Location: Microbiome and Metabolism Research Unit2018 Annual Report
Overall objective is to gather evidence about important environmental factors that have long-term consequences on child development/health, and their health as children become adults. 1: Continue Beginnings study, longitudinal study of growth/development/body composition in infants breast-fed or fed soy/cow milk formula. 2: Determine if soy feeding affects estrogen receptor beta using chromatin immunoprecipitation analysis; gene deletion studies in appropriate animal models to ascertain if soy protein affects reproductive development/metabolism/body composition via activation of ERbeta-mediated signaling. 3: Determine body composition/metabolism of prepubertal pigs fed breast milk/milk formula/soy formula as neonates, then weaned onto either low or high fat diet. Compare data with body composition/metabolism in children age 5 from Beginnings Study. 4: Determine effects of early diet in pig model on gut-associated lymphoid tissue development/function; ... 5: Characterize effects of neonatal diet on composition of intestinal microbiota, Collect urine/fecal samples from Beginnings Study infants/children at 3/6/9/12 months and yearly thereafter. 6: Determine if feeding blueberries (BB) and other fruits/vegetables containing phenolic acid (PA) chlorogenic acid (CA) or treatment with CA metabolite hippuric acid stimulate bone growth in rodent model; examine role of G-coupled receptor protein GPR109A as potential mediator of PA effects on bone. 7: Perform peripheral quantitative computerized tomography to study bone morphology; measure urine/serum bone turnover markers in lean/obese prepubertal children with/without additional symptoms of insulin resistance. 8: Determine ability of diets containing BB to block obesity-induced impairment in bone quality/strength in weaning rats; determine method of activiation in underlying mechanisms by which this occurs. Determine if bone turnover markers in urine/serum of obese children are improved after short-term intervention with BB-containing diets. 9: Determine if toll-like receptor/early response protein-1 signaling is mediating embryonic/placental inflammation and epigenetic dysregulation in offspring due to maternal obesity in rodent models/human subjects. 10: Characterize effect of maternal obesity on programming offspring's metabolism and risk of obesity later in life in the Glowing study. 11: Determine if interventions prior to/during pregnancy that alter maternal hyperinsulinemia, gastrointestinal microbiome and/or inflammation prevent obesity-induced metabolic programming in animal models. 12: Determine if reprogramming of offspring energy metabolism/mitochondrial function can occur by promoting neonatal physical activity or dietary factors in rodent models. 13: Determine effects of early diet on neurocognitive development by completing neurophysiological/behavioral aspects of Beginnings study. 14: Determine effects of diet composition, meal pattern/frequency on brain development/function, and behavioral dynamics important for learning in well-characterized lean/obese school children. 15: Characterize how neurocognitive functions associated with obesity can be improved by physical activity.
Studies will focus on the various dietary factors found in foods commonly consumed by children, such as breast milk, infant formulas, fruits, grain, milk, and soy to determine their long-term health effects in infants and children. We will analyze how the early exposure to protein sources and fruits normally consumed by infants and children prevents the initiation of and protects against development of chronic diseases by altering tissue differentiation, inflammation, and/or oxidative status. We will use animal models to mechanistically address the molecular and cellular pathways regulated by intake of various dietary factors (such as in soy foods, berries, grains and milk) in mammary tissue, liver, adipose tissue, pancreas, gastrointestinal tract, bone, skeletal muscle and the immune system; identify tissue and serum biomarkers of healthy status associated with these diets; and provide new molecular targets and processes underlying chronic diseases that may be influenced by proper nutrition. Additional work will be undertaken in an observational study of infants, The Beginnings Study, which is a longitudinal study of breast-fed, milk formula-fed, and soy formula-fed children from birth through puberty, will evaluate growth, development, body composition, metabolism, bone development, and immune system development and function. Animal models such as the neonatal pig will be utilized to explore molecular mechanisms underlying the effects of early dietary exposures. Rodent models will be used to understand the parental epigenetic transmission of the effects of maternal obesity and high fat feeding to future generations and underlying molecular, biochemical, and endocrine mechanisms, in the offspring. These studies will be translated in an ongoing longitudinal clinical study of infant body composition in children of lean and overweight women (The Glowing Study). Work will be accomplished by evaluating critical periods of development and vulnerable stages of life (i.e. the nutritional status of women at the moment of conception; nutritional and developmental issues during pregnancy and lactation). Children (infants, toddlers, and school-aged youths) will be studied to evaluate the effects of infant diet (specifically, breast-milk and a variety of infant formulas) on morphological, neurophysiological, behavioral, and cognitive development in infants and children. Nutritional status assessments, anthropometric measurements, body composition, energy metabolism, physical activity fitness, urine and blood analysis, and measures of brain structure (MRI imaging), psychological and behavioral status (standardized testing), neuropsychological, and cognitive measures will be obtained and analyzed. The effects of diet composition, meal patterns, meal frequency, physical activity, and body composition on brain function, behavioral dynamics, learning, and school performance will be assessed in normal weight and overweight/obese school children using validated survey instruments and state-ofthe-art research equipment.
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.
1. Factors contained in exosomes, natural nanoparticles found in breastmilk and dairy milk-based infant formula, regulate liver metabolism. It is well-established that breastfeeding confers certain advantages to the infant with respect to health and development, yet the specific factors that drive these outcomes are not fully elaborated. Identifying said factors will be valuable in terms of the scientific evidence base for breastfeeding recommendations, understanding fundamental biological principles relevant to child health, and for modifying infant formulas to contain beneficial ingredients that are naturally contained in milk. Researchers at Little Rock, Arkansas, collaborated with University of Nebraska colleagues who have discovered that natural particles in milk (called exosomes) contain micro-RNAs; specific micro-RNAs can regulate liver metabolism of specific molecules called purines. It was found that infants consuming soy formula (exosome-free) displayed highly significant increases of indices of this pathway compared to breastfed or milk-formula fed infants, illustrating the critical importance of natural milk-derived exosome cargos in maintaining normal metabolism in babies.
2. A new tool to understand complex relationships between naturally-occurring gut bacteria (microbiota), health and development. There are billions to trillions of microbiota in the intestine, impacted by diet, birth mode, environment, and host health, yet quantifying and visualizing this complex system requires specialized informatics skills that have traditionally been beyond the reach of most scientists. Researchers at Little Rock, Arkansas, have developed an online interactive tool (web-based "app") that removes many of these barriers and allows rapid assessment of microbial DNA-based measurements. The Dynamic Assessment of Microbial Ecology (DAME) provides an interactive, flexible, and easy-to-use interface while performing the most up-to-date microbiome analysis tools for alpha-diversity, beta-diversity, and taxa based group comparisons. This innovative tool is a major asset to researchers, and has been heavily utilized worldwide to increase the speed by which scientists assess gut bacteria and their relationships to health and disease.
3. Naturally-occurring gut bacteria (microbiota) and bacterial metabolism are strongly affected by the host's metabolic health. It is well-established that the gut microbiota are critical to the host's health, and the nature of bacteria in the gut are strongly impacted by one's diet, yet the specific bacterial factors that impact host biology and disease risk remain to be identified. In addition, the degree to which the host's health regulates the microbiome is not yet clarified, since most studies have focused on changing the gut bacteria through diet in order to monitor health outcomes. Researchers at Little Rock, Arkansas, and the University of California, Davis discovered that major differences in the gut bacteria profile and metabolites they produce (xenometabolites) come about in the course of diabetes progression in rats, independent of diet. These novel results indicate that changes in host metabolic health alters gut bacteria and their potential signaling molecules, which might contribute to the risk, progression or severity of metabolic diseases such as diabetes.
4. Breastmilk feeding improves immune system development during infancy. Breastfeeding is recommended in part due to observations that breastfed children tend to have lower incidences of allergy and other immune system-associated conditions, and yet the scientific evidence explaining these associations is limited. To examine these questions, researchers at Little Rock, Arkansas, established a novel piglet model of human breastmilk (HBM, provided by a breastmilk bank) feeding and tested how dairy formula-feeding versus breastmilk-feeding during the first month of life impacts development of humoral immunity (the natural ability to raise antibodies against antigens). The results indicated that immune responses were significantly greater following HBM feeding, and this was coincident with differences in the gut microbiota (the normal population of bacteria in the intestine) in HBM versus formula fed piglets. The studies provide strong evidence in support of breastfeeding to optimize immune health of neonates, and indicate that postnatal feeding-associated differences in the gut microbiota provides a plausible mechanism by which breastfeeding confers beneficial effects on development of the immune response.
5. Evidence that low cholesterol content of infant formulas can alter normal liver cholesterol and bile acid metabolism. Breastmilk contains approximately 4 times more cholesterol than typical dairy-based infant formula, and soy formulas contain virtually no cholesterol. Since low dietary cholesterol in adults is known to upregulate one's own pathways of cholesterol synthesis, and cholesterol is a critical component of bile acid synthesis, it is possible that low formula cholesterol content disrupts normal metabolism of cholesterol and fat (bile acids participate in gut fat absorption, among other roles), in babies. Researchers at Little Rock, Arkansas, fed neonatal piglets dairy-based or soy-based formulas, comparing liver cholesterol metabolism and bile acids to sow-fed piglets. Formula led to increased expression of enzymes involved in cholesterol synthesis, and higher indices of bile acid synthesis and excretion. These findings suggest that low postnatal dietary cholesterol intake adaptively increases cholesterol synthesis and conversion into bile acids in neonates; thus, it is worthwhile to consider if infant formulas should be supplemented with bioavailable cholesterol in order to mimic normal metabolism observed with breastfeeding.
6. Dietary factors found in fruit during early life program long-term bone formation. Bone health and osteoporosis risk in adults is influenced by diet, exercise and obesity status during childhood; thus, strategies to maintain bone health throughout the life cycle are urgently needed. Components of certain fruits and vegetables such as blueberries have been suggested to have positive effects on bone growth, but specific pathways involved are not clear. Researchers at Little Rock, Arkansas, have characterized the effects 3-(3-hydroxyphenyl)-propionic acid (3-3-PPA), on senescence ("aging") signaling and promotion of mesenchymal stem cell differentiation toward osteoblasts (bone-forming cells), while suppressing adipogenesis (fat cell formation, an alternate fate) in the stem cells. The 3-3-PPA treatments suppressed osteoblastic cell senescence to promote bone accretion in mice. This finding raises the possibility that blueberry-rich diets promote bone growth through increasing systemic phenolic acids, and indicate that fruits rich in these compounds can be complementary to other bone-promoting foods such as vitamin-D fortified dairy.
7. Home food environment may influence weight status of overweight and obese pregnant women. Excessive gestational weight gain promotes risk of several obstetric and neonatal adverse outcomes including long-term programming of obesity risk. Researchers at Little Rock, Arkansas, are studying the role of home food environment on gestational weight gain: a total of 165 women of varied body mass index were asked to inventory their home for high-fat food availability, low-fat food availability, and food storage practices. Results were correlated with their gestational weight gain while adjusting for mother's age, race, marital status, and household income. At the beginning of their pregnancy, overweight and obese pregnant women stored significantly more foods in their home compared to normal weight women, and during their third trimester, obese pregnant women had significantly fewer low-fat foods in the home compared to normal weight women. These results provide evidence that will help in designing useful weight management strategies, through food environment changes, that effectively reduce excessive weight gain during pregnancy.
8. Mother's obesity impacts offspring DNA through chemical modification (epigenetic changes: DNA methylation). Obesity in the mother significantly increases the risk of obesity in the child, in part through "programming" of specific molecular pathways that are just being discovered. One mechanism by which maternal obesity signals may impact the baby is via changes in the way specific genes are expressed through epigenetic regulation (higher methylated DNA regions display increased or reduced gene expression compared to less methylated regions). Researchers at Little Rock, Arkansas, examined epigenetic modification of the DNA among genes important in fetal growth and metabolism, in umbilical cord tissue collected at birth from 78 infants of normal weight and overweight/obese mothers enrolled in the longitudinal Glowing Study. This analysis showed that infant sex and gestational length were associated with methylation of two genes important in metabolism, while maternal BMI influenced the methylation of the non-coding RNA H19 and metabolic regulator PPARGC1A. These findings provide a novel mechanism to help explain transgenerational obesity, and support the idea that maternal obesity persistently affects offspring metabolism and developmental programming.
9. Development of brain activity critical for brain function and cognition is modulated by infant diet and sex. Brain electroencephalography (EEG) gamma activity reflects neuronal activities that promote brain and behavioral development and maintain a balance of excitatory and inhibitory processes essential for normal brain function. However, there is limited information regarding the early development of this activity during the first 6 postnatal months—a critical period when brain cells generating this activity (interneurons using GABA—the chief inhibitory neurotransmitter in the central nervous system) are maturing and beginning to establish neural networks. Researchers at Little Rock, Arkansas, made high density EEG recordings obtained monthly from 2 to 6 months in 518 healthy infants who were exclusively breastfed, or fed milk formula or soy formula. The results showed gradual increases in gamma activity that varied across brain regions and revealed a previously unrecognized role for infant diet-sex interactions in this process, i.e., being greater in breastfed boys than girls, but greater in formula-fed girls than boys. Since early brain development establishes the platform for later development, these findings may reflect organizational variations that will influence the future development of behavioral and neurocognitive functions, sensitive to early-life diet.
10. Resting state frontal brain EEG alpha asymmetry is a potential obesity biomarker in preadolescent girls. The growing incidence of obesity among children has placed increased emphasis on the identification of biologic markers that might aid in the development of early weight management intervention strategies. One potential strategy is to identify brain regions and activities that relate to early obesity development, including hemispheric balance of resting frontal alpha EEG activity (8-12 Hz) — obese adults show greater levels of right than left hemisphere resting frontal alpha activity, associated with reduced efficiency of appetitive processes and decisions regarding food intake. Researchers at Little Rock, Arkansas, compared hemispheric levels of resting frontal alpha activity in healthy normal weight (n = 47) and obese (n = 48) 10 yr olds, and found significantly greater right than left hemisphere alpha power for obese girls than either normal weight girls or obese boys, with no significant differences between obese boys and normal weight children. Frontal alpha asymmetry was associated with significantly lower measures of intelligence and executive function in obese than normal weight girls, but not obese boys—suggesting that underlying obesity-related processes contributing to reduced cognitive functioning engage sex-specific mechanisms. The findings, for the first time, have identified in children the presence of sex-related influences on frontal brain regulation of functions relevant to eating behavior and decision-making, and this discovery can aid in the development of early weight management intervention strategies.
11. Identification of new markers of muscle function using a novel interstitial fluid metabolite profiling platform during rest and exercise. It is well-established that regular physical activity promotes whole-body health and reduces risk for any diseases including type 2 diabetes, yet the specific muscle-derived factors associated with these benefits are not elaborated. Furthermore, there is little understanding of the signaling molecules that drive fatigue and exertion perception, which can be important barriers to motivation toward optimal physical activity. Researchers at Little Rock, Arkansas, in collaboration with investigators at the University of Utah, Florida State University, and the University of California, Davis studied these questions, by using special catheters embedded within muscle of exercising rats and human participants that allowed for collection of the fluid surrounding muscle (interstitial fluid). It was discovered that exercise increases and decreases the interstitial concentrations of hundreds of small-molecule metabolites, including at least one specialized lipid called oleamide that is known from other studies outside of muscle to serve in a signaling role to neurons. These studies have revealed, for the first time on a global scale, the specific pathways that change in muscle with physical activity, and identified at least on potential signal of fatigue and exertion that is a candidate for explaining inter-individual differences in fatigue perception and exercise motivation.
12. Studies with the fatty acid palmitate raise doubt about the long-held view that saturated fat is pro-inflammatory. Excess dietary fat in children and adults, when in excess, has been associated with increased risk for cardiometabolic diseases such as cardiovascular disease, and saturated fatty acids in particular have been considered to have pro-inflammatory effects detrimental to metabolic health. However, studies in which saturated fats are provided in the context of regular meals have failed to demonstrate consistent changes in markers of inflammation, and cell culture studies are equivocal with respect to inflammation outcomes. Researchers at Little Rock, Arkansas, studied the effect of palmitate, a common saturated fatty acid, on inflammation in immune cells and muscle cells in culture, to definitively test if the fat is pro-inflammatory. Experimental conditions such as the means to solubilize the fat had profound influence on inflammation outcomes, and overall there was little evidence for a pro-inflammatory effect of palmitate. The results are consistent with published findings showing little to no inflammation of dietary fats when part of meal-feeding, and highlight the equivocal evidence for detrimental effects of saturated fat on inflammation; the latter can be important for shaping public policy related to dietary intakes of fats.
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