Metagenomic analysis reveals associations between salivary microbiota and body composition in early childhood.

Several studies have shown that body mass index is strongly associated with differences in gut microbiota, but the relationship between body weight and oral microbiota is less clear especially in young children. We aimed to evaluate if there is an association between child growth and the saliva microbiome. We hypothesized that associations between growth and the saliva microbiome would be moderate, similarly to the association between growth and the gut microbiome. For 236 toddlers participating in the New Hampshire Birth Cohort Study, we characterized the association between multiple longitudinal anthropometric measures of body height, body weight and body mass. Body Mass Index (BMI) z-scores were calculated, and dual-energy x-ray absorptiometry (DXA) was used to estimate body composition. Shotgun metagenomic sequencing of saliva samples was performed to taxonomically and functionally profile the oral microbiome. We found that within-sample diversity was inversely related to body mass measurements while community composition was not associated. Although the magnitude of associations were small, some taxa were consistently associated with growth and modified by sex. Certain taxa were associated with decreased weight or growth (including Actinomyces odontolyticus and Prevotella melaninogenica) or increased growth (such as Streptococcus mitis and Corynebacterium matruchotii) across anthropometric measures. Further exploration of the functional significance of this relationship will enhance our understanding of the intersection between weight gain, microbiota, and energy metabolism and the potential role of these relationships on the onset of obesity-associated diseases in later life.

Bronchiolitis hospitalizations in rural New England: clues to disease prevention.

Background: An improved understanding of the clinico-epidemiology of bronchiolitis hospitalizations, a clinical surrogate of respiratory syncytial virus (RSV) disease, is critical to inform public health strategies for mitigating the in-patient burden of bronchiolitis in early life. Methods: A retrospective chart review was conducted of all bronchiolitis first admissions (N = 295) to the Children's Hospital at Dartmouth-Hitchcock, CHaD, between 1 November 2010 and 31 October 2017 using the relevant International Classification of Diseases (ICD)-9 and ICD-10 codes for this illness. Abstracted data included laboratory confirmation of RSV infection, severity of illness, duration of hospitalization, age at admission in days, weight at admission, prematurity, siblings, and relevant medical pre-existing conditions. Results: Admissions for bronchiolitis were strongly associated with age of the child, the calendar month of an infant's birth, and the presence of older children in the family. Medical risk factors associated with admission included premature birth and underlying cardiopulmonary disease. Conclusion: The very early age of hospitalization emphasizes the high penetration of RSV in the community, by implication the limited protection afforded by maternal antibody, and the complexity of protecting infants from this infection. Plain Language Summary: Although risks for respiratory syncytial virus (RSV)/bronchiolitis hospitalization are well described, few studies have examined, with precision, the age-related frequency and severity of RSV/bronchiolitis. We also explore the implications of RSV clinico-epidemiology for our understanding of the pathogenesis of the disease and development of optimal approaches to prevention.

Impact of antibiotics on off-target infant gut microbiota and resistance genes in cohort studies.

BACKGROUND: Young children are frequently exposed to antibiotics, with the potential for collateral consequences to the gut microbiome. The impact of antibiotic exposures to off-target microbes (i.e., bacteria not targeted by treatment) and antibiotic resistance genes (ARGs) is poorly understood. METHODS: We used metagenomic sequencing data from paired stool samples collected prior to antibiotic exposure and at 1 year from over 200 infants and a difference-in-differences approach to assess the relationship between subsequent exposures and the abundance or compositional diversity of microbes and ARGs while adjusting for covariates. RESULTS: By 1 year, the abundance of multiple species and ARGs differed by antibiotic exposure. Compared to infants never exposed to antibiotics, Bacteroides vulgatus relative abundance increased by 1.72% (95% CI: 0.19, 3.24) while Bacteroides fragilis decreased by 1.56% (95% CI: -4.32, 1.21). Bifidobacterium species also exhibited opposing trends. ARGs associated with exposure included class A beta-lactamase gene CfxA6. Among infants attending day care, Escherichia coli and ARG abundance were both positively associated with antibiotic use. CONCLUSION: Novel findings, including the importance of day care attendance, were identified through considering microbiome data at baseline and post-intervention. Thus, our study design and approach have important implications for future studies evaluating the unintended impacts of antibiotics. IMPACT: The impact of antibiotic exposure to off-target microbes and antibiotic resistance genes in the gut is poorly defined. We quantified these impacts in two cohort studies using a difference-in-differences approach. Novel to microbiome studies, we used pre/post-antibiotic data to emulate a randomized controlled trial. Compared to infants unexposed to antibiotics between baseline and 1 year, the relative abundance of multiple off-target species and antibiotic resistance genes was altered. Infants who attended day care and were exposed to antibiotics within the first year had a higher abundance of Escherichia coli and antibiotic resistance genes; a novel finding warranting further investigation.

Association of Cesarean Delivery and Formula Supplementation with the Stool Metabolome of 6-Week-Old Infants.

Cesarean delivery and formula feeding have both been implicated as important factors associated with perturbations to the infant gut microbiome. To investigate the functional metabolic response of the infant gut microbial milieu to these factors, we profiled the stool metabolomes of 121 infants from a US pregnancy cohort study at approximately 6 weeks of life and evaluated associations with delivery mode and feeding method. Multivariate analysis of six-week stool metabolomic profiles indicated discrimination by both delivery mode and diet. For diet, exclusively breast-fed infants exhibited metabolomic profiles that were distinct from both exclusively formula-fed and combination-fed infants, which were relatively more similar to each other in metabolomic profile. We also identified individual metabolites that were important for differentiating delivery mode groups and feeding groups and metabolic pathways related to delivery mode and feeding type. We conclude based on previous work and this current study that the microbial communities colonizing the gastrointestinal tracts of infants are not only taxonomically, but also functionally distinct when compared according to delivery mode and feeding groups. Further, different sets of metabolites and metabolic pathways define delivery mode and diet metabotypes.

The infant gut resistome is associated with E. coli and early-life exposures.

BACKGROUND: The human gut microbiome harbors a collection of bacterial antimicrobial resistance genes (ARGs) known as the resistome. The factors associated with establishment of the resistome in early life are not well understood. We investigated the early-life exposures and taxonomic signatures associated with resistome development over the first year of life in a large, prospective cohort in the United States. Shotgun metagenomic sequencing was used to profile both microbial composition and ARGs in stool samples collected at 6 weeks and 1 year of age from infants enrolled in the New Hampshire Birth Cohort Study. Negative binomial regression and statistical modeling were used to examine infant factors such as sex, delivery mode, feeding method, gestational age, antibiotic exposure, and infant gut microbiome composition in relation to the diversity and relative abundance of ARGs. RESULTS: Metagenomic sequencing was performed on paired samples from 195 full term (at least 37 weeks' gestation) and 15 late preterm (33-36 weeks' gestation) infants. 6-week samples compared to 1-year samples had 4.37 times (95% CI: 3.54-5.39) the rate of harboring ARGs. The majority of ARGs that were at a greater relative abundance at 6 weeks (chi-squared p < 0.01) worked through the mechanism of antibiotic efflux. The overall relative abundance of the resistome was strongly correlated with Proteobacteria (Spearman correlation = 78.9%) and specifically Escherichia coli (62.2%) relative abundance in the gut microbiome. Among infant characteristics, delivery mode was most strongly associated with the diversity and relative abundance of ARGs. Infants born via cesarean delivery had a trend towards a higher risk of harboring unique ARGs [relative risk = 1.12 (95% CI: 0.97-1.29)] as well as having an increased risk for overall ARG relative abundance [relative risk = 1.43 (95% CI: 1.12-1.84)] at 1 year compared to infants born vaginally. CONCLUSIONS: Our findings suggest that the developing infant gut resistome may be alterable by early-life exposures. Establishing the extent to which infant characteristics and early-life exposures impact the resistome can ultimately lead to interventions that decrease the transmission of ARGs and thus the risk of antibiotic resistant infections.