Gut microbiota-host metabolic interactions in human development

Abstract

The microbial communities living in the gut exist in symbiosis with the host and perform biological functions that are fundamental to human physiology. Evidence from animal studies suggests that disturbing host-microbe interactions during developmental phases has lasting consequences, but evidence in humans is lacking. Aberrant metabolism was investigated during two periods of development - pregnancy and early childhood - to define functional associations between the gut microbiota and aspects of altered development. Maternal obesity is associated with fetal overgrowth, but the relationship between obesity, the maternal gut microbiota and neonatal outcomes has not been thoroughly investigated. This thesis details longitudinal shifts in gestational metabolism with maternal body mass index, which were linked to elevated insulin resistance during pregnancy, elevated neonatal insulin levels and high birth weight. A direct association between the maternal gut microbiota and neonatal outcomes was not observed. However, maternal insulin resistance, which is thought to contribute to fetal overgrowth, was positively correlated with bacteria-derived metabolites. Obese women with a previous weight loss surgery had reduced insulin resistance during pregnancy, which was associated with changes in gut microbial composition and host-microbe co-metabolism. The identified metabolites were linked to lower birth weight, demonstrating the metabolism of the maternal gut microbiota may influence fetal growth either directly, or through modulation of maternal insulin resistance. In addition to prospective associations, retrospective microbiota-associated signatures of altered neurodevelopment were sought in a childhood cohort, but could not be identified. However, subgroups of children with Autism Spectrum Disorder were distinguished based on patterns of host-microbe co-metabolism of dietary protein, which may be associated with gastrointestinal dysfunction. Collectively, this thesis deciphers several associations between microbial and metabolic profiles, demonstrating the systemic capacity of gut microbes to influence human metabolism. The results presented herein provide a foundation for investigating mechanistic links between the metabolic activity of the gut microbiota during pregnancy and fetal development, but prospective birth cohorts are needed to study the relationship between gut microbial communities and altered neurodevelopment.