Secretor status-dependent modulation of in vitro immune responses by human milk oligosaccharides.

Human milk oligosaccharides (HMOs) are structurally diverse carbohydrates found in high concentrations in human milk, supporting infant immune development and gut microbiota colonization. Their composition is influenced by maternal Secretor (Se) status, determined by the FUT2 gene. While immunological HMO effects are increasingly recognized, the influence of an infant's own Se status on immune responses remains understudied. This study explores how peripheral blood mononuclear cells (PBMCs) from Se-positive (Se+) and Se-negative (Se-) individuals respond to Se+ and Se- HMOs under bacterial and viral stimulation. PBMCs from 14 healthy adult donors, classified based on FUT2 expression, were exposed to 0.1% pooled Se+ or Se- HMOs, individual HMOs (2'-fucosyllactose and 3-fucosyllactose), and immune triggers (αCD3/CD28, LPS, and/or Poly I:C) for 24-48 h. Cytokine secretion (IFNγ, IL10, IL13, TNFα) was measured. Basal cytokine secretion did not differ between Se+ and Se- PBMCs. Upon stimulation, Se+ PBMCs secreted more IL10, particularly in response to Se+ or Se- HMOs. Individual HMOs did not replicate effects seen with pooled mixtures, highlighting the importance of HMO complexity. Under LPS stimulation, TNFα secretion was significantly reduced only with genotype-matched HMOs, suggesting Secretor-specific immune modulation. This is the first study showing that PBMC cytokine responses are shaped mainly by host Secretor status than HMO composition. Both genotype and HMO profile influence immune reactivity and should be considered in HMO research and personalized infant nutrition strategies.