Background: Human milk oligosaccharides (HMOs) are the third-largest solid component of human milk and comprise fucosylated, neutral, and sialylated structures. Among the sialylated HMOs, 6′-sialyllactose (6′SL) and 3′-sialyllactose (3′SL) are predominant. In early human milk (0–3 months), the concentration of 6′SL is approximately 2–3 times higher than that of 3′SL (1,2). Sialic acid (Sia), a key component of sialyllactose (SL), plays important roles in infant immune development and neurodevelopment (3). However, the metabolic fate of 6′SL following oral ingestion remains poorly understood.
Methods: We investigated the metabolic fate of orally administered 6′SL in weaning mice using in vivo and ex vivo optical/fluorescence imaging with Cy7-labeled 6′SL and stable isotope tracing with 13C-labeled 6′SL. The experimental protocol was approved by the Animal Ethics Committee of the Beijing Association for Science and Technology (License No. SYXK-2019-0004).
Results: Following oral administration, 6′SL-Cy7 rapidly reached the brain in an intact form, with brain accumulation detected as early as 0.5 h. The cumulative amount reached approximately 0.3% and 1.54% of the administered dose in female and male weaning mice, respectively, followed by a rapid decline to approximately 0.05% at 12 h. No detectable 6′SL accumulation was observed in the colon within 30 min, suggesting that early brain uptake occurs independently of colonic fermentation. Stable isotope tracing further confirmed the presence of intact 13C-6′SL in the brain, with approximately 0.25% of the administered dose detected at 1 h. Approximately 66% of brain-associated 13C-6′SL remained at 3 h, whereas only 0.01% remained at 6 h, indicating rapid subsequent metabolism or clearance. These findings suggest that dietary 6′SL can directly reach the brain and potentially provide Sia for the biosynthesis of polysialic acid (polySia) and gangliosides in neuronal cells.
Conclusions: Orally administered 6′SL rapidly crosses the blood–brain barrier and reaches the brain in an intact form, independently of colonic fermentation. This direct delivery may provide a source of Sia for neuronal biosynthesis of polySia and gangliosides, potentially supporting neurodevelopment. These findings provide novel evidence for the direct transport and metabolic utilization of dietary 6′SL in the brain.
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