Calibrating Lactoferrin protein in milk may boost learning and protect neurons

Diets with different concentrations of lactoferrin (Lf), a protein found naturally in human and cow milk, have significantly different impacts on brain development and neuroprotection, a new study co-led by UC Davis Professor Frederic A. Troy II has found.  

“Our studies revealed an unexpected and rather paradoxical finding,” Troy said.

The study, published in the journal Molecular Nutrition and Food Research, showed that lower Lf levels were linked to better neurodevelopment and learning. Higher levels were strongly correlated with the protection of neurons and possibly the prevention of neurological-associated disorders.

What is lactoferrin?

Lactoferrin is the most abundant sialic acid-rich glycoprotein in human milk whey. It comes in a higher concentration in colostrum (the first breast milk after a baby is born) than in mature milk.

Multiple studies have shown Lf has important biological functions. For example, lactoferrin can modulate immune responses, regulate the body’s iron absorption, and function as an antioxidant and anti-inflammatory. In humans, lactoferrin can reduce fungal infections and late-onset sepsis and lower psychological distress.

The study on lactoferrin

The researchers wanted to determine whether the level of Lf in the diet was associated with neurodevelopment and cognition. They tested that in newborn piglets.

“Neonatal piglets are the preferred animal model for dietary interventional studies,” said Troy, professor and chairman emeritus at the Department of Biochemistry and Molecular Medicine at UC Davis School of Medicine and co-senior author on the study. “Because of their rate of brain growth, the pattern of neural growth and development, and the overall anatomy and physiology, they are closer to humans than any other animal model except the chimpanzee.” 

The team tested and observed 51 male piglets from the age of 3 days until they were 38 days old – the equivalent age of a 10-month-old human infant. Seventeen piglets had diets supplemented with low Lf, 18 piglets with high Lf, and 15 piglets with no Lf.

Lactoferrin levels linked to short-term and long-term memory

The researchers assessed the short and long term memory and learning rate of piglets through an eight-arm radial maze test. They gave the piglets easy and hard learning tasks and observed their behavior.

The maze with eight almost identical doors had only one door that could be used to access milk. This door was marked with three black dots, while the remaining seven doors had one dot (in the easy trial) or two dots (in the hard trial). The researchers used the number of times the piglet chose a wrong door as a measure of learning. They defined differences in learning as the number of trials required to learn the visual cues.

Piglets in the two Lf groups learned faster than the control group in both the easy and difficult learning tests. Yet, piglets on the low Lf diet always performed better than those on the high Lf diet. These piglets showed an improvement in the rate of learning and the long-term memory test.

Lactoferrin and the neural signaling pathways

To understand the molecular basis of these findings, the researchers also looked at the concentration of brain-derived neurotrophic factors (BDNF) in the hippocampus of the piglets. BDNF is a protein linked to neural survival and new neuron development. They found that BDNF was notably more present in piglets on the low than the high Lf concentration. Yet, high Lf levels seemed to help regulate neural and cellular processes, leading to better protection of the neurons.

The researchers conducted a gene expression profile, an analysis to show all the genes in a cell that are making messenger RNA (mRNA) needed to produce proteins. They discovered that 1,187 genes were differentially expressed in piglets with low Lf concentration, and 63 genes in piglets with high Lf concentration, compared to the piglets’ genes in the control group.

The researchers also analyzed the levels of two stress hormones, cortisol and adrenocorticotropic hormone (ACTH), in the plasma of piglets during the 38-day developmental period. They did not find differences in stress levels among piglets in the three groups.

“This study builds on a long research on sialic acid-rich glycoprotein such as lactoferrin,” Troy said. “One possible clinical application from our study is the potential calibration of lactoferrin in infant diet to support neurodevelopment, learning and neuroprotection.”

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Co-authors on this study are Yue Chen, Bing Wang, Changwei Yang, Yujie Shi, and Zhizhong Dong.

This study was supported by the School of Medicine at Xiamen University, China, an Edward A. Dickson Distinguished Emeritus Professorship Grant from the University of California, and the Nestle Research (NRC) Beijing. Partial support was also provided by a Mizutani Foundation for Glycoscience Grant 130097.

Article: Chen et. Al. (2021). Functional Correlates and Impact of Dietary Lactoferrin Intervention and its Concentration-dependence on Neurodevelopment and Cognition in Neonatal Piglets. Molecular Nutrition and Food Research. DOI: 10.1002/mnfr.202001099