Human Milk Bioactive Compounds and Allergic‐ and Infectious‐Related Infant Outcomes: A Systematic Review

The impact of Human Milk (HM) bioactive compounds on infant health is crucial yet complex. Current research highlights their role in immune system development and disease prevention. This review aims to synthesize existing literature on the role of HM's bioactive compounds in the onset of diagnosed allergies, immunological diseases, and responses to infectious diseases by infants and children up to 18 years. The systematic review adhered to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). A comprehensive search strategy was employed across PubMed, Web of Science, SCOPUS, Scientific Electronic Library Online (SciELO), Cochrane Library, Latin American and Caribbean Health Sciences Literature (LILACS), and LIVIVO. Quality assessment utilized Joanna Briggs Institute checklists for various study designs. Protocol: CRD42023432030. The systematic review encompassed 34 studies, published from 1983 to 2024, representing a total of 9,298 mother-infant dyads. Included studies reported that allergic-related conditions, particularly food allergy, sensitization, and atopic dermatitis, were inversely associated with HM linolenic and linoleic acid. In a meta-analysis of three studies, infants with atopic dermatitis showed lower total omega-3 levels (SMD = -0.46, 95% CI: -1.82 to -0.90, I² = 91%, p < 0.01), with reduced EPA and DGLA, suggesting, but not confirming, a potential protective role of omega-3 and involvement of inflammatory pathways. Furthermore, results on infectious-related conditions, primarily diarrhoea and Group B Streptococcus (GBS) infections, suggested inverse associations with 2'-fucosyllactose (2´-FL), lacto-N-difucohexaose I (LDFH-I), and immunoglobulins (Anti-GBS secretory immunoglobulin A (SIgA), anti-lipopolysaccharide IgA (Anti-LPS IgA), anti-cholera toxin IgA, respectively). Results of studies on upper and lower respiratory tract infections, otitis media, and dental caries suggested inverse associations with galectins and galectin-3, lacto-N-tetraose (LNT), 2´-FL, and Haemophilus influenzae. Data suggest that HM bioactive compounds, such as polyunsaturated fatty acids (PUFAs), HMOs, and a number of specific immunoglobulin A (IgA) antibodies may influence allergic and infectious outcomes in infants. In pooled analyses of omega-3 levels, HM fed to infants with atopic dermatitis showed reduced EPA and DGLA. However, these pooled estimates are severely limited by high statistical heterogeneity (I² = 91%) and should be interpreted as exploratory findings. Despite of the limited overall evidence due to heterogeneity, low replication, and methodological variability, this review offers a broad synthesis of current findings and highlights key knowledge gaps, providing a foundation for future research focused on elucidating the immunological roles of understudied components, such as antimicrobial peptides, through multi-omics and longitudinal approaches.