Secretor Status-Dependent Modulation of in Vitro Immune Responses by Human Milk Oligosaccharides

Why It Matters

Recognizing that an infant’s FUT2 genotype shapes immune reactions to HMOs enables more precise nutritional strategies and could improve outcomes in infant formula design and therapeutic interventions.

Key Takeaways

• PBMCs from Secretor‑positive donors secreted higher IL‑10 levels.
• Mixed Secretor‑positive HMOs, not individual sugars, drove cytokine changes.
• TNF‑α reduction under LPS occurred only with genotype‑matched HMOs.
• Host FUT2 genotype outweighs milk HMO composition in immune response.

Pulse Analysis

Human milk oligosaccharides (HMOs) are among the most abundant bioactive components in breast milk, providing both prebiotic support for the gut microbiome and direct immunomodulatory signals. Their structural diversity—driven largely by the mother’s Secretor status via the FUT2 gene—has spurred extensive research into how specific sugars influence infant health. However, the infant’s own genetic makeup, particularly their Secretor phenotype, has been largely overlooked despite its potential to alter how immune cells perceive and react to these complex carbohydrates.

In a controlled laboratory experiment, peripheral blood mononuclear cells from 14 adult donors, classified as Secretor‑positive or Secretor‑negative, were exposed to pooled HMOs reflecting each genotype as well as isolated fucosylated sugars. The results revealed a clear pattern: Secretor‑positive cells released more IL‑10, an anti‑inflammatory cytokine, regardless of whether the HMOs were matched or mismatched. Moreover, only when the HMO pool matched the donor’s genotype did TNF‑α—a pro‑inflammatory marker—significantly decline under bacterial lipopolysaccharide challenge. The lack of effect from single‑sugar components highlights that the synergistic complexity of whole‑milk HMO mixtures is essential for observable immune modulation.

These findings carry weight for the infant formula industry and clinical nutrition. As manufacturers aim to replicate the protective benefits of breast milk, incorporating genotype‑specific HMO blends could enhance efficacy, especially for infants lacking functional FUT2 alleles. Personalized nutrition strategies that account for both maternal and infant Secretor status may reduce inflammation‑related disorders and support healthier immune development. Future research should expand to pediatric cohorts, explore long‑term clinical outcomes, and investigate how tailored HMO formulations could integrate with probiotic or vaccine programs to optimize early‑life immunity.