Human Milk Oligosaccharides Support Coordinated Microbiome and Immune Development and Function in Infancy

BACKGROUND: Human milk contains functional ingredients that shape the microbiome and immune development of infants. Human milk oligosaccharides (HMOs) are among the largest and most diverse components of human milk. Their heterogeneity enables unique structure-function relationships that contribute to their physiological effects. This narrative review will focus on how HMOs directly and indirectly protect the infant from pathogens and educate the immune system. SUMMARY: Preclinical research, observational studies, and intervention trials demonstrate that HMOs provide multilayer modulation of host defense and immune development. HMOs are soluble glycans that are acetylated, sialylated, or fucosylated, which mediate their interactions with viruses and bacteria to reduce infectivity. Additionally, HMOs enhance pathogen exclusion by promoting intestinal cell maturation, mucin production, and barrier function. Moreover, HMOs directly interact with immune cells through binding to carbohydrate recognition domains. HMOs promote the growth of beneficial bacteria, particularly Bifidobacterium longum subspecies infantis, which is also immunomodulatory. Lastly, HMOs are fermented to short-chain fatty acids, which lower the pH of the intestinal lumen, providing further antimicrobial defense. KEY MESSAGES: Breastfed infants have a reduced risk of infectious disease compared to non-breastfed infants, attributable in part to the high concentration and structural diversity of HMOs. Clinical trials using formulas supplemented with synthetic human-identical milk oligosaccharides (HiMOs) have demonstrated benefits to adaptive and innate immunity, reduced infections, increased bifidobacteria, and reduced pathogenic bacteria. These benefits are amplified in formulas containing higher concentrations and greater varieties of HiMOs. However, the clinical benefit of routinely supplementing term infant formulae with HiMOs remains unsettled due to variability across existing clinical trials. Further research in healthy infants focused on short- and long-term immune outcomes is needed.