Project : USDA ARS

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Research Project: Pediatric Clinical Nutrition

Location: Children's Nutrition Research Center

2018 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
Significant research progress was accomplished during the year. To review the progress, please refer to project 3092-51000-057-02S (Project #2), 3092-51000-057-03S (Project #3) and 3092-51000-057-04S (Project #4).

Accomplishments
1. New test for children's gut health. Rural African children often are stunted because of gut inflammation. Children's Nutrition Research Center researchers based in rural Malawi, Africa worked closely with 300 young children to compare their gut health measured by two different tests. Traditionally, gut health is measured by a sugar absorption test and this test was compared to a panel of small molecules that indicate cellular function in the gut. The comparison found that either test can be used to identify poor gut health. With this test we can more easily identify children who need interventions to improve their gut health in a less expensive way.

2. Molecular changes in severe childhood malnutrition affect genes important to over-nutrition. Previous studies from researchers in Houston, Texas demonstrated a lower level of DNA methylation (chemical modifications of DNA) in samples from children with more severe- rather than the mild- forms of malnutrition. In recent studies, we show that these methylation changes alter the amount of the gene that is present, and the genes affected by this methylation change are in diseases where there is over-nutrition, such as diabetes and obesity. Further, the relationship between methylation at different sites was also affected by the severe undernutrition, and these changes occurred at sites where methylation is disturbed in cancer. These results suggest that the molecular changes occurring in under-nutrition are also highly relevant to studies of cancer and common nutritional diseases.

3. Immune system activation may identify children who may respond to dietary treatment for abdominal pain. Activation of the immune system and gut nerves account for pain related to certain meals. Up to 15% of children worldwide experience chronic abdominal pain and in a large percent of these cases the pain is related to diet. Researchers in Houston, Texas have discovered that in many of these children there is activation of the immune system and nerves within the gut that appear to be responsible for the pain. Using tests to detect this activation, we can begin to identify children for whom specific changes in diet will relieve their pain. These findings are important as it provides a nutritional change that may relieve chronic abdominal pain in this young population worldwide.

4. Adverse effect on small blood vessels related to fat deposition in the liver. Endothelial dysfunction, is an early marker of atherosclerosis (hardening of the arteries that can lead to heart attacks and/or strokes), and can be measured non-invasively by measuring the blood flow in the small vessels of the fingers. Researchers in Houston, Texas, utilized this method to investigate the influence of increased fat in the liver on endothelial function in obese youth suffering from prediabetes and type 2 diabetes. We demonstrated a direct relationship between liver fat accumulation and impairment in vessel function in these youth. These findings indicate that increased fat in the liver is associated with an added risk for cardiovascular disease in obese youth. This has important implications for childhood health and supports the need for surveillance for liver disease in obese youth with prediabetes and type 2 diabetes and intensifying prevention efforts in these children.

U.S. DEPARTMENT OF AGRICULTURE

Children's Nutrition Research Center: Houston, TX