Breastfeeding and the developmental origins of mucosal immunity: how human milk shapes the innate and adaptive mucosal immune systems

Abstract

Purpose of review: Breastfeeding provides passive immunity while the neonatal immune system matures, and may also protect against chronic immune-mediated conditions long after weaning. This review summarizes current knowledge and new discoveries about human milk and mucosal immunity.

Recent findings: New data suggest that certain microbes in maternal milk may seed and shape the infant gut microbiota, which play a key role in regulating gut barrier integrity and training the developing immune system. Human milk oligosaccharides, best known for their prebiotic functions, have now been shown to directly modulate gene expression in mast and goblet cells in the gastrointestinal tract. Epidemiologic data show a reduced risk of peanut sensitization among infants breastfed by peanut-consuming mothers, suggesting a role for milk-borne food antigens in tolerance development. Cross-fostering experiments in mice suggest the soluble Toll-like receptor 2, found in human milk, may be critical in this process. Finally, interest in human milk antibodies surged during the pandemic with the identification of neutralizing severe acute respiratory syndrome coronavirus 2 antibodies in maternal milk following both natural infection and vaccination.

Summary: Human milk provides critical immune protection and stimulation to breastfed infants. Understanding the underlying mechanisms could identify new therapeutic targets and strategies for disease prevention across the lifespan.

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FIGURE 1

Timeline of innate and adaptive mucosal immune development during gestation and infancy and the bridging role of human milk. (Original). Gut barrier development beings in utero and continues until weaning, correlating with a decline in gut permeability and an increased thickness of the mucus layer. Levels of neutrophils increase toward the end of gestation and rapidly decrease to normal levels within the first hours after birth. Levels of Tregs are higher in the fetal period, which leads to immune suppression and tolerance toward maternal immune factors, such as immunoglobulins. After birth, the neonatal immune system gradually switches to an effector immune response with the increased exposure to environmental and milk immune factors, including microbiota. The innate and adaptive immune systems mature after birth, increasing the local production of mucosal antibodies. Milk components, such as microbiota, maternal cells, antibodies, cytokines, growth factors, soluble receptors, and HMOs, play an important role in promoting the normal development of the neonatal mucosal immune system (Figure 1); many are especially abundant in colostrum.

FIGURE 2

Milk immune factors and mucosal immunity. (Original). Several aspects of the mucosal immune system are developed under the influence of human milk components in early life. Maternal sIgA is the most abundant immunoglobulin in human milk; it inhibits pathogens and facilitates colonization of commensal microbiota. Maternal IgG is present at lower levels in milk and can be found complexed with dietary antigens; these complexes can translocate across the gut epithelium through the neonatal FcRn receptor and then stimulate expansion of regulatory T cells (Tregs). Human milk cytokines, including the TGF-β family, IL-6, IL-10, and TNF, are essential in the homeostasis of mucosal immunity via enhancing epithelial integrity and proliferation, expanding Tregs and endogenous sIgA secretion from infant B cells. Lactoferrin blocks pro-inflammatory cytokines and free-radical activity, and inhibits pathogen growth by chelating iron. Human milk microbiota may colonize the infant's gut and promote the development of mucosal immunity, including intestinal integrity, Tregs expansion, and sIgA production, either directly via signaling through innate immune receptors or indirectly via metabolizing human milk oligosaccharides (HMOs) into short-chain fatty acids (SCFAs) that serve as an energy source for gut epithelial cells. Soluble receptors in milk (such as sTLR2 and sCD14) are essential in regulating the inflammatory response, acting as decoy receptors that bind pathogenic bacterial ligands.