Location: Microbiome and Metabolism Research Unit
2018 Annual Report
Objectives
The mission of Cooperator's Arkansas Children’s Nutrition Center (ACNC) is to determine the effects of diet, physical activity and nutritional status in childhood and in mothers during the pre- and post-conception periods on growth, development and health by conducting research on: 1) central nervous system and cognitive development and function of infants and children; 2) roles of maternal and child body composition, metabolism and genes (including responses to food macronutrients, phytochemicals and microbe-derived factors) on infant and child growth, development and the long-term health consequences of these factors; and 3) impact of parental and child physical activity on these parameters, singly or in combination with diet, and the biological basis for exercise-associated behaviors and health outcomes. To accomplish this mission, the ACNC has the following objectives and as appropriate, others as mutually agreed upon:
A. Determine how maternal/parental diet, exercise, and metabolic health associate with psychological/behavioral, neurologic and physiological function and development in children.
B. Understand how postnatal diet, childhood physical activity, and nutrition associate with psychological/behavioral, neurologic and physiological function and development in children.
C. Characterize the interaction between the microbiome, host health and nutrition to modify physiology and promote health and development (skeleton, gastrointestinal and hepatic tissues, immune system, cardiovascular, and muscle, e.g.).
Approach
To accomplish these objectives, a research plan encompassing the specific research described below is authorized. Research is to be accomplished over a multi-year period as resources are available and as readiness for research and management capabilities develops. The plan shall be divided into the following areas:
A. Determine how dietary components, dietary patterns, and metabolic health influence psychological-behavioral outcomes, neurodevelopment, and physiological function in children. Children will be studied longitudinally and cross-sectionally to evaluate the effects of child/parental diet, metabolic health, and body composition on psychological-behavioral, neurologic and physiological function.
B. Determine how physical activity and fitness influence psychological-behavioral outcomes, neurodevelopment, and physiological function in children. Children will be studied longitudinally and cross-sectionally to evaluate the effects of child/parental physical activity patterns, fitness, metabolic health, and body composition on psychological-behavioral, neurologic and physiological function.
C. Characterize the impact of host-microbe interactions on health and development. Children will be studied longitudinally and cross-sectionally to evaluate the factors linking child/parental microbiome with metabolic health, body composition, physical activity outcomes, psychological/behavioral, neurologic and physiological functions.
D. Center Development. Cooperator has the following general areas of research in the Arkansas Children’s Nutrition Center (ACNC), which address the mission area of parental/child health: Brain Development and Central Nervous System Function; Dietary Factors and Physical Activity Effects on Health, Development and Function of Organ Systems (skeleton, gastrointestinal and hepatic tissues, immune system, cardiovascular, and muscle, e.g.); and Obesity and its Effects on Cellular and Physiologic Function in mothers, infants and children.
Progress Report
Examining maternal-infant cohorts over many years, from the pre-partum period to birth to infancy and childhood, provides critical information related to the long-term impact of infant and child diet, maternal obesity, and other factors on the body's development and health. The Arkansas Children's Nutrition Center (ACNC) is uniquely-positioned to make strong progress toward understanding the basis of diet-, exercise-, and maternal obesity-associated changes in offspring's body fat, childhood obesity risk, bone health, gut and immune functions, and brain development. The ACNC also conducts novel research to determine the mechanisms underlying muscle function and the means by which physical activity improves metabolic health and reduces disease risk.
"Dietary Factors in Development" Project: The Beginnings Study follows growth, body composition, bone and brain development from birth-6 yr fed breastmilk, soy- or dairy milk-based formulas (n=300 ea.): it is the world's largest longitudinal study of its kind. This year enrollment was completed. Despite controversy as to potential "estrogen-like" effects of soy, no soy-formula-related differences in reproductive organ development has been observed. To fully consider if formula feeding impacts long-term health and reproductive development, studies of participants returning at age 14 began (>30 children enrolled). In experiments examining if soy feeding activates estrogen receptor signaling pathways and reproductive development in a pre-pubertal rat model, no adverse estrogenic effects on testicular development was found. Thus, results to date indicate that soy foods have little effect on reproductive development. “Phytoestrogens” have also been implicated in promoting bone growth. ACNC investigators completed bone architecture and abundance assessments in 5 yr old children from the Beginnings Study. These results are currently being analyzed.
"Effects of Early Diet on Gastrointestinal Development and Function" Project: Breastfeeding is associated with optimal immune system development; yet, 50-70% of U.S. infants are formula-fed. How this impacts health and development remains to be fully elaborated. We tested how dairy formula-feeding versus breastmilk-feeding during the first mos. of life impacts development of immune cells and humoral immunity (the natural ability to raise antibodies), utilizing a novel piglet model of human breastmilk (HBM) feeding. The results indicate that immune responses are significantly greater following HBM feeding. There were differences in the gut microbiota (the normal population of bacteria in the intestine) in HBM versus formula fed piglets: this is a plausible mechanism by which breastfeeding confers beneficial effects on development of the immune response. The studies provide evidence for a positive effect of breastfeeding on infant immunity, and highlight the value of the newly-developed HBM-fed piglet model for studying postnatal feeding effects on the body. Formula-feeding may also differentially regulate cholesterol pathways. Breastmilk contains ~4 times more cholesterol than typical dairy-based infant formula, and soy formulas contain virtually no cholesterol. ACNC scientists fed piglets dairy-based or soy-based formula, comparing liver cholesterol metabolism to sow-fed piglets. Formula led to increased expression of enzymes involved in cholesterol synthesis. Expression of the enzyme Cyp7a1 was also increased--Cyp7a1 is responsible for cholesterol metabolism to bile acids (molecules important to fat digestion); higher expression coincided with elevated fecal bile acid concentrations. These novel findings suggest that low postnatal dietary cholesterol intake adaptively increases cholesterol synthesis and conversion into bile acids in neonates.
"The Role of Dietary Factors in Skeletal Development" Project: Bone health and adult osteoporosis risk may be influenced by in utero conditions, early-life diet, exercise and obesity. The full suite of dietary or gene-level factors that influence bone turnover and integrity remain to be determined. We investigated the effects of maternal diet-induced obesity (DIO) in rats on fetal osteoblast (bone-forming cells), finding that a pathway called p300/CBP was activated—this associated with chemical modifications (“epigenetic” changes) to specific DNA sites involved with senescence (aging). This “bone cell aging” phenotype was recapitulated in human umbilical cord stem cells isolated from offspring of pregnant obese mothers. In other studies, adult offspring from DIO rat mothers showed suppressed bone formation, which may in part be due to prenatal epigenetic regulation of bone cell genes. Thus, early-life programming of long-term bone formation is strongly influenced by maternal obesity. Diet might reverse negative effects of maternal obesity. ACNC scientists have studied the effects of blueberry diet-derived 3-(3-hydroxyphenyl)-propionic acid (3-3-PPA) on bone development during early life: 3-3-PPA altered the stem cell differentiation program and reduced bone cell "aging." Specific blueberry-derived molecules also have effects on suppressing bone resorption (osteoclasts). This provides evidence relevant to dietary guidance for infants and children.
"Maternal Programming of Offspring Metabolism and Obesity" and "Interventions to Mitigate Maternal Obesity-Associated Programming" Projects: These studies focus on intergenerational transmission of obesity and metabolic health to offspring. The Glowing Study is the first prospective long-term study testing if obesity influences offspring developmental programming. This year all visits were completed (to age 2 yr; ~300 mother-child dyads). Maternal, paternal and cord blood factors plus maternal body fat are being investigated for relationships to offspring body fat growth. Umbilical cords were utilized for epigenetic analysis of DNA near specific growth- and body size-related genes. Correlative associations with mothers' obesity and metabolic health, and children's obesity and body fat outcomes, are being analyzed. Studies in 5 and 8 yr olds will provide a definitive test for the hypothesis that maternal adiposity programs offspring metabolism and obesity risk. A DIO mouse model showed that exposure to maternal obesity programs susceptibility of male offspring to obesity. A key focus of several of our studies in both clinical and animal models includes analysis of the placenta, since this represents an important avenue for developmental programming. In mice that specifically lack placental MyD88 (important to inflammation), results showed that MyD88 is necessary for transmission of maternal obesity to offspring. These pathways can be evaluated in human samples: we conducted genome-wide DNA epigenetics and gene expression studies in placentas from the Glowing cohort, and differences between normal-weight and obese samples are being evaluated for associations to offspring growth and body fat. These studies provide a first-ever glimpse into the molecular underpinnings of mother-child obesity transmission. It was found in mice that maternal DIO persistently alters the composition of the gut microbiome in offspring: this may be a non-genetic, diet-sensitive pathway of transmitting risk of metabolic dysfunction. To explore the significance of this in humans, we analyzed the gut microbiota from normal weight and overweight women at each pregnancy trimester, and examined the establishment of the microbiome in their offspring over 1 yr. Preliminary data suggest that in addition to maternal obesity, mode of delivery and breastfeeding influence the infant gut microbiome. These analyses are the most detailed ever in examining maternal diet, body composition and neonatal factors on offspring microbiome development.
The Expecting Study investigates if physical activity in obese pregnant mothers can ameliorate effects of maternal obesity-associated offspring programming of obesity risk (>130 total women enrolled to date). In complementary studies, the effects of maternal voluntary wheel running in mice suggest robust epigenetic changes in the placenta. Other rodent studies examining the impact of early-life physical activity in mitigating future obesity revealed that early exposure to voluntary exercise does not prevent weight gains on an obesogenic diet in later life. Finally, to determine factors that regulate muscle function and drive physical activity-associated health benefits, studies have focused on pathways involved with fat burning and exercise. Myoglobin (which gives muscle red color and ferries oxygen within the cells) was found to bind fat molecules and likely plays an important role in regulating fat metabolism. Other studies identified novel factors in exercising muscle that could have signaling roles relevant to fatigue and muscle function.
"Dietary Influences on Psychological and Neuropsychological Development and Function in Children" Project: Studies use non-invasive brain imaging (MRI) and brain EEG technologies at rest and during information processing, to test effects of maternal programming, obesity and diet on brain function. Data acquisition was completed for the Beginnings Study that has tracked the physical, physiological and behavioral development from 2 mo to 6 yr in children who were breastfed or fed milk-based or soy-based formulas. Resting cardiovascular and brain electrical activity measures from infancy through 6 yr will provide first-ever normative data describing sex and infant diet influences on autonomic and brain development. A second study detailed psychological and neurocognitive characteristics of obese preadolescents. Initial analyses have identified a potential sex-related EEG-related biomarker associated with childhood obesity. A related project was initiated that examines if a high-protein breakfast optimizes brain processes in obese preadolescents.
Accomplishments
