Background Breastmilk confers numerous benefits to infants relative to formula milk, such as promoting metabolic health and supporting immune homeostasis. However, in-depth mechanistic insights comparing the influence of breastmilk versus formula milk across different compartments are lacking. Methods Several datasets interrogating the effects of breastmilk versus formula milk were curated, including transcriptomes of infant intestinal organoids, intestinal gene expression microarray, and single cell RNA-seq data for infant peripheral blood mononuclear cells (PBMCs). Comparative analyses were performed, with a specific focus on differences at a signal pathway level. Results Comparative analyses revealed that intestinal exposure to breastmilk was linked to elevated gluconeogenesis, as well as reprogramming of other metabolic, nutrient-sensing and immune-related pathways. Contrarily, in PBMCs, formula milk feeding was linked to upregulation of apoptosis-related pathways across all PBMC subsets. Conclusions Breastmilk reprograms the transcriptomic landscapes of infant intestine, particularly promoting intestinal gluconeogenesis. This might explain its metabolic advantages via modulating metabolic homeostasis. Different effects were found in PBMCs, where formula milk is linked to enhanced apoptotic signalling in the infant's developing immune cell subsets.

The authors have declared no competing interest.

This project is supported by the Norman Ernest Bequest Fund.

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Data is available as Gene Expression Omnibus ID: GSE253501, GSE31075, GSE296678.

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Data is available as Gene Expression Omnibus ID: GSE253501, GSE31075, GSE296678.