Breast Milk Bioactive Components and Early-Life Epigenetic Programming: Implications for Nutrigenomics and Population Health.

Multifactorial diseases cannot be fully explained by genetic variation alone, highlighting the importance of epigenetic mechanisms that integrate early-life environmental exposures with long-term health outcomes. Within the Developmental Origins of Health and Disease (DOHaD) framework, human breast milk has emerged as a critical regulator of early-life epigenetic programming. Breast milk-derived bioactive components, including non-coding RNAs, extracellular vesicles, immune factors, hormones, and human milk oligosaccharides, actively modulate DNA methylation, chromatin structure, and gene expression involved in immune, metabolic, and developmental pathways, according to recent mechanistic, clinical, and epidemiological evidence. From a nutrigenomic perspective, breast milk represents a highly individualized exposure shaped by maternal genetics, physiology, and environment, potentially influencing infant gene regulation during sensitive developmental windows. This concept provides a biological basis for exploring "milk kinship," a culturally recognized relationship established through shared breastfeeding, as a model of shared early-life exposure. Available evidence indicates that common exposure to breast milk bioactive signals provides a biologically plausible mechanism for partial convergence of epigenetic regulation among unrelated infants. However, direct human studies demonstrating measurable epigenetic or long-term health effects associated with milk kinship remain scarce. Integrating current evidence supports a hypothesis-driven framework linking epigenetics, nutrigenomics, and population health while identifying important knowledge gaps. Longitudinal, multi-omics studies are needed to determine whether shared lactational exposure produces stable, functionally relevant epigenetic signatures and whether these influence disease susceptibility or prevention across the life course.KEY TEACHING POINTSBreast milk contains diverse bioactive components, including microRNAs, extracellular vesicles, human milk oligosaccharides, immune factors, hormones, and growth factors, that may influence infant gene regulation, immune maturation, metabolic programming, and epigenetic development during critical early-life windows.Shared breastfeeding provides a biologically plausible model for examining potential epigenetic convergence among milk siblings through common exposure to milk-derived regulatory signals; however, this hypothesis remains speculative, and direct human evidence demonstrating measurable or persistent epigenetic convergence among milk siblings is currently lacking.Longitudinal, multi-omics studies integrating epigenomic, transcriptomic, microbiome, and detailed breastfeeding data are needed to determine whether shared lactational exposure produces functionally relevant molecular signatures and whether these signatures have implications for health and disease across the life course.