In addition to being a source of nutrients for the developing newborn, human milk contains thousands of bioactive compounds, which influence infant health in the short-term as exemplified by its major benefits on infectious disease prevention. Many of the human milk compounds also have the required characteristics to instruct immune development and guide long-term health. Prebiotics, probiotics, and varied antimicrobial molecules all have the potential to shape the composition and function of the establishing gut microbiota, which is known to be a major determinant of immune function. Another and less explored way human milk can instruct long-term immunity is through antigen shedding. Here, we will review the evidence that antigens from maternal environment and more specifically from allergen sources are found in human milk. We will discuss data from rodent models and birth cohorts showing that allergen shedding in breast milk may influence long-term allergy risk. We will uncover the variables that may underlie heterogeneity in oral tolerance induction and allergy prevention in children breast-fed by allergen-exposed mothers. We will focus on the parameters that control antigen transfer to breast milk, on the unique biological characteristics of allergens in breast milk, and on the milk bioactive compounds that were found to influence immune response in offspring. We propose this understanding is fundamental to guide maternal interventions leading to lifelong allergen tolerance.
