Functional gut variability drives metabolic and transcriptional features in neonatal piglets

The inherent inter-individual variability and associated complexity of dietary response constitute a major research challenge, but also present an opportunity to trace personalized patterns that may serve as targets for improving health. Here, we investigated the function of α-lactalbumin, a rich source of tryptophan, in a formula feeding study. We leveraged neonatal piglets as a preclinical model for human infants and took a systems-level approach that integrates evidence from serum, urine, liver, brain, and the gastrointestinal tract. Transcriptional and metabolomics analysis revealed an individualized, divergent response to α-lactalbumin linked to either efficient utilization of tryptophan by the host or production of indole-3-lactate by intestinal microbiota. This variability was further highlighted by differences in metabolic and immunological effects in a tissue-specific manner. Our work highlights the importance of considering the nutrition-microbiota-host metabolism axis to optimize the phenotypic response of a diet.