In a recent article published in Nutrients, researchers investigated the current evidence of the impact of milk oligosaccharides (MOS) on early life neurocognitive and brain development.
The team analyzed preclinical and human observational studies identified in the PubMed database. They critically appraised this evidence to discuss the complex interplay of MOS and cognition in early life, its potential mechanism(s) of action, and identify knowledge gaps to focus on in future studies.
Background
The milk of all mammals contains MOS; however, human milk oligosaccharides (HMOs) are unique due to sialic acid (SA) and fucose. Studies have associated these two HMO components with brain development.
SA is an essential component of gangliosides in the brain and also supports synapse formation and neurotransmission. It is bound to lactose in milk to form sialyllactose (SL), which makes HMOs structurally more complex than bovine MOS.
Human milk also contains fucosylated oligosaccharides, such as fucosyllactose (FL) and fucosylated glycans that participate in neuronal processes underpinning learning and memory.
Preclinical studies have suggested that intact 2′-FL, an α1,2-fucosylated compound, does not invade the blood-brain barrier (BBB), even though it might reach the brain in its cleaved form or as a gut-synthesized metabolite. Thus, MOS components may exert direct effects or use the gut-brain axis to exert indirect effects on the brain.
Understanding the effect of MOS on brain development might help develop early nutrition strategies for optimal neurocognitive and brain developmental outcomes in children.
About the study
In the present study, researchers aimed to identify all animal model-based and in-human observational studies related to MOS exposure in early life and its effects on cognitive development. In addition, they searched for studies related to the gut-brain axis.
Three reviewers evaluated the search criteria and extensively searched the PubMed database until April 2023. They extracted study data, including the authors, publication year, study site, experimental design, cohort size, interventions used, duration of the study, and its relevance.
Results
Only 26 articles met the inclusion criteria and constituted the analytic set of this study. Of these, 69% used animal models (piglet or rodent), and eight were in-human observational studies.
Preclinical studies in the current review investigated the influence of SL or FL supplementation or SL gene knockout, while human studies focused on the associations between the abundance of HMOs and infant cognitive outcomes.
There are many HMOS with different structures, which might have differential effects on infant cognitive development. Notably, research on less abundant HMOS is scarce. However, animal studies revealed that sialylated HMOs, e.g., 3′-SL and 6′-SL, improved recognition and memory to increase overall cognitive performance. Piglet studies provided additional evidence that formula 3′-SL or 6′-SL supplementation upregulated expression of genes related to SA metabolism.
As reported by several recent studies, SA in human milk plays a distinct role in the structure of neural cells, and the SA content of brain glycoproteins is involved in memory formation.
Most animal studies evaluated the effects of MOS supplementation on memory through quantifying hippocampal long-term potentiation (LTP), a cellular analog of learning and memory.
In rodents, oral administration of L-fucose and 2′-FL markedly improved hippocampal LTP memory skills and influenced synaptic plasticity. It is well-recognized that lactating mothers secrete abundant fucosylated HMOs, especially 2′-FL.
The observations made in eight human studies included in this review were inconsistent. One study reported an association between LNFP III concentration and cognitive scores in infants, while another found negative associations between less abundant disialyllacto-N-tetraose
(DSLNT) and sialyllacto-N-tetraose b (LSTb) HMOs and infant cognitive outcomes. They used infant behavioral assessment questionaries to measure cognitive development.
Most studies also identified marked relationships between HMO concentrations and brain structures. For instance, a study showed a correlation between 2′-FL levels at one month with increased mean diffusivity (MD) and reduced fractional anisotropy (FA) in the mantle of the brain cortex, as assessed by a brain magnetic resonance imaging (MRI) scan.
Conclusions
The current review remarkably demonstrated a consistent link between early life HMO intake and infant neurocognitive developmental outcomes, including intelligence quotient, motor skills, linguistic abilities, and memory.
So far, studies have shown that MOS impacts neurodevelopmental outcomes mechanistically by modulating the gut microbiota and enhancing neuronal signaling.
However, more randomized controlled trials (RCTs) are warranted to elucidate the precise mechanisms by which MOS exerts its effects and understand their long-term implications to advance the understanding of its effects.