Nutrition and development Understanding early-life tryptophan metabolism

Early life represents a critical window for intestinal and immune development, during which microbial and metabolic processes shape long-term health outcomes. This thesis investigates how early-life tryptophan metabolism is influenced by microbial colonization, diet and developmental maturation, and how perturbations in these factors contribute to immune dysregulation and disease susceptibility. Particular focus is placed on microbial-derived tryptophan metabolites and their ability to activity the aryl hydrocarbon receptor (AhR).
Longitudinal profiling of fecal metabolites in term infants displayed that indole-3-lactic acid (ILA) is the dominant microbial-derived indole in early infancy and correlates with Bifidobacterium. With dietary diversification, ILA declines and is replaced by a broader diversity of indole metabolites, reflecting functional maturation of the gut microbiome. Infants who later develop eczema exhibit alterations in tryptophan metabolism, suggesting early metabolic deviations associated with disease risk.
Prematurity is associated with delayed microbial indole production and increased host-derived kynurenine and serotonin pathway metabolites, while exclusive human milk feeding promotes higher ILA levels and distinct microbial profiles. Functional analyses demonstrate that microbial-derived indoles activate AhR, attenuate epithelial inflammation and preserve barrier integrity in intestinal cells and human fetal organoids. Furthermore, germ-free and AhR-deficient mice experiements confirmed that microbial colonization and AhR signaling are essential for normal intestinal development. Finally, we evaluate the diagnostic potential of oligo-hybridization capture sequencing for neonatal microbiome profiling, showing improved taxonomic resolution compared to 16S rRNA sequencing and current technical limitations.
Collectively, this work establishes early-life tryptophan metabolism as a developmentally regulated system linking the microbiome to intestinal and immune maturation, with potential diagnostic and therapeutic relevance.