Project : USDA ARS

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Research Project: Pediatric Clinical Nutrition

Location: Children's Nutrition Research Center

2019 Annual Report

Objectives
There is an ongoing need to enhance our understanding of the influences and role of various nutrients on fetal, postnatal, and childhood health, growth, and development as well as the etiology of obesity. A goal of this project is to provide evidence-based nutrient bioavailability data for the development of nutritional guidelines in children 6-24 months of age by: 1) using stable isotopes to assess the absorption of calcium, zinc, and magnesium over a range of usual dietary intakes in groups of children at 6-12, 12-18, and 18-24 months of age; 2) relate mineral absorption values to dietary mineral intake and body composition as determined by DXA; 3) evaluate mineral absorption and body composition in a group of preterm infants. We plan to increase understanding of how diet and age influence gut microbial population composition and promote health; we will: 4) determine effects of diet/age on gut microbial composition and relate these to gut barrier function and inflammation in children 7-18 years of age; 5) develop de novo method to assemble short sequence reads into contigs; apply method to assemble gut microbiome sequence reads; develop statistical method to cluster contigs and quantify abundance of these clusters; perform genetic association testing for haplotype-microbiome interactions that affect risk of childhood obesity; and 6) identify panel of human mRNAs indicative of environmental enteropathy (EE); evaluate as biomarker for EE in other populations; test whether micronutrient and/or fish oil supplements can reduce EE; explore microbiome of children with and without EE; correlate mRNA panel markers with child growth parameters. Additionally we will determine: 7) negative effect of obesity-induced inflammation and oxidative stress on women's fertility and if it can be reversed by weight loss and supplemental nutrients with antioxidant and anti-inflammatory properties; 8) if pre-pregnant lipid supply underlies the insulin resistance and increased susceptibility to gestational diabetes in obese women, and if exercise and modified diet will decrease the prevalence of gestational diabetes; 9) whether children born to obese and/or gestational diabetic mothers have an altered macronutrient metabolism; 10) the relationship of vascular function to insulin resistance in youth; and relationship of monocyte function and serum inflammatory markers and vascular reactivity to insulin sensitivity; 11) the effect of hyperglycemia on endothelial function, monocyte function and inflammatory markers; 12) no longer applies; and 13) identify genomic and epigenomic markers associated with clinically relevant manifestations in severe childhood malnutrition.

Approach
A multi-discipline approach will be undertaken to improve our understanding of how foods support health, meet dietary requirements, and reduce disease risk such as cardiovascular disease and obesity. Our studies will utilize stable isotope techniques to provide accurate, practically applicable information that may be obtained from the study populations in a safe manner. Comparison will be made of intake and absorption of calcium and magnesium with total body bone mineral as determined by Dual Energy X-ray Absorptiometry. For magnesium and zinc, comparisons will be made of estimated retained minerals with expected tissue accretion rates in early childhood. We will also evaluate these values in a group of preterm infants who may have greater nutrient requirements due to the need to have catch-up growth. For other studies, obese and normal weight infertile women will be recruited, measured, and assigned a calorie-specific diet. Numerous biological measurements will be taken and correlations between body fat and other outcomes will be made. Additionally, we will conduct a cross-sectional study to evaluate endothelial dysfunction in obese youth with and without Type 2 diabetes compared with normal weight controls with the primary aim to explore the effect of insulin resistance vs. hyperglycemia on endothelial function. A cross-sectional study design will also take place comparing non-obese/obese adolescents wherein plasma samples will be collected and DNA will be sequenced and analyzed. Furthermore we will determine the effects of diet and age on gut microbial composition, ascertain the metagenomic profile of the gut microbes, and relate these to gut barrier function and inflammation in children 7-18 years of age; and develop a new de novo assembly method to assemble short sequence reads into long contiguous reads and apply this method to assemble gut microbiome sequence reads. Development of a statistical method to cluster contigs and quantify abundance of these clusters will occur, and we will perform genetic association testing for haplotype-microbiome interactions that affect the risk of childhood obesity. Researchers will identify a panel of human mRNAs in fecal samples indicative of environmental enteropathy, evaluate this panel as a biomarker for environmental enteropathy in other populations, and test whether micronutrient and/or fish oil supplements can reduce environmental enteropathy. Scientists will determine by using genome-wide technologies, whether epigenetic markers can be used as surrogate biomarkers of sever childhood malnutrition phenotypes.

Progress Report
To review the progress made during the year, please refer to the following projects: 3092-51000-062-20S (Project #1), 3092-51000-062-30S (Project #2), and 3092-51000-062-40S (Project #3).

Accomplishments
1. Genetic differences in body metabolism are associated with the risk for different types of undernutrition. Severe undernutrition in children, commonly found in impoverished countries, is known to occur as one of two forms – a severe form known as ESAM that is associated with body swelling and widespread organ dysfunction, and a less severe form associated with the rapid loss of weight and muscle bulk. The reasons why some children get one form over the other has remained a mystery despite decades of study. By assessing the human genome in the first molecular study of severe undernutrition, researchers in Houston, Texas, have demonstrated that changes in DNA that affect how the body breaks down and uses specific amino acids and vitamins (one-carbon metabolism) are associated with an increased risk of developing the severe form of undernutrition (ESAM). Previously we showed that one-carbon metabolism is abnormal in those with ESAM and that there is also decreased levels and abnormal patterns of DNA methylation. These results suggest that nutritional supplementation of one-carbon metabolism substrates (choline, vitamin B12, and methionine) could be important in improving the outcomes for those suffering from ESAM.

2. Impaired integrity of the intestinal lining and inflammation in the intestine are related to diet. Between 10-15% of school age children and adults worldwide suffer from intermittent chronic abdominal pain. This pain is sometimes associated with constipation and/or diarrhea and the economic cost of this condition in the United States (for adults) has been calculated to be $30 billion per year. Scientists in Houston, Texas, conducted research that showed that impaired integrity of the intestinal lining and/or inflammation in the intestine are associated with abdominal pain conditions and that carbohydrate ingested is linked to both. This relationship between dietary carbohydrate and impaired integrity of the intestinal lining and inflammation in the intestine is not associated with obesity. Studies by other researchers have shown that, in addition to abdominal pain, impaired integrity of the intestinal lining and/or inflammation in the intestine have been associated with a number of health problems such as liver disease, depression, and pancreatic disease; thus, our results have relevance to other disorders associated with impaired integrity of the intestinal lining. These results add to the understanding of how diet can affect the intestinal lining and contribute to poor health.

3. Vitamin D deficiency in overweight children is associated with higher risks for early forms of diabetes, heart and blood vessel disease. Low vitamin D levels (Vitamin D deficiency) are present in overweight children and in minorities, and these low levels appear to contribute to an increased risk of cardiovascular disease later as an adult. Researchers in Houston, Texas, evaluated the relationship of vitamin D (that is more readily available in the blood) and the risk for heart and blood vessel disease in overweight and obese youth. We found that children with lower vitamin D levels in their blood had higher body fat, worse blood vessel function, lower insulin sensitivity (how well the body responds to insulin), and higher markers of inflammation (a measure of risk for heart disease). These findings have important implications for future studies evaluating vitamin D status in obese and overweight children as we can now derive more accurate guidelines for these children. In addition, we can now evaluate if resolving this vitamin D deficiency in these children will restore their heart and blood vessel health over time.

U.S. DEPARTMENT OF AGRICULTURE

Children's Nutrition Research Center: Houston, TX