Dr. Steven Zeisel
(Photo by Chad Mitchell)

What's essential for the prenatal brain?

October 15, 2017


Steven Zeisel, MD, PhD
Kenan Distinguished University Professor of nutrition and pediatrics
Director, Nutrition Research Institute, Kannapolis, N.C.


In science, 10 percent of successful scientific discovery is the result of skill and hard work – but 90 percent comes from asking the right question. During my graduate training, I was very lucky to ask the right question. I wondered where the choline in acetylcholine comes from.

Acetylcholine is an organic chemical that serves as a neurotransmitter – it’s released by nerve cells and sends signals to other cells, such as in muscles.

At the time, all the textbooks stated that people could make their own supply of this nutrient in the liver and did not need to obtain it through food. I knew that this was not true for rats, mice and dogs, and I doubted it was true for people.

As soon as I got my first job as an assistant professor,  I wrote a grant proposal. It was funded, and I did the experiment. I placed people in the hospital research unit, fed them a diet very low in choline, and proved that most men, most postmenopausal women, and about half of premenopausal women got sick when fed a low choline diet for many weeks.

Most people in the study developed short-term liver damage. About 10 percent developed muscle damage – all of which was reversed when choline was reintroduced into their diet.

We had proven that choline was an essential nutrient for humans. This discovery led the U.S. Institute of Medicine (now the National Academies of Sciences’ Division of Health and Medicine) to set a dietary intake recommendation for choline in 1998 and the U.S. Food and Drug Administration to establish food-labeling rules in 2017.

Q: What foods a contain choline?

A: We worked with the U.S. Department of Agriculture to develop a database of foods that are high in choline. (See the report at tinyurl.com/USDA-choline.) Good sources include eggs, milk and fatty foods – exactly the foods nutritionists told you to avoid if you need to lower your cholesterol.

Our research team then asked why some young women got sick when fed a low-choline diet, while others did not. We found that estrogen can ‘turn on’ a gene in the liver that’s needed for choline production, and that young women, especially during pregnancy, had enough estrogen to do this, thereby making themselves less reliant on dietary choline.

Q: Why did half of young women in the study still get sick when deprived of choline?

A: They had an alternate variation, or ‘spelling,’ of the choline-producing gene in liver that makes it unresponsive to estrogen. These women had to obtain choline from their diets because they could not make enough in their livers.

With further study, we were able to describe a number of other genes which, when their genetic codes were “misspelled,” required that a person obtain greater amounts of dietary choline. This discovery still is among the most dramatic examples of how important it can be to individualize nutritional needs. This field of personalized nutrition, also called precision nutrition, is a primary focus for researchers in the UNC Nutrition Research Institute in Kannapolis, N.C., which I am fortunate to direct.

I went to The Gambia, in Africa, to determine whether these spelling differences in genes for choline metabolism were present in people there. Choline intake in the diet in The Gambia is about half of that in the U.S. Also, since humans first evolved in Africa and then migrated to Europe and Asia, we wondered whether these spelling differences occurred only after people left Africa.

We found that almost all of the spelling differences that made people require more choline in their diets were missing in The Gambia. However, when we studied the genes of the Maasai people in Kenya, we found the same gene misspellings that occur in people of European descent. (The Maasai eat diets rich in milk and cow blood, both high in choline.)

This meant that, over tens of thousands of years, a diet low in choline selected, by evolutionary pressures, for people without the spelling errors – an example of how traditional diet can affect evolution.

In other studies, we found that many infant formulas did not contain the same amount of choline as did mother’s milk. In 2007, all commercially available infant formulas were adjusted to deliver the same amount of choline as does human milk.

Q: Why is this important?

A: Our research team showed that development of the brain during fetal and early life depends upon the mother’s supplying enough choline to the child. In mouse experiments, we and others showed that when a mother eats low choline for only a few days during pregnancy, her pups are born with brains that have fewer nerve cells, and the memory of these pups is worse throughout their lifetimes.

Our work has updated the nutrition textbooks, changed the composition of infant formulas and made the public aware of the need for sufficient choline in their diets. Each of us needs about one-half gram of choline every day. Soon, food labels may list how much of it a food provides.

Scientific discovery can change the world. We want to continue to ask more of the right questions.


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