Systemic Availability of Human Milk Oligosaccharides in Infants and Adults: A Narrative Review

Human milk contains many components with physiological effects beyond basic nutrition, including large quantities of structurally diverse oligosaccharides. Human milk oligosaccharides (HMOs) have been linked to health outcomes through microbiome-dependent and -independent mechanisms. To investigate the microbiome-independent effects of individual HMOs and their role in human health, it is necessary to understand their systemic availability. This narrative review focuses on the systemic availability of HMOs and summarizes studies that investigated the presence of HMOs in blood and urine following oral intake in humans. We searched PubMed using the following terms individually or in combination: human milk oligosaccharides, HMO, 2'-fucosyllactose, 3-fucosyllactose, 3'-sialyllactose, 6'-sialyllactose, difucosyllactose, lacto-N-tetraose, and lacto-N-neotetraose. The inclusion criteria were: (1) study design observational or interventional; (2) cohort included breastfed infants, HMO-formula-fed infants or individuals taking HMO supplements; and (3) methods defined HMO absorption/excretion and described analysis. We identified 15 human studies. They varied in design, populations (healthy infants, infants with medical indications, adults), administration (breastfeeding, formula, supplement), ingested dose, sampling time points, and analytical methods. HMOs were absorbed into the bloodstream and excreted in urine, as they were detected in the blood and urine of breastfed infants, infants receiving HMO-fortified formula, and adults receiving HMO supplements, demonstrating their systemic availability. Most orally ingested HMOs appeared in blood, but some structures were not absorbed. Studies also reported that blood and urine concentrations of HMOs correlated with increasing doses. Some studies showed a difference between the number of HMOs ingested and the number of oligosaccharides found in urine. Current evidence supports the systemic availability of HMOs in both infants and adults, but absorption kinetics, rates, mechanisms and metabolic fate remain unknown. Further research investigating the systemic availability of HMOs is needed to improve our understanding of the microbiome-independent effects of HMOs on human health. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE WHERE IT WAS OBTAINED: (not applicable) REGISTRY AND REGISTRY NUMBER FOR SYSTEMATIC REVIEWS OR META-ANALYSES: (not applicable) STATEMENT OF SIGNIFICANCE: This narrative review of recent studies confirms that human milk oligosaccharides (HMOs) taken orally by infants and adults are absorbed into the blood and excreted in urine, indicating their systemic availability and supporting the hypothesis that physiological benefits of HMOs may not be limited to their prebiotic mode of action, but may also be due to their systemic availability and effects. Key questions remain about the mechanisms of absorption, absorption kinetics, structure-specific differences, and metabolic fate of HMOs - these insights are essential for advancing our understanding of HMOs as bioactive components with systemic relevance.