There is growing interest in the use of microbial-seeding interventions to mitigate the impacts of prenatal antibiotics, C-section, and lack of breastfeeding on mother-child microbe sharing. However, the relative importance of maternal vaginal vs. fecal microbiota in this process is unclear. Analyzing 16S rRNA sequences from five US birth cohorts, we found that maternal vaginal and fecal microbiota became more similar as pregnancy progressed, and both niches influenced the child's fecal microbiota. The relative contribution of maternal vaginal microbiota increased when vaginal sampling occurred later in gestation. As children aged from birth to 5 years, their fecal microbiota increasingly resembled their mother's fecal microbiota as compared to vaginal microbiota. Patterns of sharing appeared to differ by prenatal antibiotic use, birth mode (C-section vs. vaginal), and breastfeeding. Our findings enhance understanding of niche-specific mother-child microbe sharing and may inform microbial-seeding interventions. Metagenomic studies are needed to identify specific shared strains.

Summary: Background: Lung function trajectories (LFTs) have been shown to be an important measure of long-term health in asthma. While there is a growing body of metabolomic studies on asthma status and other phenotypes, there are no prospective studies of the relationship between metabolomics and LFTs or their genomic determinants. Methods: We utilized ordinal logistic regression to identify plasma metabolite principal components associated with four previously-published LFTs in children from the Childhood Asthma Management Program (CAMP) (n = 660). The top significant metabolite principal component (PCLF) was evaluated in an independent cross-sectional child cohort, the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (n = 1151) and evaluated for association with spirometric measures. Using meta-analysis of CAMP and GACRS, we identified associations between PCLF and microRNA, and SNPs in their target genes. Statistical significance was determined using an false discovery rate-adjusted Q-value. Findings: The top metabolite principal component, PCLF, was significantly associated with better LFTs after multiple-testing correction (Q-value = 0.03). PCLF is composed of the urea cycle, caffeine, corticosteroid, carnitine, and potential microbial (secondary bile acid, tryptophan, linoleate, histidine metabolism) metabolites. Higher levels of PCLF were also associated with increases in lung function measures and decreased circulating neutrophil percentage in both CAMP and GACRS. PCLF was also significantly associated with microRNA miR-143-3p, and SNPs in three miR-143-3p target genes; CCZ1 (P-value = 2.6 × 10−5), SLC8A1 (P-value = 3.9 × 10−5); and TENM4 (P-value = 4.9 × 10−5). Interpretation: This study reveals associations between metabolites, miR-143-3p and LFTs in children with asthma, offering insights into asthma physiology and possible interventions to enhance lung function and long-term health. Funding: Molecular data for CAMP and GACRS via the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI).

Objective The determinants of preterm birth remain unknown. Excessive maternal inflammation during pregnancy may play an important role in the pathogenesis of preterm birth. Our objective was to describe the association of prenatal levels of proinflammatory C-reactive protein (CRP) and interleukin-8 (IL-8) with preterm birth in participants of the Vitamin D Antenatal Asthma Reduction Trial. Study Design Five hundred and twenty-eight patients with available samples of both first- and third-trimester plasma were included in this analysis. CRP and IL-8 were measured from maternal prenatal samples. We examined the association between prenatal CRP and IL-8 with maternal health characteristics and the outcome of preterm birth. We also described the patterns of change in CRP and IL-8 from first to third trimester and their association with preterm birth. A subgroup analysis comparing only those with a spontaneous preterm birth phenotype to those with term birth was also performed. Results Maternal characteristics including lower educational attainment, higher prepregnancy body mass index, gestational diabetes, lower vitamin D, and an unhealthy diet were associated with elevated levels of prenatal CRP and IL-8. Higher third trimester CRP and an increase in CRP from first to third trimester were associated with an increased odds of preterm birth when compared to lower levels of CRP (adjusted odds ratio [aOR] = 1.49, 95% confidence interval: 1.02, 2.23, p = 0.04) or a decrease in CRP over pregnancy (aOR = 3.06, 95% CI = 1.31,7.55, p = 0.01), after adjusting for potential confounders. These associations were strengthened when comparing only patients with spontaneous preterm birth (n = 22) to those with term births. Conclusion Higher levels of the proinflammatory markers CRP and IL-8 are associated with indicators of poor maternal health and preterm birth. Prenatal CRP levels may reflect maternal prenatal health status and serve as a predictor of preterm birth, especially among those with spontaneous preterm birth. Key Points

Rationale: The role and timing of vitamin D supplementation in the prevention of asthma has not been fully elucidated. Objective: To describe the association between prenatal and postnatal vitamin D with offspring asthma outcomes in participants of the Vitamin D Antenatal Asthma Reduction Trial. Methods: We classified 748 mother-offspring pairs into four groups based on the mother's randomization to receive high-dose versus low-dose (4,400 IU vs. 400 IU) vitamin D supplementation during pregnancy and the offspring parent-reported high-dose versus low-dose (⩾400 IU vs. <400 IU) vitamin D supplementation as estimated by intake of vitamin D drops or infant formula. We used logistic regression to test the association of the four vitamin D exposure groups-"mother-low/infant-low (reference)," "mother-high/infant-high," "mother-high/infant-low," and "mother-low/infant-high"-with offspring asthma and/or recurrent wheeze at age 3 years, active asthma at age 6 years, and atopic asthma at age 6 years. Results: The risk of asthma and/or recurrent wheeze at 3 years was lowest in the mother-high/infant-low group (adjusted odds ratio vs. mother-low/infant-low, 0.39; 95% confidence interval, 0.16-0.88, P = 0.03). When stratifying by history of exclusive breastfeeding until age 4 months, the protective effect in the mother-high/infant-low group was seen only among exclusively breastfed infants (odds ratio vs. mother-low/infant-low, 0.19; 95% confidence interval, 0.04-0.68; P = 0.02). We did not observe any significant associations with active or atopic asthma at age 6 years. Conclusions: We observe that high-dose prenatal and low-dose postnatal vitamin D supplementation may be associated with reduced offspring asthma or recurrent wheeze by age 3 years, but this association may be confounded by the protective effect of breastfeeding.

The influence of genotype on defining the human gut microbiome has been extensively studied, but definite conclusions have not yet been found. To fill this knowledge gap, we leverage data from children enrolled in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) from 6 months to 8 years old. We focus on a pool of 12 genes previously found to be associated with the gut microbiome in independent studies, establishing a Bonferroni corrected significance level of p-value < 2.29 × 10 -6 . We identified significant associations between SNPs in the FHIT gene (known to be associated with obesity and type 2 diabetes) and obesity-related microbiome features, and the children's BMI through their childhood. Based on these associations, we defined a set of SNPs of interest and a set of taxa of interest. Taking a multi-omics approach, we integrated plasma metabolome data into our analysis and found simultaneous associations among children's BMI, the SNPs of interest, and the taxa of interest, involving amino acids, lipids, nucleotides, and xenobiotics. Using our association results, we constructed a quadripartite graph where each disjoint node set represents SNPs in the FHIT gene, microbial taxa, plasma metabolites, or BMI measurements. Network analysis led to the discovery of patterns that identify several genetic variants, microbial taxa and metabolites as new potential markers for obesity, type 2 diabetes, or insulin resistance risk.

BACKGROUND:We aimed to understand the association between maternal stress in the first year of life and childhood body mass index (BMI) from 2 to 4 years of age in a large, prospective United States-based consortium of cohorts. METHODS:We used data from the Environmental influences on Child Health Outcomes program. The main exposure was maternal stress in the first year of life measured with the Perceived Stress Scale (PSS). The main outcome was the first childhood BMI percentile after age 2 until age 4 years. We used an adjusted linear mixed effects model to examine associations between BMI and PSS quartile. RESULTS:The mean BMI percentile in children was 59.8 (SD 30) measured at 3.0 years (SD 1) on average. In both crude models and models adjusted for maternal BMI, age, race, ethnicity, infant birthweight, and health insurance status, no linear associations were observed between maternal stress and child BMI. CONCLUSIONS:Among 1694 maternal-infant dyads, we found no statistically significant relationships between maternal perceived stress in the first year of life and child BMI after 2 through 4 years. IMPACT:Although existing literature suggests relationships between parental stress and childhood BMI, we found no linear associations between maternal stress in the first year of life and childhood BMI at 2-4 years of age among participants in ECHO cohorts. Higher maternal stress was significantly associated with Hispanic ethnicity, Black race, and public health insurance. Our analysis of a large, nationally representative sample challenges assumptions that maternal stress in the first year of life, as measured by a widely used scale, is associated with offspring BMI.

PROBLEM:Promotion of a healthy pregnancy is dependent on a coordinated immune response that minimizes inflammation at the maternal-fetal interface. Few studies investigated the effect of fetal sex on proinflammatory biomarkers during pregnancy and whether maternal race could impact this association. We aimed to examine whether fetal sex could, independently of maternal race/ethnicity and the condition of pregnancy (normal vs. complicated), impact inflammatory markers (C-reactive protein [CRP] and interleukin-8 [IL-8] levels) in early and late pregnancy. METHODS OF STUDY:This study was a cohort analysis using prospectively collected data from pregnant women who participated in the Vitamin Antenatal Asthma Reduction Trial (VDAART, N = 816). Maternal serum CRP and IL-8 levels were measured in early and late pregnancy (10-18 and 32-38 weeks of gestation, respectively). Five hundred and twenty-eight out of 816 pregnant women who participated in the trial had available CRP and IL-8 measurements at both study time points. We examined the association of fetal sex with early and late CRP and IL-8 levels and their paired sample difference. We further investigated whether maternal race/ethnicity, pregnancy complications (i.e., preeclampsia and gestational diabetes), and early pregnancy body mass index (BMI) could affect the association between these two biomarkers and fetal sex adjusting for potential confounders. For this purpose, we used generalized linear and logistic regression models on log-normalized early and late CRP and IL-8 levels as well as their split at median to form high and low groups. RESULTS:Women pregnant with male fetuses (266/528 = 56.5%) had higher CRP levels in early to mid-pregnancy (β = .18: 95% confidence interval [CI]: CI = 0.03-0.32; p = .02). Twenty-seven percent (143/528) of the study subjects were Hispanic. Hispanic African American [AA] women and women of races other than White and AA had higher levels of CRP at early to mid-pregnancy compared with White women (β = .57; 95% CI: 0.17-0.97; p < .01 and β = .27; 95% CI: 0.05-0.48; p = .02, respectively). IL-8 levels were not associated with fetal sex in early and late pregnancy (p's > .05). Other factors such as gestational diabetes and early pregnancy BMI were associated with higher CRP levels and higher CRP and IL-8 levels, respectively. Dichotomizing log-normalized cytokine levels at the median in a sensitivity analysis, women with male fetuses had lower odds of high (above-median) IL-8 levels at early pregnancy. Also, women with races other than AA and White carrying male fetuses had higher odds of having high (above-median) late-pregnancy CRP and early-pregnancy IL-8 levels (adjusted odds ratio [aOR] = 3.80, 95% CI: 0.24-1.23; p = .02 and aOR = 3.57; 95% CI: 0.23-1.03; p = .02, respectively). Of the pregnancy complications, women with gestational diabetes mellitus had a higher paired difference of early and late pregnancy CRP levels (β = .38; 95% CI: 0.09-0.68; p = .01), but no difference in IL-8 levels (p's > .05). No associations between the inflammatory markers and preeclampsia were found. CONCLUSION:Fetal sex is associated with CRP in early pregnancy and an association with IL-8 in early pregnancy is implied. Our study further indicates that maternal race/ethnicity could be a contributing factor in the relationship between fetal sex and inflammatory responses during pregnancy. However, the specificity and level of the contribution might vary by type of cytokine, pregnancy stage, and other confounding factors such as BMI that may impact these associations.

Despite significant heterogeneity in asthma and other allergic diseases, these conditions become clinically apparent in the first few years of life in most cases. This observation, alongside epidemiologic and experimental evidence of prenatal and early postnatal risk factors for asthma and allergies, provides fundamental support for the developmental origins of health and disease theory, which posits that those environmental exposures during early life, and particularly during the in utero period, can permanently influence health and vulnerability to disease in later life.1Gillman M.W. Developmental origins of health and disease.N Engl J Med. 2005; 353: 1848-1850Crossref PubMed Scopus (439) Google Scholar Putting together the developmental origins of health and disease theory and the profound potential for the human microbiome to influence health and disease risk, it is logical to hypothesize that prenatal influences on the maternal and infant microbiome can influence offspring health in childhood and beyond, including the risk of asthma and allergies (Fig 1). Not only do microbes engage antigenically, locally in their niche with host cells, but they also produce a biochemically staggering variety of metabolites, many of which are bioactive and able to circulate through the human host, affecting immunity and biochemistry at body sites distant from the original habitat of the microbes. Although these host-microbe interactions play critical roles throughout the lifespan, they may be especially important in setting the stage for immune development and tolerance acquisition by the fetus before and after birth. Although whether the intrauterine environment during pregnancy is sterile remains a topic of controversy, there are metabolites derived from the maternal microbiome that cross the placenta, and vertical transmission of resident microbiota that sets the substrate for microbiome health in the child occurs from mother to neonate during delivery. Although the effect of the maternal microbiome on offspring risk of asthma and other allergic diseases is an area that has been understudied to date, there are already several well-supported examples of how prenatal influences on the microbiome have clinical implications, a few of which will be reviewed here. Short-chain fatty acids (SCFAs) (eg, butyrate, propionate, and acetate) are metabolites produced by gut microbes through fermentation of dietary fiber; they have numerous immune-modulating and largely health-promoting properties, including promotion of regulatory T cell differentiation. Evidence from multiple birth cohorts suggest that higher levels of fecal SCFAs in infancy are associated with reductions in atopic asthma and other allergic diseases.2Schjødt M.S. Gürdeniz G. Chawes B. The metabolomics of childhood atopic diseases: a comprehensive pathway-specific review.Metabolites. 2020; 10: 511Crossref PubMed Scopus (18) Google Scholar SCFAs are known to cross the placenta, and in a murine model, a high-fiber diet/acetate supplementation was linked to a reduction in offspring allergic airway disease.3Thorburn A.N. McKenzie C.I. Shen S. Stanley D. Macia L. Mason L.J. et al.Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites.Nat Commun. 2015; 6: 7320Crossref PubMed Scopus (608) Google Scholar This finding has been supported in human studies, including in a small study of 40 mother-child pairs in whom low maternal serum acetic acid level was associated with increased cough or wheeze in infant offspring and in a study of 150 mother-child participants in the Vitamin D Antenatal Asthma Reduction Trial (VDAART), in which higher relative abundance of maternal fecal acetate was associated with reduced offspring atopic asthma.3Thorburn A.N. McKenzie C.I. Shen S. Stanley D. Macia L. Mason L.J. et al.Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites.Nat Commun. 2015; 6: 7320Crossref PubMed Scopus (608) Google Scholar,4Lee-Sarwar K.A. Kelly R.S. Lasky-Su J. Zeiger R.S. O'Connor G.T. Sandel M.T. et al.Fecal short-chain fatty acids in pregnancy and offspring asthma and allergic outcomes.J Allergy Clin Immunol Pract. 2020; 8: 1100-1102.e13Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Mode of delivery is another example whereby the maternal microbiome and the success of its transfer to offspring are very likely to be of clinical importance. There are highly reproducible differences in the microbiomes of infants born by cesarean section versus in the microbiomes of those born by vaginal delivery, including disruptions to vertical transmission of maternal microbes and reductions in infant fecal Bacteroides. Although in human observational studies, mode of delivery has exhibited inconsistent associations with occurrence of offspring asthma and allergy, advances in the availability of longitudinal gut microbiome profiling in human cohorts alongside bioinformatic techniques to interpret these data are beginning to enable investigators to disentangle the microbial and nonmicrobial effects of mode of delivery on offspring risk of asthma and allergic diseases. Data from both VDAART5Lee-Sarwar K.A. Chen Y.C. Chen Y.Y. Kozyrskyj A.L. Mandhane P.J. Turvey S.E. et al.The maternal prenatal and offspring early-life gut microbiome of childhood asthma phenotypes.Allergy. 2023; 78: 418-428Crossref PubMed Scopus (9) Google Scholar and the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC)6Stokholm J. Thorsen J. Blaser M.J. Rasmussen M.A. Hjelmsø M. Shah S. et al.Delivery mode and gut microbial changes correlate with an increased risk of childhood asthma.Sci Transl Med. 2020; 12eaax9929Crossref Scopus (78) Google Scholar suggest that retaining an infant microbial signature of cesarean section birth may be the factor that increases risk of asthma in offspring rather than the mode of delivery itself. These insights into prenatal influences on the microbiome have the potential for major clinical impact and new ways to reduce the burden of asthma and allergic diseases in childhood. Maternal SCFAs could be increased via dietary changes or other microbiome-modifying strategies. Vaginal or microbial seeding, whereby neonates delivered by cesarean section are exposed to the maternal vaginal and/or fecal microbiome that they bypassed in the process of cesarean section, has been shown to help restore the infant microbiome to resemble that of infants born by vaginal delivery.7Hourigan S.K. Dominguez-Bello M.G. Mueller N.T. Can maternal-child microbial seeding interventions improve the health of infants delivered by cesarean section?.Cell Host Microbe. 2022; 30: 607-611Abstract Full Text Full Text PDF PubMed Google Scholar The long-term impact of this intervention on offspring disease risk, including risk of asthma and allergies, is under study in multiple randomized clinical trials (eg, NCT03298334, NCT03567707, and NCT03809390).7Hourigan S.K. Dominguez-Bello M.G. Mueller N.T. Can maternal-child microbial seeding interventions improve the health of infants delivered by cesarean section?.Cell Host Microbe. 2022; 30: 607-611Abstract Full Text Full Text PDF PubMed Google Scholar Other exposures that could be targeted to optimize the maternal microbiome but require further investigation include antibiotic exposure during pregnancy and maternal psychosocial stress.8Gao Y. Nanan R. Macia L. Tan J. Sominsky L. Quinn T.P. et al.The maternal gut microbiome during pregnancy and offspring allergy and asthma.J Allergy Clin Immunol. 2021; 148: 669-678Abstract Full Text Full Text PDF PubMed Google Scholar Although we have focused on the host microbiome and the disease areas of asthma and allergies, the clinical implications of the prenatal microbiome do not stop there. In addition to the host microbiome, the environmental microbiome is another potential area for preventative intervention, given the well-established literature on the protective effect of a farm environment or having furry pets in the home on asthma risk, including evidence that living on a farm during pregnancy may be especially protective.8Gao Y. Nanan R. Macia L. Tan J. Sominsky L. Quinn T.P. et al.The maternal gut microbiome during pregnancy and offspring allergy and asthma.J Allergy Clin Immunol. 2021; 148: 669-678Abstract Full Text Full Text PDF PubMed Google Scholar The protective farm effect may not be independent of effects of prenatal nutrition (such as maternal vitamin D sufficiency) and the microbiome on asthma risk. Asthma and allergies are among many diseases that could be influenced by prenatal microbial factors; other conditions that currently result in large public health burdens and could be addressed by modifying the prenatal microbiome include obesity and neurodevelopmental outcomes.9Zhang S. Qin X. Li P. Huang K. Effect of elective cesarean section on children's obesity from birth to adolescence: a systematic review and meta-analysis.Front Pediatr. 2022; 9793400Crossref Scopus (8) Google Scholar,10Kim S. Kim H. Yim Y.S. Ha S. Atarashi K. Tan T.G. et al.Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring.Nature. 2017; 549: 528-532Crossref PubMed Scopus (407) Google Scholar The weight of evidence to date favors the concept that the prenatal and perinatal periods are critical periods in which interventions could reduce incidence of asthma and allergies. Although some strategies, such as prenatal vitamin D supplementation, may be partly mechanistically independent of the microbiome, others such as dietary supplementation and vaginal seeding are very likely to operate at least in part via microbiome changes. The microbiome is dynamic over the lifespan (including over pregnancy), is highly influenced by the diet, engages in cross talk with the host metabolome, and is likely to have effects that are modified by maternal and offspring epigenetic and genetic variation. For example, breast-feeding has a well-established and strong effect on the offspring microbiome, and breast milk composition is influenced by environmental, genetic, and physiologic factors. This complexity, along with the heterogeneity in asthma and allergy phenotypes and endotypes, points to a likely need for precision medicine approaches to tailor effective prenatal microbiome-modifying strategies to the correct target populations. With some potential interventions already in clinical trials and microbiome profiling and bioinformatic approaches advancing rapidly, we are hopeful that in the future, we will be seeing the mechanistic insights that we have described here translated into a real-world reduction in the incidence of asthma, allergies, and many other diseases. Our current recommendations to physicians caring for pregnant women at high risk of having children with asthma and allergies is to supplement those women with 4400 IU of vitamin D daily following conception and avoid cesarian section as a mode of delivery if medically possible. Supported by grant K08 HL148178 (to K.L.S.) and grant 5UH3OD023268 (to A.A.L., S.T.W., and Y.Y.L.). Disclosure of potential conflict of interest: A. A. Litonjua has received author royalties from UpToDate. S. T. Weiss has received royalties from UpToDate and is on the board of Histolix. The rest of the authors declare that they have no relevant conflicts of interest.

Importance:The prevalence of obesity among youths 2 to 19 years of age in the US from 2017 to 2018 was 19.3%; previous studies suggested that school lunch consumption was associated with increased obesity. The Healthy, Hunger-Free Kids Act of 2010 (HHFKA) strengthened nutritional standards of school-based meals. Objective:To evaluate the association between the HHFKA and youth body mass index (BMI). Design, Setting, and Participants:This cohort study was conducted using data from the Environmental Influences on Child Health Outcomes program, a nationwide consortium of child cohort studies, between January 2005 and March 2020. Cohorts in the US of youths aged 5 to 18 years with reported height and weight measurements were included. Exposures:Full implementation of the HHFKA. Main Outcomes and Measures:The main outcome was annual BMI z-score (BMIz) trends before (January 2005 to August 2016) and after (September 2016 to March 2020) implementation of the HHFKA, adjusted for self-reported race, ethnicity, maternal education, and cohort group. An interrupted time-series analysis design was used to fit generalized estimating equation regression models. Results:A total of 14 121 school-aged youths (7237 [51.3%] male; mean [SD] age at first measurement, 8.8 [3.6] years) contributing 26 205 BMI measurements were included in the study. Overall, a significant decrease was observed in the annual BMIz in the period following implementation of the HHFKA compared with prior to implementation (-0.041; 95% CI, -0.066 to -0.016). In interaction models to evaluate subgroup associations, similar trends were observed among youths 12 to 18 years of age (-0.045; 95% CI, -0.071 to -0.018) and among youths living in households with a lower annual income (-0.038; 95% CI, -0.063 to -0.013). Conclusions and Relevance:In this cohort study, HHFKA implementation was associated with a significant decrease in BMIz among school-aged youths in the US. The findings suggest that school meal programs represent a key opportunity for interventions to combat the childhood obesity epidemic given the high rates of program participation and the proportion of total calories consumed through school-based meals.

Environmental, genetic, and microbial factors are independently associated with childhood asthma. We aimed to determine the roles of environmental exposures and 17q21 locus genotype in the maturation of the early-life microbiome in childhood asthma. We analyzed fecal 16s rRNA sequencing at 3-6 months and 1 year of age to characterize microbial maturation of offspring of participants in the Vitamin D Antenatal Reduction Trial (VDAART). We determined associations of microbial maturation and environmental exposures in the mediation of asthma risk at age 3 years. We examined 17q21 genotype and microbial maturation associations with asthma risk in VDAART and sought replication of key results in the Copenhagen Prospective Studies on Childhood Asthma 2010 (COPSAC) cohort. Accelerated fecal microbial maturation at 3-6 months and delayed microbial maturation at 1 year of age were associated with asthma (p<0.001 in VDAART). In VDAART participants, fecal Bacteroides was reduced at age 3-6 months in association with subsequent asthma (p=0.006) and among subjects with lower microbial maturation at 1 year of age (q=0.009). Breastfeeding was associated with reduced asthma in VDAART participants, and 61% of the association between breastfeeding and asthma was mediated by microbial maturation at 3-6 months of age. In both VDAART and COPSAC cohorts, microbial maturation and 17q21 genotypes exhibited independent, additive effects on childhood asthma risk. The intestinal microbiome and its maturation mediates associations between environmental exposures including breastfeeding and asthma. The intestinal microbiome and 17q21 genotype appear to exert additive and independent effects on childhood asthma risk.

Background It has been widely recognized that a critical time window for neurodevelopment occurs in early life and the host's gut microbiome plays an important role in neurodevelopment. Following recent demonstrations that the maternal prenatal gut microbiome influences offspring brain development in murine models, we aim to explore whether the critical time window for the association between the gut microbiome and neurodevelopment is prenatal or postnatal for human.Methods Here we leverage a large-scale human study and compare the associations between the gut microbiota and metabolites from mothers during pregnancy and their children with the children's neurodevelopment. Specifically, using multinomial regression integrated in Songbird, we assessed the discriminating power of the maternal prenatal and child gut microbiome for children's neurodevelopment at early life as measured by the Ages & Stages Questionnaires (ASQ).Findings We show that the maternal prenatal gut microbiome is more relevant than the children's gut microbiome to the children's neurodevelopment in the first year of life (maximum Q2 = 0.212 and 0.096 separately using the taxa at the class level). Moreover, we found that Fusobacteriia is more associated with high fine motor skills in ASQ in the maternal prenatal gut microbiota but become more associated with low fine motor skills in the infant gut microbiota (rank = 0.084 and -0.047 separately), suggesting the roles of the same taxa with respect to neurodevelopment can be opposite at the two stages of fetal neurodevelopment.Interpretation These findings shed light, especially in terms of timing, on potential therapeutic interventions to prevent neurodevelopmental disorders.

The early life microbiome plays an important role in developmental and long-term health outcomes. However, it is unknown whether adverse pregnancy complications affect the offspring's gut microbiome post-natally and in early years. In a longitudinal cohort with a five-year follow-up of mother-child pairs affected by preeclampsia (PE) or spontaneous preterm birth (sPTB), we evaluated offspring gut alpha and beta diversity as well as taxa abundances considering factors like breastfeeding and mode of delivery. Our study highlights a trend where microbiome diversity exhibits comparable development across adverse and normal pregnancies. However, specific taxa at genus level emerge with distinctive abundances, showing enrichment and/or depletion over time in relation to PE or sPTB. These findings underscore the potential for certain adverse pregnancy complications to induce alterations in the offspring's microbiome over the course of early life. The implications of these findings on the immediate and long-term health of offspring should be investigated in future studies.

Associations of omega-3 fatty acids (n-3) with allergic diseases are inconsistent, perhaps in part due to genetic variation. We sought to identify and validate genetic variants that modify associations of n-3 with childhood asthma or atopy in participants in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC). Dietary n-3 was derived from food frequency questionnaires and plasma n-3 was measured via untargeted mass spectrometry in early childhood and children aged 6 years old. Interactions of genotype with n-3 in association with asthma or atopy at age 6 years were sought for six candidate genes/gene regions and genome-wide. Two SNPs in the region of DPP10 (rs958457 and rs1516311) interacted with plasma n-3 at age 3 years in VDAART (p = 0.007 and 0.003, respectively) and with plasma n-3 at age 18 months in COPSAC (p = 0.01 and 0.02, respectively) in associationwith atopy. Another DPP10 region SNP, rs1367180, interacted with dietary n-3 at age 6 years in VDAART (p = 0.009) and with plasma n-3 at age 6 years in COPSAC (p = 0.004) in association with atopy. No replicated interactions were identified for asthma. The effect of n-3 on reducing childhood allergic disease may differ by individual factors, including genetic variation in the DPP10 region.

Shifts in the maternal gut microbiome and vitamin D deficiency during pregnancy have been associated, separately, with health problems for both the mother and the child. Yet, they have rarely been studied simultaneously. Here, we analyzed the gut microbiome (from stool samples obtained in late pregnancy) and vitamin D level (from blood samples obtained both in early and late pregnancy) data of pregnant women in the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a randomized controlled trial of vitamin D supplementation during pregnancy, to investigate the association of vitamin D status on the pregnant women’s microbiome. To find associations, we ran linear regressions on alpha diversity measures, PERMANOVA tests on beta diversity distances, and used the ANCOM-BC and Maaslin2 algorithms to find differentially abundant taxa. Analyses were deemed significant using a cut-off p-value of 0.05. We found that gut microbiome composition is associated with the vitamin D level in early pregnancy (baseline), the maternal gut microbiome does not show a shift in response to vitamin D supplementation during pregnancy, and that the genus Desulfovibrio is enriched in women without a substantial increase in vitamin D level between the first and the third trimesters of pregnancy. We conclude that increasing the vitamin D level during pregnancy could be protective against the growth of sulfate-reducing bacteria such as Desulfovibrio, which has been associated with chronic intestinal inflammatory disorders. More in-depth investigations are needed to confirm this hypothesis.

Background: Environmental, genetic, and microbial factors are independently associated with childhood asthma. Objective: We sought to determine the roles of environmental exposures and 17q12-21 locus genotype in the maturation of the early-life microbiome in childhood asthma. Methods: We analyzed fecal 16s rRNA sequencing at age 3 to months and age 1 year to characterize microbial maturation offspring of participants in the Vitamin D Antenatal Reduction Trial. We determined associations of microbial maturation and environmental exposures in the mediation of asthma risk at age 3 years. We examined 17q12-21 genotype and microbial maturation associations with asthma risk in Vitamin D Antenatal Reduction Trial and the replication cohort Copenhagen Prospective Studies on Childhood Asthma 2010. Results: Accelerated fecal microbial maturation at age 3 to 6 months and delayed maturation at age 1 year were associated with asthma (P < .001). Fecal Bacteroides was reduced at age 3 6 months in association with subsequent asthma (P = .006) and among subjects with lower microbial maturation at age 1 year (q = 0.009). Sixty-one percent of the association between breast-feeding and asthma was mediated by microbial maturation at age 3 to 6 months. Microbial maturation and 17q12-21 genotypes exhibited independent, additive effects on childhood asthma risk. Conclusions: The intestinal microbiome and its maturation mediates associations between environmental exposures including breast-feeding and asthma. The intestinal microbiome and 17q12-21 genotype appear to exert additive and independent effects on childhood asthma risk. (J Allergy Clin Immunol 2023;151:1494-502.)

Characterizing the metabolic profile of a microbial community is crucial for understanding its biological function and its impact on the host or environment. Metabolomics experiments directly measuring these profiles are difficult and expensive, whereas sequencing methods quantifying the species composition of microbial communities are well developed and relatively cost-effective. Computational methods that are capable of predicting metabolomic profiles from microbial compositions can save considerable efforts needed for metabolomic profiling experimentally. Yet, despite existing efforts, we still lack a computational method with high prediction power, general applicability and great interpretability. Here we develop a method called metabolomic profile predictor using neural ordinary differential equations (mNODE), based on a state-of-the-art family of deep neural network models. We show compelling evidence that mNODE outperforms existing methods in predicting the metabolomic profiles of human microbiomes and several environmental microbiomes. Moreover, in the case of human gut microbiomes, mNODE can naturally incorporate dietary information to further enhance the prediction of metabolomic profiles. Furthermore, susceptibility analysis of mNODE enables us to reveal microbe–metabolite interactions, which can be validated using both synthetic and real data. The results demonstrate that mNODE is a powerful tool to investigate the microbiome–diet–metabolome relationship, facilitating future research on precision nutrition. Computational models can help predict metabolic profiles of microbial communities such as human gut microbiomes or environmental microbiomes, but they lack generalizability and interpretability. To address this challenge, Wang et al. report a deep learning approach for metabolic profile prediction called mNODE that incorporates a neural network module with hidden layers described by ordinary differential equations.

BACKGROUND:While dysregulated sphingolipid metabolism has been associated with risk of childhood asthma, the specific sphingolipid classes and/or mechanisms driving this relationship remain unclear. We aimed to understand the multifaceted role between sphingolipids and other established asthma risk factors that complicate this relationship. METHODS:We performed targeted LC-MS/MS-based quantification of 77 sphingolipids in plasma from 997 children aged 6 years from two independent cohorts (VDAART and COPSAC2010 ). We examined associations of circulatory sphingolipids with childhood asthma, lung function, and three asthma risk factors: functional SNPs in ORMDL3, low vitamin D levels, and reduced gut microbial maturity. Given racial differences between these cohorts, association analyses were performed separately and then meta-analyzed together. RESULTS:We observed elevations in circulatory sphingolipids with asthma phenotypes and risk factors; however, there were differential associations of sphingolipid classes with clinical outcomes and/or risk factors. While elevations from metabolites involved in ceramide recycling and catabolic pathways were associated with asthma and worse lung function [meta p-value range: 1.863E-04 to 2.24E-3], increased ceramide levels were associated with asthma risk factors [meta p-value range: 7.75E-5 to .013], but not asthma. Further investigation identified that some ceramides acted as mediators while some interacted with risk factors in the associations with asthma outcomes. CONCLUSION:This study demonstrates the differential role that sphingolipid subclasses may play in asthma and its risk factors. While overall elevations in sphingolipids appeared to be deleterious overall; elevations in ceramides were uniquely associated with increases in asthma risk factors only; while elevations in asthma phenotypes were associated with recycling sphingolipids. Modification of asthma risk factors may play an important role in regulating sphingolipid homeostasis via ceramides to affect asthma. Further function work may validate the observed associations.