hormones, HM oligosaccharides (HMOs), and immunomodulatory components are reported here, based on 75 articles from 69 unique studies reporting observations from 9980 dyads. Research designs, milk collection strategies, sampling times, geographic and socioeconomic settings, reporting practices, and outcomes varied considerably. Meta-analyses were not possible because data collection times and reporting were inconsistent among the studies included. Few measured infant HM intake, adjusted for confounders, precisely captured breastfeeding exclusivity, or adequately described HM collection protocols. Only 5 studies (6%) had high overall quality scores. Hormones were the most extensively examined bioactive with 46 articles (n = 6773 dyads), compared with 13 (n = 2640 dyads) for HMOs and 12 (n = 1422 dyads) for immunomodulatory components. Two studies conducted untargeted metabolomics. Leptin and adiponectin demonstrated inverse associations with infant growth, although several studies found no associations. No consistent associations were found between individual HMOs and infant growth outcomes. Among immunomodulatory components in HM, IL-6 demonstrated inverse relationships with infant growth. Current research on HM bioactives is largely inconclusive and is insufficient to address the complex composition of HM. Future research should ideally capture HM intake, use biologically relevant anthropometrics, and integrate components across categories, embracing a systems biology approach to better understand how HM components work independently and synergistically to influence infant growth.

The protective associations of breastfeeding with infant overweight and asthma are not dependent on maternal FUT2 secretor status.

Breastfeeding supplies infant gut bacteria with human milk oligosaccharides (HMOs) as a nutrient source. HMO profiles are influenced by the FUT2 gene, which encodes an enzyme affecting the fucosylation of milk sugars. 20 to 40% of individuals have a "non-secretor" polymorphism that inactivates the FUT2 gene, resulting in variable HMO proportions in milk. This has engendered a concerning, yet unfounded, perception that non-secretor milk is "inferior." To address this untested hypothesis, we re-analyzed two datasets in which we previously showed that breastfeeding was protective against early life asthma and excessive infant weight gain in the Canadian CHILD Cohort Study. Using stratified regression models, we found that the protective association of exclusive breastfeeding and infant asthma was not modified by maternal secretor status (secretors aOR: 0.53, 95% CI 0.31 to 0.92; non-secretors aOR: 0.36, 95% CI 0.12 to 1.04; p for interaction = 0.50, N = 2086 children). Similarly, the association of breastfeeding with lower infant BMI and weight gain velocity did not vary by maternal secretor status (infant BMI: secretors aß -0.47, 95% CI -0.66 to -0.29; non-secretors aß -0.46, 95% CI -0.78 to -0.13; p for interaction = 0.60; N = 1971 infants). Our results indicate that secretor and non-secretor mothers can equally promote infant growth and respiratory health through breastfeeding. These findings run contrary to the idea that non-secretor milk is an inferior food source, and instead reify the importance of breastfeeding for all infants. The results of this study can inform feeding recommendations that are applicable to all infants, regardless of maternal secretor status.

Cohort profile: investigating SARS-CoV-2 infection and the health and psychosocial impact of the COVID-19 pandemic in the Canadian CHILD Cohort.

The coronavirus disease 2019 (COVID-19) pandemic has affected all Canadian families, with some impacted differently than others. Our study aims to: (1) determine the prevalence and transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among Canadian families, (2) identify predictors of infection susceptibility and severity of SARS-CoV-2, and (3) identify health and psychosocial impacts of the COVID-19 pandemic. This study builds upon the CHILD Cohort Study, an ongoing multi-ethnic general population prospective cohort consisting of 3,454 Canadian families with children born in Vancouver, Edmonton, Manitoba, and Toronto between 2009 and 2012. During the pandemic, CHILD households were invited to participate in the CHILD COVID-19 Add-On Study involving: (1) brief biweekly surveys about COVID-19 symptoms and testing; (2) quarterly questionnaires assessing COVID-19 exposure and testing, vaccination status, physical and mental health, and pandemic-driven life changes; and (3) in-home biological sampling kits to collect blood and stool. In total, 1,462 households (5,378 participants) consented to the CHILD COVID-19 Add-On Study: 2,803 children (mean±standard deviation [SD], 9.0±2.7 years; range, 0-17 years) and 2,576 adults (mean±SD, 43.0±6.5 years; range, 18-85 years). We will leverage the wealth of pre-pandemic CHILD data to identify risk and resilience factors for susceptibility and severity to the direct and indirect pandemic effects. Our short-term findings will inform key stakeholders and knowledge users to shape current and future pandemic responses. Additionally, this study provides a unique resource to study the long-term impacts of the pandemic as the CHILD Cohort Study continues.

Corrigendum: The human milk proteome and allergy of mother and child: exploring associations with protein abundances and protein network connectivity.

[This corrects the article DOI: 10.3389/fimmu.2022.977470.].

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.

Early sex-dependent differences in metabolic profiles of overweight and adiposity in young children: a cross-sectional analysis.

BACKGROUND: Childhood obesity is a global health concern and can lead to lifetime cardiometabolic disease. New advances in metabolomics can provide biochemical insights into the early development of obesity, so we aimed to characterize serum metabolites associated with overweight and adiposity in early childhood and to stratify associations by sex. METHODS: Nontargeted metabolite profiling was conducted in the Canadian CHILD birth cohort (discovery cohort) at age 5 years (n = 900) by multisegment injection-capillary electrophoresis-mass spectrometry. Clinical outcome was defined using novel combined measures of overweight (WHO-standardized body mass index ≥ 85th percentile) and/or adiposity (waist circumference ≥ 90th percentile). Associations between circulating metabolites and child overweight/adiposity (binary and continuous outcomes) were determined by multivariable linear and logistic regression, adjusting for covariates and false discovery rate, and by subsequent sex-stratified analysis. Replication was assessed in an independent replication cohort called FAMILY at age 5 years (n = 456). RESULTS: In the discovery cohort, each standard deviation (SD) increment of branched-chain and aromatic amino acids, glutamic acid, threonine, and oxoproline was associated with 20-28% increased odds of overweight/adiposity, whereas each SD increment of the glutamine/glutamic acid ratio was associated with 20% decreased odds. All associations were significant in females but not in males in sex-stratified analyses, except for oxoproline that was not significant in either subgroup. Similar outcomes were confirmed in the replication cohort, where associations of aromatic amino acids, leucine, glutamic acid, and the glutamine/glutamic acid ratio with childhood overweight/adiposity were independently replicated. CONCLUSIONS: Our findings show the utility of combining measures of both overweight and adiposity in young children. Childhood overweight/adiposity at age 5 years has a specific serum metabolic phenotype, with the profile being more prominent in females compared to males.

Evidence for human milk as a biological system and recommendations for study design-a report from "Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN)" Working Group 4.

Human milk contains all of the essential nutrients required by the infant within a complex matrix that enhances the bioavailability of many of those nutrients. In addition, human milk is a source of bioactive components, living cells and microbes that facilitate the transition to life outside the womb. Our ability to fully appreciate the importance of this matrix relies on the recognition of short- and long-term health benefits and, as highlighted in previous sections of this supplement, its ecology (i.e., interactions among the lactating parent and breastfed infant as well as within the context of the human milk matrix itself). Designing and interpreting studies to address this complexity depends on the availability of new tools and technologies that account for such complexity. Past efforts have often compared human milk to infant formula, which has provided some insight into the bioactivity of human milk, as a whole, or of individual milk components supplemented with formula. However, this experimental approach cannot capture the contributions of the individual components to the human milk ecology, the interaction between these components within the human milk matrix, or the significance of the matrix itself to enhance human milk bioactivity on outcomes of interest. This paper presents approaches to explore human milk as a biological system and the functional implications of that system and its components. Specifically, we discuss study design and data collection considerations and how emerging analytical technologies, bioinformatics, and systems biology approaches could be applied to advance our understanding of this critical aspect of human biology.