Amino acids help kids overcome fetal malnutrition
Inadequate essential Amino Acids lead to stunted growth in millions. Worldwide, an estimated 25 percent of children under age 5 suffer from stunted growth and development.
The most visible characteristic of fetal malnutrition is "stunting" or short stature, but the effects of stunted growth — an outcome of pregnancy starvation — are profound. Children starved while developing in their mother's womb don't reach their cognitive (intellectual) potential, are more susceptible to illness and infection, and don't live as long as children of healthy pregnancies.
While infant and childhood nutritional intervention makes a significant impact on reducing deaths from acute "stunting", the overall impact is modest. Fetal malnutrition is devastating.
Now, a team of researchers led by senior author Mark J. Manary MD, at Washington University School of Medicine in St. Louis, has identified a diet inadequate in essential amino acids— including the nutrient choline — as linked to stunting in fetal malnutrition. This information may help with new ways to treat these children.
The findings are published online in EBioMedicine1.
"Stunting affects half of the children in rural Africa and millions more elsewhere in the world. Many efforts are undertaken to reduce stunting's impact — from introducing various food supplements to reducing a child's exposure to infections — but we haven't really gotten anywhere. But new findings obtained with the help of cutting-edge technology, shed light on the biological reasons for this age-old, globally significant problem."
Mark J. Manary MD, Washington University School of Medicine in St. Louis, Missourir, USA, spends several months a year in Africa treating children with malnutrition.
Manary's team partnered with researchers at Johns Hopkins University, scientists at the National Institute of Aging in the USA, the University of Malawi in sub-Saharan Africa and many other institutions who examined metabolites in a child's cells and tissue (a metabolomic approach). Metabolites are molecules indispensable to tissue growth. Molecules considered significant are amino acids, vitamins (B2 and B12), organic acids, as well as nucleotides (inosine-5'-monophosphate and guanosine-5'-monophosphate). Blood samples were taken from 313 children ages 12-59 months in order to evaluate their metabolite levels.
Children chosen had no observable evidence of severe acute malnutrition, congenital or chronic disease, or even diarrhea. But after each child's height and weight were measured, health-care workers found 64 percent were stunted when compared to World Health Organization growth charts.
Using blood samples, researchers determined that more than 80 percent of the stunted children had low levels of all nine essential amino acids when compared with children who were not stunted. Essential amino acids — the building blocks of proteins — are important to human health and can't be produced solely within the body. They must come from food.
Stunted children 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. They also had alterations in the concentration of a lipid linked to the development of cell membranes in their brain and nervous tissues.
"The message here is not that these children are sort of low in one thing or even 10 things but that they're low in all of these amino acids and all of these kinds of fats, and each has a role in turning on a necessary switch for growth."
Mark J. Manary MD, the Helene B. Roberson Professor of Pediatrics at Washington University, and senior author.
The new research adds to the ever-developing picture of childhood malnutrition. Manary, along with Jeffrey Gordon MD — the Dr. Robert J. Glaser Distinguished University Professor and director of Washington University's Center for Genome Sciences and Systems Biology — have authored a study published in Science2 that points to a dysfunctional community of microbes in a child's gut as a critical result of childhood malnutrition.
Gut bacteria may have far-ranging influence on the body. Manipulating their makeup has the potential to provide new treatment of childhood malnutrition to 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 believe when a diet is low in particular amino acids, a cell protein complex designed to sense nutrients may instead be triggered to repress the fusion of proteins and lipids needed for cell tissue growth. The cell protein complex acts as a switch that also regulates bone growth and determines height. "These children don't seem to have what they need to turn on that switch," Manary adds.
The team plans to probe further, with the intention of forming 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. According to Manary: "A possible goal is something analogous to RUTF, but targeting stunting."
Stunting affects about one-quarter of children under five worldwide. The pathogenesis of stunting is poorly understood. Nutritional interventions have had only modest effects in reducing stunting. We hypothesized that insufficiency in essential amino acids may be limiting the linear growth of children.
We used a targeted metabolomics approach to measure serum amino acids, glycerophospholipids, sphingolipids, and other metabolites using liquid chromatography-tandem mass spectrometry in 313 children, aged 12–59 months, from rural Malawi. Children underwent anthropometry.
Sixty-two percent of the children were stunted. Children with stunting had lower serum concentrations of all nine essential amino acids (tryptophan, isoleucine, leucine, valine, methionine, threonine, histidine, phenylalanine, lysine) compared with nonstunted children (p < 0.01). In addition, stunted children had significantly lower serum concentrations of conditionally essential amino acids (arginine, glycine, glutamine), non-essential amino acids (asparagine, glutamate, serine), and six different sphingolipids compared with nonstunted children. Stunting was also associated with alterations in serum glycerophospholipid concentrations.
Our findings support the idea that children with a high risk of stunting may not be receiving an adequate dietary intake of essential amino acids and choline, an essential nutrient for the synthesis of sphingolipids and glycerophospholipids.
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.
Funding: 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.
Abstract2: Science - Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children
As we come to appreciate how our microbial communities (microbiota) assemble following birth, there is an opportunity to determine how this facet of our developmental biology relates to the healthy or impaired growth of infants and children. Childhood undernutrition is a devastating global health problem whose long-term sequelae, including stunting, neurodevelopmental abnormalities, and immune dysfunction, remain largely refractory to current therapeutic interventions.
To test the hypothesis that perturbations in the normal development of the gut microbiota are causally related to undernutrition, we first applied random forests (RF), a machine learning method, to bacterial 16S ribosomal RNA data sets generated from fecal samples that were collected serially from healthy Malawian infants and children during their first 3 postnatal years. Age-discriminatory bacterial taxa were identified with distinctive time-dependent changes in their relative abundances; they were used to construct a sparse RF-derived model describing a program of normal postnatal gut microbiota development that is shared across biologically unrelated individuals. A metric based on this model (microbiota-for-age Z-score) was used to define the state of development (maturation) of fecal microbiota from infants and children with varying degrees of undernutrition. Fecal samples obtained from 6- and 18-month-old children with healthy growth patterns or with varying degrees of undernutrition were transplanted into young germ-free mice that were fed a representative Malawian diet. The recipient animals’ rate of lean body mass gain was characterized by serial quantitative magnetic resonance, their metabolic phenotypes were determined by targeted mass spectrometry, and their femoral bone morphologic features were delineated by microcomputed tomography.
Undernourished children in the Malawian birth cohort that we studied have immature gut microbiota. Unlike microbiota from healthy children, immature microbiota transmit impaired growth, altered bone morphology, and metabolic abnormalities in the muscle, liver, and brain to recipient gnotobiotic mice. The representation of several age-discriminatory taxa in the transplanted microbiota harbored by recipient animals correlated with their growth rates. Microbiota from 6-month-old infants produced greater effects on growth than did microbiota from 18-month-old children, although in each age bin, the growth effects produced by a healthy donor’s community were greater than those produced by an undernourished donor’s community. Cohousing coprophagic mice shortly after they received microbiota from healthy or severely stunted and underweight 6-month-old infants resulted in the invasion of age- and growth-discriminatory taxa from the former into the latter microbiota in the recipient animals, with associated prevention of growth impairments. Introducing cultured members from this group of invasive species ameliorated growth and metabolic abnormalities in recipients of microbiota from undernourished donors.
These preclinical findings provide evidence that gut microbiota immaturity is causally related to childhood undernutrition. The age- and growth-discriminatory taxa that we identified should help direct studies of the effects of host and environmental factors on gut microbial community development, and they represent therapeutic targets for repairing or preventing gut microbiota immaturity.
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Mar 1, 2016 Fetal Timeline Maternal Timeline News News Archive
Children chosen had no observable evidence of severe acute malnutrition. But after each was
measured for height and weight, 64 percent were stunted when compared to WHO growth charts.
Image Credit: Science Magazine