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Dietary link to stunted growth identified

Study links inadequate intake of amino acids to debilitating condition that affects millions

Washington University School of Medicine

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IMAGE: Former Washington University medical student Lacey LaGrone -- now a resident physician -- measures a child's height in Malawi. A team of researchers led by the School of Medicine's Mark... view more

Credit: Indi Trehan/Washington University

National Institutes of Health, Intramural Research Program of the National Institute on Aging, Children's Discovery Institute of Washington University and St. Louis Children's Hospital, Hickey Family Foundation

Worldwide, an estimated 25 percent of children under age 5 suffer from stunted growth and development. The most visible characteristic is short stature, but the effects of stunting are far more profound: The condition prevents children from reaching their cognitive potential; makes them more susceptible to illness and infection; and shortens their life spans.

While nutritional interventions have had a significant impact on reducing deaths from acute malnutrition, their impact on stunting is modest, leaving researchers vexed and the enduring problem of stunting largely unanswered.

But now, a team of researchers led by senior author Mark J. Manary, MD, at Washington University School of Medicine in St. Louis, has found that inadequate dietary intake of essential amino acids and the nutrient choline is linked to stunting. That knowledge may unlock the door to new approaches to treat the debilitating condition.

The findings are published online in EBioMedicine.

"Stunting affects half of the children in rural Africa and millions more elsewhere in the world," said Manary, who spends several months a year in Africa treating children with malnutrition. "Many efforts have been undertaken to reduce stunting's impact -- from introducing various food supplements to reducing exposure to infections -- but we haven't really gotten anywhere. But these new findings, obtained with the help of cutting-edge technology, shed light on the biological reasons for this age-old, globally significant problem."

Manary's team partnered with researchers at Johns Hopkins University, including first author Richard A. Semba, MD, and scientists at the National Institute of Aging of the National Institutes of Health (NIH), the University of Malawi and other institutions in taking a targeted metabolomics approach to evaluate blood samples of 313 children, ages 12-59 months, from rural Malawi, in sub-Saharan Africa. Metabolomics is the study of the metabolites present in an organism, cell or tissue.

At the time of enrollment, children chosen for the study had no evidence of severe acute malnutrition, congenital or chronic disease or diarrhea. After each study participant's height and weight were measured, health-care workers determined that 64 percent of them were stunted, based on growth curves defined by the World Health Organization.

Using blood samples, the researchers then determined that more than 80 percent of the stunted children in the study had low levels of all nine essential amino acids compared with the children who were not stunted. (Essential amino acids -- the building blocks of proteins -- are important to human health and can't be produced by the body. Therefore, they have to come from food.)

The stunted children also had significantly lower concentrations of so-called conditionally essential amino acids, nonessential amino acids and six sphingolipids. Found in cell membranes, sphingolipids keep cell membranes strong and impermeable, reducing exposure to microbes. The stunted children also had alterations in the concentration of another lipid linked to cell membranes of the brain and nervous tissue.

The findings suggest that children at high risk of stunting may not receive a sufficient amount of essential amino acids and choline, a nutrient essential for the synthesis of lipids noted in the study.

"The message here is not that these children are sort of low in one thing or 10 things but that they're low in all of these amino acids and all of these kinds of fats," said Manary, the Helene B. Roberson Professor of Pediatrics at Washington University. "And each of these has a role in turning on a key, necessary switch for growth."

The new research adds to the ever-developing picture of childhood malnutrition. Manary, along with Jeffrey I. Gordon, MD, the Dr. Robert J. Glaser Distinguished University Professor and director of Washington University's Center for Genome Sciences and Systems Biology, authored a study published Feb. 18 in Science that points to a dysfunctional community of microbes in the gut as a critical factor in childhood malnutrition. Their study indicates that the effects of gut bacteria may have far-ranging influence in the body and that manipulating the makeup of gut microbes has the potential to provide new ways to treat childhood malnutrition and promote overall healthy growth.

Previous unrelated research indicates that human growth is controlled by what is referred to as the master growth regulation pathway. Manary and his team of researchers believe that when certain amino acids are deficient in the diet, a protein complex that functions as a nutrient sensor inside cells may repress the synthesis of proteins and lipids and cellular growth. That switch also regulates bone growth, which determines height.

"These children don't seem to have what they need to turn on that switch," Manary said.

The researchers plan to probe further, with the eventual goal of finding a means -- perhaps in the form of a food product or additive -- to reduce stunting. Decades-long efforts by Manary and other experts in malnutrition have resulted in the widespread development and use of nutrient-rich ready-to-eat food (RUTF) in Africa, Asia and Central America.

"A possible goal could be to roll out something analogous to RUTF, but for stunting," Manary said.

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This work was supported by the National Institutes of Health (NIH), grant numbers R01 AG027012, R01 EY024596 and R01 HL11271; the Intramural Research Program of the National Institute on Aging of the NIH; the Children's Discovery Institute of Washington University and St. Louis Children's Hospital; and the Hickey Family Foundation.

Semba RD, Shardell M, Ashour FAS, Moaddel R, Trehan I, Maleta KM, Ordiz MI, Kraemer K, Khadeer MA, Ferrucci L, Manary MJ. Child Stunting Is Associated with Low Circulating Essential Amino Acids. EBioMedicine. Published online Feb. 19, 2016.

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 sixth 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.

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