Sialylated HMOs are Shaping the Development of Cognitive Functions.

Objectives and Study:

Human milk oligosaccharides (HMOs) are a key component of breast milk and have been proposed to be one of the mediators of breast feeding beneficial effects on neurodevelopment and associated adult brain functions. Among the different types of HMOs, the sialylated HMOs are suggested to play a key role in brain development and functions. There is however a lack of understanding of the mechanisms of action for this long-term programming effects of sialylated HMOs. Here, we used a dysfunctional mutant of both beta-galactoside alpha-2,6-sialyltransferase 1 (St6gal1) and beta-galactoside alpha-2,3-sialyltransferase 4 (St3gal4) genes that results in the absence of
6’sialyllactose (6’SL) and a reduction of about 80% of 3’sialyllactose (3’SL) in dams milk respectively. To distinguish between the effects due to the HMOs deficiency in milk and those due to the mutations we used a full cross-fostering design and evaluated the
adult mice in behavioural tests assessing attention and mnesic functions.

Methods:

At birth, we performed a full cross-fostering procedure involving C57BL/6J wild-type mice and double KO mice for St6gal1 (B6.129-St6gal1tm2Jxm/J) and St3gal4 (B6.129-St3gal4tm1.1Jxm/J) at birth. The mutation in this line rendered dysfunctional both
St6gal1 and St3gal4 genes, thereby resulting in an absence of 6’SL and a reduction of about 80% of 3’SL in the milk. This design resulted in four treatment groups (dams x pups genotype): WT x WT (control group), MUT x WT (milk group), WT x MUT (mutant
group) and MUT x MUT (milk+mutant group). Adult offspring (> post-natal day 65), were tested for their spatial and recognition memory, and attention. Data were analyzed using factorial ANOVA.

Results:

Mice receiving HMOs deficient milk exhibited a reduced performance in prepulse inhibition and in working memory assessed in the T-maze. Both the mice receiving HMOs deficient milk and the mutant exhibited a reduction of retention of spatial memory
assessed in the Barnes maze. Furthermore, mice receiving HMOs deficient milk showed a reduced attentional performance compared to control group in the attentional set-shifting task. There was no effect of milk or mutant group on recognition memory assessed in the novel object recognition task or anxiety assessed in the elevated zero maze. Finally, we also observed an increase of maternal behavior in the mutant mice and a reduction of body weight in the mutant offspring.

Conclusion:

This study further confirms the previous findings using single KO cross-fostering strategies for either 6’SL or 3’SL, that absence of early life source of dietary sialylated HMOs lead to impaired cognitive functions, specifically attention, and spatial and working memory.