Human milk is more than nutrition for growing human infants. This rich liquid is a personalized, biological system containing myriad bioactive factors, including nutrients, human and bacterial cells, immunomodulators, and extracellular vesicles (EVs), which all build and shape the health and development of the smallest and most vulnerable recipient. This biological fluid generated by a mother's own body is custom-made for her growing infant, matching not only its nutritional needs through fat content or nutritional balance, but also immunological needs through antigen matching and providing for the infant's developing intestinal microbiome, through bacterial seeding and nutrients in the form of human milk oligosaccharides (HMOs). This review summarizes the vast literature describing the numerous bioactive components of human milk, including how they serve the developing infant and how they are impacted by the mother1 and the environment2 (Figure 1).

Until the early 2000s, human milk was considered sterile3, 4, 5. Since 2003 the number of studies describing the “human milk microbiome” has skyrocketed. This term refers to the collective bacteria and their genetic material present within a biological tissue or system6, in this case, human milk. The human milk microbiome is diverse and complex, containing a wide variety of bacterial species7. The bacterial community is generally stable over time, although variation between mothers results from differences in the maternal diet, body mass index (BMI), delivery mode, and overall maternal health, including the use of certain medications2,8, and preterm delivery2,9. Many of the bacteria present within human milk are the first colonizers of the infant intestinal microbiome, with a proportion of the genera present within the infant fecal microbiota matching those present within human milk10. Some of the core bacterial genera found within human milk include Pseudomonas, Staphylococcus, Streptococcus, Bifidobacterium, Lactobacillus, and Propionibacterium7,8, 10, 11, 12, 13, 14 and include genera found on the skin, within the infant mouth15, the mother's intestinal tract16, 17, 18, 19, and the mammary gland8,10. The composition of the milk microbiome is influenced by feeding mode and changes with feeding pumped human milk or tube feeding compared to breastfeeding, demonstrating the role of an infant's oral microbiota in shaping the microbial composition of the milk20. These early colonizers stimulate appropriate immune system development and function in the infant21, 22, 23 and provide competition for other pathogenic species that otherwise may colonize the infant intestinal tract, thereby protecting the infant from enteric diseases such as necrotizing enterocolitis (NEC)24. Notably, studies using germ-free mice (lacking all microbes) suggest that the timing of colonization in early development is key to preventing later disease through appropriate immune cell priming25. Establishing a healthy intestinal microbiome from birth is associated with long-term benefits to overall health, reducing the risk of allergies21,26,27, asthma21, inflammatory bowel diseases21, obesity28,29, and metabolic disease30. Understanding which bacterial species confer beneficial effects on infant health and development over the short and long-term is crucial when developing infant formulas or probiotic supplements. Additionally, defining the nutrient sources these bacteria require to survive will be vital for promoting their colonization in the infant gut.