Bing Wang is a professor of physiology and nutrition at Charles Sturt University in Australia and she's been conducting some fascinating research on the relationship between cognition and lactoferrin. Leapfrog's founder, Stephanie Drax, interviewed her to find out if and why lactoferrin can make you smarter. 

SD: How long have you been working with lactoferrin and what has sparked your interest in it?

BW: I’ve been working with lactoferrin since 2007. I’m interested in early life nutrition particularly for neural cognitive or brain development and so the starting point for me is that lactoferrin in a milk protein – mom’s milk and cow’s milk – is a natural source of lactoferrin. After birth, the first food newborn infants eat is milk, and the brain grows fast. By age two the brain has already reached 80% of that of a human adult. So, my question has been: what nutrient components in the human milk contribute to brain growth development? Milk is biology. Milk is a unique source for specifically providing entire nutrients for the newborn. So, milk must have important essential nutrients for the brain. So far, what the WHO have approved is DHA - if you go to different countries DHA is a compulsory regulation for adding to preterm infant formula. But if milk is key for neurodevelopment and for brain development, it’s not only DHA that is key - there must also be other contributors. One candidate is lactoferrin.

And what made you isolate lactoferrin and its potential?

I did my PhD at the University of Sydney and I had an interest in the molecule HMO - human milk oligosaccharides – and its sialic acid. During my early PhD postdoctoral fellow training, I discovered sialic acid is an essential nutrient for early neurodevelopment and cognition. Because lactoferrin is a sialic glycoprotein, I became interested. Lactoferrin also has another essential nutrient: iron. Everyone knows if iron is deficient in the body, then the infant will develop anaemia. In my early career, I was a treating medical doctor in Tianjin Medical University - I’m a pediatrician and neonatologist - and I saw that when kids get anaemia and iron deficiency it has an impact on their neural cognitive function.

This iron impairment is very difficult to rescue. Importantly in our human organs, we do not have iron metabolic detectors to get rid of iron absorption. So, iron supplements can be difficult for infants because they can very easily upset their stomachs. Kids are then vomiting, and parents become nervous. So lactoferrin carries the key nutrient of iron which can be useful here, but also sialic acid - a key molecule essential for the development of gangliosides, which is itself critical in brain development and function, accounting for 10% of brain lipid mass.

How do you compare the brain development over those first two years of a child who has been breastfed and a child who has not been breastfed? Do we have any statistics on that?

The WHO has already documented that breastfeeding has a huge advantage over formula feed. There are a lot of benefits such as immunity, growth, also long-term benefits like obesity and type II diabetes. Breastfed infants also have an advantage of cognitive performance over formula fed infants, but it was not known which nutrient, why, what, or how.

In America in 2013 they started using very powerful neuroimaging tools that can target white matter volume in the brain. During early life after being born, our neural full-term brain already has 100 billion neuro - a number of neural cells similar to a human adult. However, connectivity is a fibre; we call white matter, and this is easy to see with neural imaging tools. Neuro imaging can target postnatal growth of neuro cells and white matter. So, researchers have been using neuroimaging tools on nine-year-olds and they found if the child had been breastfed in early life, then their white matter was heavy and had density higher compared to those who had been bottle fed. And the density was related to the duration of breastfeeding: the longer they were breastfed, the heavier, better white matter they would have. Because the density was higher in the nine-year-old children, that is a marker foundational neurodevelopment outcome. It’s similar to your house: your double brick house is much stronger than a wood house. They also they found that this highly density of white matter reflected a certain type of connectivity and high cognitive function. They demonstrated that breastfed versus a formula fed child has a morphological difference at nine years old. That implies that early milk is doing something – and so then we look closely at lactoferrin.

How would you describe lactoferrin's effects and its potential for health beyond cognition?

Lactoferrin has nutraceutical role - to modulate immunity - but also it can have a clinical and pharmaceutical role, to treat diseases. But mostly lactoferrin is used to modulate immunity – like T-cells and B cells. It’s also used for its anti-cancer effect, antibacterial effect, antiviral effect, and it also has benefits for cardiovascular function. People are researching lactoferrin and bone health and muscle performance and to regulate gut microbiota. Scientists like lactoferrin because it is very diverse, its even used to support the gastrointestinal system, to modulate the metabolism for obesity, and to help with type II diabetes. In Europe, lactoferrin is being used by pregnant women to boost immune function and for early life virus infections. My research group has been focusing on using piglets, as an animal model. It’s a very slow and precise study as guidance for a human clinical trial, as a model for human infants. We are doing a lactoferrin intervention with dose response.

And can you explain why working with piglets is the preferred model for this interventional study? What is the relationship between the piglet and the human that is so useful?

We must mimic humans, as we need the preclinical study, so we needed to find the best model. And why did we choose pigs? People doing organ transplants use pigs, they do not use rodents. The biology of their organs function similarly to humans – from anatomy, to physiology and the brain. They are closer to humans than any other animal model apart from the chimpanzee. Even their vision is like human vision, and they are mono gastro - only one stomach. The aim is to resemble human infants to be able to guide human clinical trials based on human physiology. I love working with pigs very much. They are very understanding, very emotional. And they get to know you!

Your study was co-authored with Professor Federic A. Troy II (chairman emeritus at UC Davis School of Medicine) and published in Molecular Nutrition and Food Research. Can you please describe the study design and the difference between those pigs who had received the lactoferrin supplementation and those who had not? 

Our study – which was double blind, randomised, controlled - observed 51 male piglets from the age of 3 days until they were 38 days old, which is the equivalent age of a 10-month-old human infant. Seventeen piglets had diets supplemented with low lactoferrin (500mg per litre), 18 piglets with high lactoferrin (1g per litre), and 15 piglets with no lactoferrin. We assessed the short and long term memory and learning rate of piglets through a maze test. We gave the piglets easy and hard learning tasks and observed their behaviour.

The maze had eight almost identical doors with only one door that had the milk behind it. 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). We looked at the number of times the piglet chose a wrong door as a measure of learning. We defined differences in learning as the number of trials required to learn the visual cues.

Our results found that the piglets in the two lactoferrin groups learned faster than the control group in both the easy and difficult learning tests – they could read the visual cues. The piglets with no lactoferrin did not read the visual cues – they would just go one by one checking the doors, and then sometimes go back to an arm again, rechecking when it has no milk. They have poor working memory.

"The treatment group had faster learning ability than the control group and better long-term memory, of 3 hours and 40 minutes."  

Remember, piglets are like you; so, if I give you my mobile phone number that means that you can remember it for beyond three hours. Interestingly, the piglets on the low lactoferrin diet always performed better than those on the high lactoferrin diet. These piglets showed an improvement in the rate of learning and the long-term memory tests. These were positive and significant results.

Also, we found the learning speed was faster and the working memory was better. A poor working memory is when you lock your car, and then have to recheck that you locked it. Our results found that this working memory was better with the lactoferrin diet piglets.

And was that in both the low and high treatment groups, or was there any difference again between those two treatment groups? 

There was no difference in the treatment groups, low dose and high dose were similar, so our study showed that there doesn't have to be a high dose to have better learning ability. However, we found that high dose does have a profound role in neural protection. So, this high dose might be better in preterm infants, because of its signal pathway prevention for damage and neural rescue. Why does a preterm mom have high lactoferrin levels herself? Because the injured needs early rescue, so there is some physiology behind that. Both the low dose and high dose lactoferrin offer cognitive benefit, but the high dose has more neural protection while the low dose helps with neuro-development.

This is preclinical human trial research, but is there any way we can correlate what that might be for human supplementation? I'm thinking the low dose one which is effective as you say for short-term memory, working memory, active memory and then the high dose that has got neuro-protective benefit.

So in order for the baby to have the neurodevelopmental effects, we are looking at 500 mg of lactoferrin in a day to have that neurodevelopmental effect. However, a lot of research needs to done and in particular a human clinical study.

For adults, there is epigenetic consideration, early life, a focus on early nutrition, metabolic syndrome, cardiovascular diseases, and some non-communication disease.  Every disease is brain related - your stress, and mental health problems of course influence your metabolic function and all kinds of diseases. You may develop cancer because you are depressed and then that will suppress your immunity. The first 1000 days of your life impact your adulthood. So, it’s important to make sure that kids not only have a good strong body, but they have a good strong brain and that they are able to adapt. And then in adulthood, you have to keep your adult brain healthy, to slow down your neurodegeneration.

Do you have a belief that lactoferrin as a supplementation could help to slow down neurodegeneration? Based on the research that you've done with your piglet trial, could there be those protective benefits?

I think everything is possible. Lactoferrin can delay neurodegeneration and promote healthy growth of cells so as not to turn to neurodegeneration. People have said to me to focus on the documentation of lactoferrin - on immunity; that when immunity is strong, then a human is healthy and the brain is healthy. But there’s no evidence of this. They're thinking indirectly because their focus is on immunity. But what we’ve discovered is so important, I can now see that everything possible, because lactoferrin has the two key nutrients – the sialic acid and the iron-binding. But we need action - we need to do some fundamental basic research, and discovery research to find out more.

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