Vitamin A deficiency influences nerve development in the bowel

Most of us take for granted that our bowels work normally. But their function depends on the proper development of an estimated 500 million nerve cells in the bowel called the enteric nervous system. When this part of the nervous system does not form normally, movement or sensation in the bowel may be abnormal. This may result in disorders such as irritable bowel syndrome, which affects up to 15 percent of the U.S. population. An even more severe pediatric disease of the enteric nervous system is called Hirschsprung disease, a potentially fatal disorder where the enteric nervous system is completely missing from the end of the bowel.

In their efforts to understand the cells involved in normal bowel function, researchers at Washington University School of Medicine in St. Louis have found that a common nutrient — Vitamin A, or its metabolite, retinoic acid — has a direct effect on the development of nerve cells, or neurons, in the bowel wall that control gastrointestinal function. The results of the research were published in Developmental Biology.

Using embryonic mouse enteric nervous system precursor cells grown in a laboratory, the researchers found that during early development of a fetus, levels of retinoic acid signal the cells to become either neurons, which receive and transmit chemical signals, or glia, which provide support and protection to neurons. The neurons then populate the bowel from beginning to end to ensure proper function.

When the researchers added retinoic acid to the cells, those cells were more likely to become neurons, but if they took away the retinoic acid, they developed fewer neurons. The researchers also were surprised that adding retinoic acid to the nerve cells in the bowel made the cells’ neurites, or axons and dendrites, shorter, which is the opposite of what happens in neurons in the rest of the nervous system.

“If this type of effect occurs in people, Vitamin A deficiency would be likely to influence the number of neurons in the bowel,” said Robert O. Heuckeroth, M.D., Ph.D., associate professor of pediatrics at the School of Medicine and senior author of the paper. “You might expect that Vitamin A deficiency or excess would influence not only the number of neurons and the ratio of neurons to glia, but also the length of neurites. This in turn would be expected to influence the way that the nervous system and bowel function,” Heuckeroth said. “Therefore, for a developing fetus, the likelihood of having abnormal intestinal function, motility or sensation could be related to the mother’s nutrition and the level of Vitamin A the mother has during her first trimester of pregnancy.”

By the time most women recognize they are pregnant and start taking prenatal vitamins, many important aspects of fetal development are complete, said Heuckeroth, a pediatric gastroenterologist who treats children with Hirschsprung disease and other gastrointestinal disorders at St. Louis Children’s Hospital. Although women may take prenatal vitamins while trying to get pregnant, half of pregnancies in the United States are unplanned.

“The challenge is to figure out which micronutrients are important to optimize nutrition and whether unrecognized nutritional deficiencies contribute to birth defects,” he said. “Optimize does not mean maximize, because too much of a nutrient is bad, too. If we can sort through this, we have the potential to reduce the frequency or severity of intestinal motility disorders through proper control of maternal nutrition,” he said.

Vitamin A deficiency is not a large problem in the United States, however, it is a significant problem in developing countries, in sub-Saharan Africa and southeast Asia. Prior research at Johns Hopkins University shows that more than 20 percent of mothers in Ethiopia, Kenya, Nigeria, Senegal and South Africa are deficient in Vitamin A. Among preschool-age children, more than 60 percent in Kenya are Vitamin-A deficient; more than 57 percent in India; and nearly 14 percent in Brazil.

“When you think about what we do at St. Louis Children’s Hospital, we take care of a lot of sick kids who have defects in the way their bodies formed,” he said. “If we’re right about this, we might be able to prevent some of these birth defects instead of trying to treat them after they’ve already occurred. The real goal is to try to understand enough about the disease processes that occur in children so we can keep them from occurring in the first place or find better ways to treat them.”

Heuckeroth, whose research is funded by the Children’s Discovery Institute, said as research in this area progresses, he and his colleagues will carry these observations from animals models into human studies.

Sato, Y, Heuckeroth, RO. Retinoic acid regulates murine enteric nervous system precursor proliferation, enhances neuronal precursor differentiation and reduces neurite growth in vitro. Developmental Biology August 2008; 320(1):185-98.

Funding from the National Institutes of Health and the March of Dimes supported this research.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.