Abstract

Neonatal exposures can affect long term health outcomes, particularly within childhood asthma, obesity, and diabetes. Early microbial exposures have been well characterized, showing the importance of inoculation events related to birth route (natural versus cesarian section). However, maturation of the infant gastrointestinal metabolome remains largely uncharacterized. In this work, we further characterize infant fecal metabolome development across the first year of life in addition to investigating the impact the gastrointestinal microbiome has in shaping this chemical space. We utilize two approaches for the identification of significant metabolite shifts through the first 12 months of life; the first relies on random regression models of the presence or absence of a feature and the second is based on random forest machine learning. Analysis of presence/absence trajectories identified decreased prevalence of glucuronidated cholestanes while also identifying increases in the prevalence of metabolites related to tocopherol (vitamin E) and β-carotene. RF analysis identified decreases in sulfated cholate and bile acid (BA)-related metabolites with age. Both sulfation and glucuronidation are known detoxification methods and, given the prevalence of neonatal cholestasis (~1:2500 infants, globally), detoxifying BAs is an essential host process of particular importance early in life. Investigating cocorrelations between metabolome and microbiome data via presence/absence trajectories shows that bacteria within the family Lachnospiraceae, particularly within the genus Ruminococcus, noticeably impact the fecal metabolome as they are involved in 71 of 140 microbe-metabolite cocorrelations. Finally, we sought to characterize how external factors impact both the metabolome and microbiome through age-stratified fitting of environmental metadata to sample ordinations. Infant metabolomes and microbiomes are similarly impacted by dietary factors (e.g., predominantly breastfeeding). However, maternal health before and after pregnancy significantly impacts the metabolome more than the microbiome. Further works is needed to understand how these changes impact long-term host, metabolome, and microbiome maturation.