Precocious infant fecal microbiome promotes enterocyte barrier dysfuction, altered neuroendocrine signaling and associates with increased childhood obesity risk.

Early life gut microbiome composition has been correlated with childhood obesity, though microbial functional contributions to disease origins remain unclear. Here, using an infant birth cohort (n = 349) we identify a distinct fecal microbiota composition in 1-month-old infants with the lowest rate of exclusive breastfeeding, that relates with higher relative risk for obesity and overweight phenotypes at two years. Higher-risk infant fecal microbiomes exhibited accelerated taxonomic and functional maturation and broad-ranging metabolic reprogramming, including reduced concentrations of neuro-endocrine signals. In vitro, exposure of enterocytes to fecal extracts from higher-risk infants led to upregulation of genes associated with obesity and with expansion of nutrient sensing enteroendocrine progenitor cells. Fecal extracts from higher-risk infants also promoted enterocyte barrier dysfunction. These data implicate dysregulation of infant microbiome functional development, and more specifically promotion of enteroendocrine signaling and epithelial barrier impairment in the early-life developmental origins of childhood obesity.

Early-life gut microbiota and attention deficit hyperactivity disorder in preadolescents.

BACKGROUND: Gut microbiota maturation coincides with nervous system development. Cross-sectional data suggest gut microbiota of individuals with and without attention deficit hyperactivity disorder (ADHD) differs. We hypothesized that infant gut microbiota composition is associated with later ADHD development in our on-going birth cohort study, WHEALS. METHODS: Gut microbiota was profiled using 16S ribosomal RNA and the internal transcribed spacer region 2 (ITS2) sequencing in stool samples from 1 month and 6 months of age. ADHD was defined by parent-reported or medical record doctor diagnosis at age 10. RESULTS: A total of 314 children had gut microbiota and ADHD data; 59 (18.8%) had ADHD. After covariate adjustment, bacterial phylogenetic diversity (p = 0.017) and bacterial composition (unweighted UniFrac p = 0.006, R2 = 0.9%) at age 6 months were associated with development of ADHD. At 1 month of age, 18 bacterial and 3 fungal OTUs were associated with ADHD development. At 6 months of age, 51 bacterial OTUs were associated with ADHD; 14 of the order Lactobacillales. Three fungal OTUs at 6 months of age were associated with ADHD development. CONCLUSIONS: Infant gut microbiota is associated with ADHD development in pre-adolescents. Further studies replicating these findings and evaluating potential mechanisms of the association are needed. IMPACT: Cross-sectional studies suggest that the gut microbiota of individuals with and without ADHD differs. We found evidence that the bacterial gut microbiota of infants at 1 month and 6 months of age is associated with ADHD at age 10 years. We also found novel evidence that the fungal gut microbiota in infancy (ages 1 month and 6 months) is associated with ADHD at age 10 years. This study addresses a gap in the literature in providing longitudinal evidence for an association of the infant gut microbiota with later ADHD development.

Maternal and cord blood vitamin D level and the infant gut microbiota in a birth cohort study.

BACKGROUND: Mounting evidence suggests both vitamin D and the early life gut microbiome influence childhood health outcomes. However, little is known about how these two important exposures are related. We aimed to examine associations between plasma 25-hydroxyvitamin D (25[OH]D) levels during pregnancy or at delivery (cord blood) and infant gut microbiota. METHODS: Maternal and cord blood 25[OH]D levels were assessed in a sample of pregnant women. Compositional analyses adjusted for race were run on the gut microbiota of their offspring at 1 and 6 months of age. RESULTS: Mean prenatal 25(OH)D level was 25.04 ± 11.62 ng/mL and mean cord blood 25(OH)D level was 10.88 ± 6.77 ng/mL. Increasing prenatal 25(OH)D level was significantly associated with decreased richness (p = 0.028) and diversity (p = 0.012) of the gut microbiota at 1 month of age. Both prenatal and cord 25(OH)D were significantly associated with 1 month microbiota composition. A total of 6 operational taxonomic units (OTUs) were significantly associated with prenatal 25(OH)D level (four positively and two negatively) while 11 OTUs were significantly associated with cord 25(OH)D (10 positively and one negatively). Of these, OTU 93 (Acinetobacter) and OTU 210 (Corynebacterium), were consistently positively associated with maternal and cord 25(OH)D; OTU 64 (Ruminococcus gnavus) was positively associated with prenatal 25(OH)D but negatively associated with cord 25(OH)D. CONCLUSIONS: Prenatal maternal and cord blood 25(OH)D levels are associated with the early life gut microbiota. Future studies are needed to understand how vitamin D and the microbiome may interact to influence child health.

Association between cesarean delivery types and obesity in preadolescence.

BACKGROUND/OBJECTIVES: The association between mode of delivery and childhood obesity remains inconclusive. Because few studies have separated C-section types (planned or unplanned C-section), our objective was to assess how these subtypes relate to preadolescent obesity. SUBJECTS/METHODS: The study consisted of 570 maternal-child pairs drawn from the WHEALS birth cohort based in Detroit, Michigan. Children were followed-up at 10 years of age where a variety of anthropometric measurements were collected. Obesity was defined based on BMI percentile (≥95th percentile), as well as through Gaussian finite mixture modeling on the anthropometric measurements. Risk ratios (RRs) and 95% confidence intervals (CIs) for obesity comparing planned and unplanned C-sections to vaginal deliveries were computed, which utilized inverse probability weights to account for loss to follow-up and multiple imputation for covariate missingness. Mediation models were fit to examine the mediation role of breastfeeding. RESULTS: After adjusting for marital status, maternal race, prenatal tobacco smoke exposure, maternal age, maternal BMI, any hypertensive disorders during pregnancy, gestational diabetes, prenatal antibiotic use, child sex, parity, and birthweight z-score, children born via planned C-section had 1.77 times higher risk of obesity (≥95th percentile), relative to those delivered vaginally ((95% CI) = (1.16, 2.72); p = 0.009). No association was found comparing unplanned C-section to vaginal delivery (RR (95% CI) = 0.75 (0.45, 1.23); p = 0.25). The results were similar but slightly stronger when obesity was defined by anthropometric class (RR (95% CI) = 2.78 (1.47, 5.26); p = 0.002). Breastfeeding did not mediate the association between mode of delivery and obesity. CONCLUSIONS: These findings indicate that children delivered via planned C-section-but not unplanned C-section-have a higher risk of preadolescent obesity, suggesting that partial labor or membrane rupture (typically experienced during unplanned C-section delivery) may offer protection. Additional research is needed to understand the biological mechanisms behind this effect, including whether microbiological differences fully or partially account for the association.

Fetal and early postnatal lead exposure measured in teeth associates with infant gut microbiota.

BACKGROUND: Lead (Pb) is an environmentally ubiquitous heavy metal associated with a wide range of adverse health effects in children. Both lead exposure and the early life microbiome- which plays a critical role in human development-have been linked to similar health outcomes, but it is unclear if the adverse effects of lead are partially driven by early life gut microbiota dysbiosis. The objective of this study was to examine the association between in utero and postnatal lead levels (measured in deciduous baby teeth) and early life bacterial and fungal gut microbiota in the first year of life. METHODS: Data from the Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS) birth cohort were analyzed. Tooth lead levels during the 2nd and 3rd trimesters and postnatally (<1 year of age) were quantified using high-resolution microspatial mapping of dentin growth rings. Early life microbiota were measured in stool samples collected at approximately 1 and 6 months of age, using both 16S rRNA (bacterial) and ITS2 (fungal) sequencing. Of the 1,258 maternal-child pairs in WHEALS, 146 had data on both tooth metals and early life microbiome. RESULTS: In utero tooth lead levels were significantly associated with gut fungal community composition at 1-month of age, where higher levels of 2nd trimester tooth lead was associated with lower abundances of Candida and Aspergillus and higher abundances of Malassezia and Saccharomyces; 3rd trimester lead was also associated with lower abundances of Candida. Though lead did not significantly associate with the overall structure of the infant gut bacterial community, it associated with the abundance of some specific bacterial taxa, including the increased abundance of Collinsella and Bilophila and a decreased abundance of Bacteroides taxa. CONCLUSIONS: The observed associations between lead exposure and infant gut microbiota could play a role in the impact of lead on childhood development. Given the paucity of research examining these associations in humans-particularly for fungal microbiota-further investigation is needed.

Gut Microbial Metabolism and Nonalcoholic Fatty Liver Disease.

The gut microbiome, the multispecies community of microbes that exists in the gastrointestinal tract, encodes several orders of magnitude more functional genes than the human genome. It also plays a pivotal role in human health, in part due to metabolism of environmental, dietary, and host-derived substrates, which produce bioactive metabolites. Perturbations to the composition and associated metabolic output of the gut microbiome have been associated with a number of chronic liver diseases, including nonalcoholic fatty liver disease (NAFLD). Here, we review the rapidly evolving suite of next-generation techniques used for studying gut microbiome composition, functional gene content, and bioactive products and discuss relationships with the pathogenesis of NAFLD.