Research Project: Impact of Maternal Influence and Early Dietary Factors on Child Growth, Development, and Metabolic Health

Location: Microbiome and Metabolism Research

2024 Annual Report

Objectives
The overall objective of this project is to gather evidence about important environmental factors that have long-term consequences on child development/health, and their health as children become adults. The following objectives will be sought via five independent research studies: 1: Evaluate the role of epigenomic and postnatal factors in maternal obesity-associated programming of offspring metabolic, skeletal and cardiovascular outcomes. (Proj 1) 2: Determine the role of maternal germ line (oocyte) and placental (trophoblast) innate immune response signaling in mediating developmental programming in offspring. (Proj 1) 3: Determine the role of postnatal nutrition and dietary factors on physiology and metabolism. (Proj 2) 4: Determine if there is a persistent effect of early life nutritional factors on bone and metabolic health. (Proj 2) 5: Define host-microbiome cross-talk and xenometabolism in humans and rodent models relevant to human health. (Proj 2) 6: Examine the effect of maternal obesity, exercise and diet on programming the offspring's metabolism and risk of obesity during the first 8 years of life. (Proj 3) 7: Investigate the role of exercise during gestation in mitigating maternal programming of offspring metabolism. (Proj 3) 8: Test the feasibility and efficacy of peri-conception exercise intervention on mitigating maternal obesity programming. (Proj 3) 9: Determine bioenergetics phenotypes that link exercise to metabolic health in normal weight (NW) and obese (OB) children. (Proj 4) 10: Examine the persistent effects of early-life exercise, and the impact on childhood and adolescent metabolic health. (Proj 4) 11: Examine molecular signals and mechanisms associated with exercise, fatigue and muscle. (Proj 4) 12: Use participants in the Beginnings cohort to determine the effects of early diet on neurocognitive development in healthy children and adolescents. (Proj 5) 13: Evaluate the impact of maternal obesity on brain development and function of offspring in early childhood. (Proj 5) 14: Determine the effects of diet composition, meal pattern, and exercise on brain function and behavioral dynamics important for learning and school performance in lean and obese children. (Proj 5) 15: Determine the role of prenatal factors on mother’s health. 16: Investigate the role of prenatal factors and postnatal factors on infants’ health.

Approach
Studies will focus on: 1) the risk of obesity and development of key physiological systems are subject to programming at conception and maternal obesity and high-fat diets during pregnancy increase the risk of offspring obesity, and co-morbidities such as cardiovascular disease and non-alcoholic fatty liver disease. We will address specific mechanisms (Ezh2-mediated gene repression) in developmental programming and the role of specific signaling pathways in the placenta and oocyte per se in long-term programming via mouse models. We will examine developmental programming of adipose tissue and energy balance, bone health and osteoblast differentiation, and peri-vascular fat and vasculature, to address programming of weight gain, skeletal health and cardiovascular function. 2) the roles of postnatal and early-life dietary factors and the gut microbiota on host health and development through clinical and animal models to investigate how dietary and microbiome factors impact childhood development, and identify and characterize molecular cross-talk between microbes and the host. 3) clinical studies to investigate how maternal obesity can influence offspring development and health outcomes. We will explore differences in umbilical cord mesenchymal stem cells from infants born to normal weight and obese mothers for adipogenesis potential, lipolysis and mitochondrial bioenergetics. We will identify exercise-specific alterations in maternal gut microbiota during pregnancy as well as the direct effects of exercise on placental inflammation and placental nutrient transfer and its implication for long-term developmental programming in the offspring. 4) determine the impact of early-life physical activity (PA) on muscle and metabolic health, determine modifying effects of PA on energy and substrate metabolism, and determine specific muscle metabolic systems that associate with fitness, PA, fatigue and exertion phenotypes. We will determine bioenergetics phenotypes that reflect PA and obesity status, through studies of mitochondrial function in circulating cells, use of carbohydrates and fat during exercise, and optimal protein needs; focus on metabolic impact of early life PA by establishing the relation between maternal obesity and the child’s PA level, determine feasibility of a PA intervention in at-risk young children, and detail the molecular and metabolic pathways affected by early life PA. 5) measuring gut microbiome associations with immune and metabolic functions, and identify specific microbe-derived metabolites that could play a role. We aim to identify and characterize mechanisms of action of dietary components and gut microbes, which will improve formula diets for the benefit of a child's growth, development and immune function; identify mechanisms by which the gut microbiota influence both short- and long-term health outcomes; enable design of evidence-based interventions to thwart immune, bone and metabolic diseases; and identify microbial and/or host molecular mechanisms that can be targeted by diet or other interventions to prevent metabolic diseases and improve function.

Progress Report
This is the final report. This project was replace by project 6026-10700-001-000D, "Early Life Factors and Microbiota Impact on Healthy Development." Evaluated epigenomic and postnatal factors in maternal obesity-associated programming of offspring metabolic, skeletal and cardiovascular outcomes. Collaborating researchers observed sex-specific differences in response to maternal high fat diet (HFD) in cholesterol, lipoprotein profiles, adipose tissue and heat shock protein expression. Phenotyping of offspring bones from Ezh2-Lysm-Cre-CKO at various developmental stages indicate that deletion of the Ezh2 gene in bone precursor cells increases bone mass in a sex-specific manner. Maternal HFD impacted programming of offspring vascular cells and cardiovascular outcomes. The role of platelets in chaperoning immune cells into perivascular adipose tissue was found to play a role in low level inflammation associated with a HFD. Examined the role of maternal germ line and placental innate immune response signaling in developmental programming. Cooperating researcjers fed female flox control and oocyte specific MyD88 knockout mice a control and HFD for 6 wk and collected ovaries for analysis of oocyte-specific genes. Collection of mature MII oocyte and associated cumulus cell from superovulated flox control and oocyte specific Myd88 knockout mice was done and cDNA libraries for single cell RNA sequencing have been prepared. The role of placental MyD88/TLR signaling in maternal HFD programming of offspring was studied. Flox control and trophoblast specific MyD88 knockout mice were generated and male flox control offspring from HFD-dams fed HFD had greater weight gain relative to flox control offspring. This effect of maternal HFD was not present in placental MyD88 knockout offspring from HFD-dams fed HFD, revealing a role for placental TLR signaling in maternal HFD programming of obesity. Investigated the role of infant feeding practices on growth and development. Cooperating researchers enrolled 16 additional participants (14 year olds) from the Beginnings study. Another 22 participants have been scheduled. In total, 170 participants have been enrolled. Analyses indicate no significant differences between children fed human milk, soy-protein based infant formula or dairy based infant formulas on growth, body composition, serum markers, age of menarche and bone mass accretion. Collaborating researcher characterized the GPR109A tissue-specific gene knockout mouse model (GPR109A CKO) by analyzing the bone phenotype in 18m old male and female CKO mice. Evidence of interactions between GPR109A, hippuric acid and 3-(3-hydroxyphenyl) propionic acid and the impact to bone pathophysiology and remodeling suggests these metabolites may prevent bone degeneration through suppression of inflammation in bone. Benefits of breastfeeding on gut microbiota and immune system were studied. ARS researcher demonstrated that differential microbiota composition impacts gut and immune response. Research to determine host-microbiome cross-talk mechanisms associated with changes in glucose homeostasis were finalized. Cooperating researcher leveraged the UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) Rat model finding that progression of diabetes in the UCD-T2DM Rat model caused increases in gut bacteria that utilize oxygen and known to cause disease. Cooperating researcher explored how excessive maternal weight during gestation increases infant weight and risk of childhood obesity (Glowing follow up). To date, 158 research study visits have been completed. Cardiovascular risk measures were assessed in 157 visits. Analyses on children (age 5) are complete and data collection is complete at age 8. The impact of maternal BMI on umbilical cord stem cell differentiation was studied and expression of key adipogenic regulators in umbilical cord mesenchymal stem cell (MSC) were differentially expressed in women with normal weight (NW) and overweight/obesity (OW/OB). This positively correlated with child fat mass index at 2 wk, 6 and 24 m of age in women with OW/OB suggesting an influence of maternal BMI on adipogenic differentiation of mesenchymal stem cells. Evaluated the impact of a physical activity intervention during pregnancy in women with obesity and sedentary behaviors. Cooperating researcher studied 264 pregnant women randomized to exercise or standard of care (SOC) with 702 research study visits in 5 years. Intervention group had higher physical activity and maintained fitness compared to SOC. Analyses of pregnancy and birth outcomes have been completed. Offspring data collection continues during the first 2 years of life with follow up to age 5 Y and 8 Y. The relationship between the gut microbiome and improvements in cardiorespiratory fitness during pregnancy was investigated. Collection of stool samples was completed at each gestational trimester. While delayed by Covid-19, correlative analyses on microbiome and metabolome patterns to cardiorespiratory fitness measurements are ongoing. Feasibility of a community-adapted exercise intervention during pregnancy was assessed. Successful implementation of a Phase 1-2 study in Pulaski County (Little Rock) was followed with a Phase 3 full randomized pilot study initiated in Pulaski (Little Rock) and Jefferson (Pine Bluff). The Community Health and Implementation Research Partnership, was also established to enhance engagement with community partners. Obj 3 research on the effects of exercise and diet on reproductive health was halted with guidance from ONP due to COVID-19 impacts and a decrease in fertility clinics in Arkansas. Pilot results are available and were used for planning of future interventions. Cooperating researchers studied bioenergetics phenotypes linking exercise to metabolic health in children. Platelet bioenergetics measurements were completed for 215 children with analyses of metabolic outcomes. In 91 children, (7-10Y) blood pressure and body fat were positively associated with mitochondria oxygen consumption rate. However, children with elevated LDL cholesterol and low fitness had decreased ability of platelets to increase oxygen consumption and produce energy. 72 children (8-10Y) participated in two sub-maximal tests to determine substrate usage. Substrate usage was influenced by obesity and training status. Evaluation of the impact of physical activity levels on dietary protein requirements for children was delayed due to COVID-19. Cooperating researchers examined persistent effects of early-life exercise, and impact on childhood metabolic health. The Glowing study was leveraged to collect additional accelerometer data for 5Y and 8Y children. A feasibility assessment for a physical activity intervention in pre-school-age children of mothers with obesity was completed. An 18-week gross motor skill program was developed and individualize resulting in improvements in body composition for both mother and child as well as improvements in locomotor and object control for children. Using a rat model bred for high or low cardiorespiratory fitness, cooperating researchers studied how parental fitness influences early-life adiposity and metabolic health. Offspring born to parents with high fitness were leaner and exhibited greater glucose tolerance, greater mitochondrial respiratory capacity and enrichment of proteins involved in lipid oxidation, compared to those born to parents with low fitness. Also, early-life exercise only partially overcomes the metabolic phenotype imparted by low fitness underscoring the role of inheritance and parental fitness in programming offspring’s metabolic function. Cooperating researcher explored the data collected under the Beginnings study. Using both non-invasive scalp recorded resting state (rEEG) and task-evoked (ERP) electrophysiological measures of cognitive function and brain structural development in relation to feeding choice (breast milk, cow or soy based formula) were studied. The evaluation of early language development across infancy (3 -12 m) and early changes in brain structural development in infants (2-6 m) have been reported. Evaluation of changes in brain dynamics across infancy and language processing at 6 y of age is complete. Research focused on 5Y and 8Y children whose mother was recruited during pregnancy for either the Expecting or Glowing follow-up studies. Scalp-recorded EEG was obtained as children either rested quietly or performed a task. Data collection for the Glowing study has been completed. Data collection for 5Y in the Expecting study, and 8Y in both studies continues. Cooperating researcher found effects high protein and carbohydrate at breakfast on children’s performance on a task. Brain activity indicated that children with Ow/Ob were less able to pay attention to task, needing to recruit additional brain resources to achieve the same performance level as NW peers. Effects of two types of activity (stretching and treadmill) were examined NW and Ow/Ob children on cognitive function in children. ARS researchers determined the role of maternal obesity on the immune system during pregnancy and demonstrated that specific gut microbes associate with immune cell gene expression. Examined maternal diet and the microbiota during pregnancy on maternal health, all animal studies have been completed. Specifically, the role of two main fatty acids, Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) during the pre-conception and pregnancy period on gut, immune system, microbiota and metabolite and nutrient transport of placenta were examined. Data analysis is in progress for publication.

Accomplishments
1. Decreased bone resorption in Ezh2 myeloid cell conditional knockout mouse model. Ezh2 (enhancer of zeste homolog 2) bone-specific knockout mice were generated by ARS researchers in Little Rock, Arkansas, and bone phenotypes analyzed at various time points across the lifespan and compared with age-matched wild-type mice. Deletion of the Ezh2 gene in bone precursor cells increased bone mass in a sex-specific manner.

2. Platelet contribution to diet induced perivascular Adipose Tissue Immune Infiltration. ARS researchers in Little Rock, Arkansas, conducted a study with the Western diet high in fat, sugar and salt altered the composition of both the perivascular adipose depots by altering the function of immune cell populations, as well as influencing the distribution of immune cells present in perivascular adipose. This shift in leukocyte populations suggests an overall phenotypic switch towards a more pro-inflammatory and thus vasoconstrictive environment.

3. Short term impact of varying ambient temperatures on mouse metabolism. During a study conducted by ARS researchers in Little Rock, Arkansas, cold exposure in female mice led to increased body mass with higher lean mass and reduced fat mass. Cold exposure in male mice resulted in reduced fat mass but not change in body mass. Gene expression in white adipose tissue depots varied with ambient temperature and specifically pathways related to mitochondrial function and mTOR signaling were most affected.

4. Impact of worsening glucose homeostasis on the gut microbiome and colon epithelial oxygen utilization. Development of diabetes can lead to impacts in gut microbiome and colon epithelial oxygen utilization. ARS researchers in Little Rock, Arkansas, examined the microbiome and colon markers of hypoxia and energy metabolism in male UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) rats, which spontaneously develop obesity concurrent with a diabetes phenotype that mimics the progression of diabetes in humans. Diabetes progression in the UCD-T2DM resulted in proliferation of oxygen consuming bacteria known to be pathogenic, but did not affect colon hypoxia. Although the reduction in colonocyte hypoxia has been previously associated with negative gastrointestinal outcomes in other conditions, it does not explain the gut microbial changes associated with the advancement of diabetes in the UCD-T2DM rat model.

5. Impact of maternal obesity on adipogenic differentiation in umbilical cord mesenchymal stem cells and associations with maternal and child anthropometric outcomes. The heightened susceptibility of children to obesity is notably linked to maternal obesity, with potential implications for programming modifications during adipocyte differentiation. ARS researchers in Little Rock, Arkansas, used umbilical cord mesenchymal stem cells (MSC, n=76) collected at the time of birth from mothers with normal weight (n = 37) or overweight/obesity (n = 39). We sought to examine the adipogenic differentiation response in MSC from mothers with obesity and assess the associations between markers of adipocyte differentiation and maternal/child anthropometric outcomes.

6. Assessment of the gut microbiome during pregnancy in women with obesity and sedentary behaviors engaged in a structured exercise program. Given the high rates of women of child bearing age with obesity in the United States and the association between obesity and changes in gut microbiome, understanding how improvements in cardiometabolic function influence the gut microbiome during pregnancy will help determine the efficacy of exercise as a low-cost and beneficial therapeutic approach to promote the health of mothers and their offspring. Cooperative researchers in Little Rock, Arkansas, have generated gut microbiome data from the Expecting Study, which represents about 200 pregnant women with obesity in which about 100 were undergoing a structured exercise program.

7. Adaptation of a clinic-based physical activity intervention during pregnancy into community settings. To adapt a clinic-based intervention for community delivery, cooperative researchers in Little Rock, Arkansas, have used the Replicating Effective Programs framework to develop virtual and hybrid models of intervention delivery to support exercise among mothers with excess weight. In both the virtual and hybrid pre-tests, engagement in live, synchronous sessions (88% of sessions) was greater than with pre-recorded sessions that could be accessed on participants’ own schedule (12 % of sessions). Further, perceived exertion was higher in the hybrid pretest (13.3) than in the virtual pre-test (11.9). Qualitative data from participants and community partner input favored refinement of data collection systems, a need to reconceptualize the social support component of the intervention, and a preference for accountability gained from live workouts.

8. Human milk content modulates gut microbial diversity and composition in infancy. To better understand the relationship between breastmilk content and the infant gut microbiome, cooperative researchers in Little Rock, Arkansas, have investigated the impact of other human milk components, other than human milk oligosaccharides, on infant gut bacterial colonization at 6 months of age. Results demonstrated that human milk total energy was associated with lower diversity of the infant microbiome, whereas inflammatory marker content was associated with greater infant gut microbiome diversity. The study also identified that specific human milk amino acids were associated with different microbiome abundance. These results underscore the complexity of the interplay between human milk content and the infant gut microbiome. They highlight the potential role of energy, free amino acids, and inflammatory and endocrine markers in modulating gut microbial diversity and composition during early development.

9. Maternal excessive weight impacts breastfeeding outcomes. To better understand the relationship between maternal weight status and breastfeeding intention, initiation, and duration, cooperative researchers in Little Rock, Arkansas, have evaluated breastfeeding outcomes of 227 women enrolled in a longitudinal study. Maternal excessive weight was associated with lower breastfeeding intention and duration. The study also identified that this relationship was mediated by depression scores. These results suggest that breastfeeding outcomes are negatively associated with maternal weight status and prenatal mental health.

10. Impact of maternal adiposity measured early in pregnancy with offspring physical activity levels at age two years. Cooperative researchers in Little Rock, Arkansas, used data from 153 mother-offspring pairs from the Glowing study to evaluate the association of maternal adiposity with offspring physical activity levels (objectively measured by accelerometers). They found that excess body fat in mothers was associated with decreased physical activity levels in their 2-year-old children. No differences were seen in activity level between boys and girls born to mothers with adiposity <7 kg/m2. However, in children born to mothers with fat content exceeding 7 kg/m2 a lower activity level was found in girls compared to boys. Further, children born to mothers without a college degree were less active than those born to women with a college degree. For boys, maternal physical activity early in pregnancy was a variable more strongly associated with physical activity levels at the age of 2 years. The results support the notion that maternal obesity affects offspring's behaviors toward physical activity in a sex-dependent manner.

11. Effects of short-term supervised exercise training on liver fat in adolescents with obesity: a randomized controlled trial. To quantify the effects of short, high-intensity interval training (HIIT) on liver fat content and cardiometabolic markers in adolescents with obesity, cooperative researchers in Little Rock, Arkansas, performed a 1-month supervised HIIT intervention in adolescents with obesity. In this preliminary study, 34 teenagers with obesity underwent HIIT training, and six controls were included for comparison. Not all participants had elevated liver fat. It was found that short-term HIIT training moderately improved markers of cardiometabolic health. When limiting the analysis to participants with elevated liver fat at the start, a within-group analysis found a decrease in liver fat due to the HIIT intervention.

12. We-Move with Windy. After completing a comprehensive needs assessment through interviews and surveys of a target population of mothers with young children, cooperative researchers in Little Rock, Arkansas, developed and performed a pre-test of a physical activity-based program called We-Move. The six-week We-Move intervention was designed for parent-child dyads to be physically active together, helping develop the gross motor skills of preschool-age children, while facilitating parent education on movement-related topics. The completion of the pre-test phase data collection demonstrated the program’s feasibility and acceptability with about 81% compliance rate among the three mom-child dyads participating. A post-intervention interview with the participating mothers elicited many positive responses to the program including participants believing the We-Move program to be a great introduction to organized sports for their children and an opportunity to provide supervised socialization. Next, the scientists were able to refine and enhance the We-Move program before launching the full pilot version of the study. Based on the results and feedback from the pre-test, the duration of the intervention was extended from 6 to 18 weeks, and the number of skills assessments increased for more accurate analysis of development, incorporating tailoring of skills practice to individualize the program for participating child, and added in a nutrition component linked with an established program driven by a wise owl mascot (Windy WISE) to support development of healthy dietary habits, which led to a renaming of the program to We-Move with Windy.

13. Myoglobin interacts distinctly at specific locations on mitochondrial membranes. Cooperative researchers in Little Rock, Arkansas, used advanced computer simulations to study how two forms of myoglobin (a protein that carries oxygen in muscles) interact with fats in the outer layer of mitochondria (the cell's powerhouse). They looked at two types of mitochondrial membranes: the usual one and a special region rich in a fat called cardiolipin. They found that both forms of myoglobin (one that carries oxygen and one that doesn't) formed more stable connections with the cardiolipin-rich membranes than with the regular ones. When they tested how strongly myoglobin stuck to these membranes, they discovered that the oxygen-free form clung more tightly to the regular membrane, while the oxygen-carrying form preferred the cardiolipin-rich areas. The computer simulations showed that these interactions were due to local electric charges between the myoglobin and the membrane fats. This study is the first of its kind to use computer models to show how myoglobin interacts with mitochondria, confirming previous experimental findings and offering new insights into how myoglobin helps transport oxygen for the cell's energy production.

14. Novel physiological functions of muscle myoglobin. Cooperating researchers in Little Rock, Arkansas, have found that myoglobin (Mb), a protein known for storing and transporting oxygen, has many other important roles in the cell. Their research shows that myoglobin moves fats around the cell, interacts with molecules like lactate and pyruvate, and is present in some cancer cells and brown fat. Studies with mice lacking myoglobin and biochemical models suggest that myoglobin helps control nitric oxide levels, a key molecule in cells. It also affects how brown fat cells produce energy, generate heat, and store fat. These findings reveal that myoglobin is not just an oxygen carrier but also an oxygen sensor influencing various signaling pathways. This new understanding changes how we view energy production and cell regulation in muscle, heart, brown fat, and certain cancer cells.

15. Maternal exercise effects on the placenta and presumably on the offspring are influenced by maternal health status and sex of the baby. Exercise during pregnancy has been shown to be beneficial to both mother and child health, however the way by which exercise of mother is mediating benefits during pregnancy is not well understood. The goal of this research was to understand how exercise/physical activity prior to and during pregnancy affects the gene expression patterns of the placenta at late pregnancy. ARS scientist and collaborators from University of Colorado and Oklahoma found that the effects of exercise prior to and during pregnancy affect the placenta in different ways depending on sex of the fetus. Male placenta showed that maternal exercise led to inhibition of signaling pathways, biological functions, and down regulation of transcripts related to lipid and steroid metabolism, while maternal exercise in female placentas led to activation of pathways, biological functions, and gene expression related to muscle growth, brain, vascular development, and growth factors. Overall, these findings suggest that effects of maternal exercise/physical activity on the placenta and presumably on the offspring are influenced by maternal health status and sex of the baby.

16. Excessive FSH doses during ART cause premature cumulus dysfunction and enhance the risk of recovering poor-quality oocytes for IVF. Excessive doses of follicle stimulating hormone (FSH) to stimulate ovulation during assisted reproduction is associated with a range of negative effects on reproduction and pregnancy outcome. This study sought to discover whether excessive FSH doses disrupt ovarian cell function and compromise the ability of bovine oocytes to mature and be fertilized. An ARS researcher in Little Rock, Arkansas, and collaborators from Michigan State University found that excessive FSH doses directed aberrant gene expression in ovarian cells of all ovulatory size follicles examined, as well as disrupting the correct regulation of oocyte maturation and ability of the oocytes to be fertilized. Importantly, excessive FSH doses result in the production of abnormal cumulus cell-oocyte complexes that are morphologically very similar to healthy complexes, thereby increasing the risk of oocyte wastage and fertilizing compromised oocytes, which can impact both agricultural production and human fertility clinics success.

17. Microbiota of infants consuming secretors or non-secretors’ mothers milk impacts gut and immune system. Human Milk Oligosaccharides (HMOs) as prebiotics to gut microbes have several health benefits for growing infants. However, the composition of HMOs could differ among the mothers depending on genetic background with FUT2+ as secretors and FUT2- as non-secretors. An ARS researcher in Little Rock, Arkansas, transplanted gut microbes from infants consuming milk of secretor or non-secretor mothers or those consuming infant formula to germ-free mouse. Scientists observed different microbial community structure based on secretor status and formula feeding while HMOs supplementation did not change the overall composition of gut microbes. Interestingly, HMOs changed the intestinal gene expression and immune cell composition and increased IgA and anti-inflammatory T cells (Treg) in mice receiving microbes from formula fed infants suggesting a beneficial role for HMO supplementation with formula feeding.

18. Early-life gut mycobiome has a role on child health. The human gut microbiota is composed of bacteria (microbiota or microbiome), fungi (mycobiome), viruses, and archaea, but most of the research is primarily focused on the bacterial component of this ecosystem. Besides bacteria, fungi have been shown to play a role in host health and physiological functions. However, studies on mycobiota composition during infancy, the factors that might shape infant gut mycobiota, and implications to child health and development are limited. ARS researchers in Little Rock, Arkansas, discuss the factors likely shaping gut mycobiota, interkingdom interactions, associations to child health outcomes, and highlight the gaps in our current knowledge of this ecosystem.

19. Human milk miRNAs associate to maternal dietary nutrients, milk microbiota, infant gut microbiota and growth. Human milk contains microRNAs (miRNA) composition is likely impacted by several factors such as age, BMI and stress. An ARS researcher in Little Rock, Arkansas, demonstrated that maternal dietary protein source (animal or plant protein) has an impact on human milk miRNA composition. Also, miRNA expression was associated with maternal dietary polyphenols and maternal microbiota. In addition, milk miRNAs were associated with infant gut microbiota and growth parameters further emphasizing the milk bioactives role on maternal and child health outcomes.

20. Microbiota and adipocyte mitochondrial damage in type 2 diabetes are linked by Mmp12+ macrophages. Obesity and related metabolic disease like Type 2 diabetes is a global pandemic. Consumption of high-fat/high-sugar diets modify microbes in the gastrointestinal tract, which also contributes to Type 2 diabetes. It is unclear how these microbes affect the organs involved in type 2 diabetes are not well explored. ARS researchers in Little in Littel Rock, Arkansas, with investigators from Oregon State University, NIH and Austria, using conventional and germ-free mice, identified that oxidative phosphorylation and mitochondrial aberration in white adipose tissue induced by a high-fat, high-sugar diet is microbiota dependent, and this aberration plays a crucial role in systemic glucose regulation. They also identified that Mmp12 is upregulated in the white adipose tissue macrophage of obese mice. Using the Mmp12 knock-out mouse or inhibition of Mmp12 protein, they showed that the absence of Mmp12 in high-fat, high-sugar-fed mice improves glucose metabolism and insulin sensitivity in conventional mice but not in germ-free mice. This suggests that Mmp12 is a microbiota-dependent regulator of glucose homeostasis. Using computational analysis, the authors identified that gut microbiota, Oscillibacter valericigenes, can induce glucose intolerance and upregulate insulin resistance-associated genes, including Mmp12, in adipose tissue macrophage. The researchers then treated the macrophage cell lines with OV and demonstrated that OV upregulates Mmp12, which is mediated by toll-like receptor 2 (TLR2), Myd88 and Atf3. In conclusion, using mouse models, in vitro cell culture and computational approaches, the investigators identified Mmp12 as the microbiota-dependent regulator of glucose intolerance and Oscillibactor valericigenes as a potential pathobiont that exacerbates the detrimental effects of high-fat, high-sugar fed mice. These findings provide insights into the importance of microbiota in glucose metabolism and possible targets for intervention of type 2 diabetes.

21. Reducing gut microbiome-driven adipose tissue inflammation alleviates metabolic syndrome. Around 35% of the United States adult population suffers from metabolic syndrome. Obesity is a crucial cause of metabolic syndrome. Adipose tissue inflammation is one of the hallmarks of this chronic condition. Polyphenol-rich plants have been shown to promote several health benefits. ARS researchers in Little Rock, Arkansas, in collaboration with investigators from Oregon State University, showed that tetrahydro xanthohumol (TXN), a semi-synthetic derivative of xanthohumol (XN) (a polyphenol from Hops), can ameliorate the detrimental effects of a high-fat diet in mice. They also showed that TXN can reduce the abundance of a pathobiont, Oscillibacter valericigenes from the gut of these mice. This gut microbe is known to have a higher abundance in the gut of high-fat-fed mice and can induce adipose tissue inflammation in these mice. Supplementation of TXN in the high-fat-fed mice also downregulated the inflammation and insulin resistance genes in the mouse adipose tissue macrophages. Similarly, the authors also demonstrated that several of these genes( Spp1, Itgax, Adam8, Atf3, MMp12, Lgals3, Plin2), which are upregulated by O. valericigenes in macrophage cell lines, are reduced by TXN supplementation in obese mice. Taken together, the authors showed that TXN can improve metabolic syndrome in obese mice by modulating the gut microbiota, specifically by reducing the abundance of O. valericigenes. This study suggests that plant polyphenols could be potential dietary interventions in metabolic syndrome.

Review Publications
Sims, C.R., Saben, J.L., Martinez, A., Sobik, S.R., Crimmins, M.R., Bulmanski, J., Turner, D., Furst, A., Jansen, L., Bode, L., Andres, A. 2024. A Mediterranean diet plan in lactating women with obesity reduces maternal energy intake and modulates human milk composition – a feasibility study. Frontiers in Nutrition. 11:1-13. https://doi.org/10.3389/fnut.2024.1303822.
Diaz, E., Williams, D.K., Howie, E.K., Borsheim, E., Andres, A. 2024. Offspring sex modifies the association between early-pregnancy adiposity and 2-year-old total physical activity – The Glowing Study. International Journal of Behavioral Nutrition and Physical Activity. 48:542-549. https://doi.org/10.1038/s41366-023-01446-7.
Yeruva, V., Mulakala, B.K., Rajasundaram, D., Gonzalez, S., Cabrera-Rubio, R., Martinez-Costa, C., Collado, M. 2023. Human milk miRNAs associate to maternal dietary nutrients, milk microbiota, infant gut microbiota and body mass index. Clinical Nutrition. 42(12):2528-2539. https://doi.org/10.1016/j.clnu.2023.10.011.
Ruebel, M., Borengasser, S.J., Zhong, Y., Kang, P., Faske, J., Shankar, K. 2023. Maternal exercise prior to and during gestation induces sex-specific alterations in the mouse placenta. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms242216441.
Munoz, B., Hayes, M., Perkins-Veazie, P., Gillet, N., Munoz, M., Kay, C., Lila, M., Ferruzzi, M.G., Iorizzo, M. 2024. Genotype and ripening method affect carotenoid content and bio-accessibility in banana. Food & Function. 15:3433-3445. https://doi.org/10.1039/d3fo04632j.
Rodriguez, K.A., Gurung, M., Talatala, R., Rearick, J.R., Ruebel, M., Stephens, K.E., Yeruva, V. 2024. The Role of Early-Life Gut Mycobiome on Child Health. Advances in Nutrition. 15(3):100185. https://doi.org/10.1016/j.advnut.2024.100185.
Gurung, M., Schlegel, B., Rajasundaram, D., Fox, R., Bode, L., Lindemann, S.R., Leroith, T., Read, Q.D., Simecka, C., Carol, L., Andres, A., Yeruva, V. 2024. Microbiota of infants consuming secretors or non-secretors mothers milk impacts gut and immune system in mice. mSystems. 9(4). Article e00294-24. https://doi.org/10.1128/msystems.00294-24.
Howie, E.K., Nelson, A., Mcveigh, J.A., Andres, A. 2024. Relationships between physical behaviour phenotypes of mothers in pregnancy and their offspring with child body composition. Acta Pediatrica. 113(3):486-494. https://doi.org/10.1111/apa.17089.
Sadler, D., Treas, L., Ross, T., Sike, J., Britton, S., Koch, L., Borsheim, E., Porter, C. 2024. Parental cardiorespiratory fitness influences early life energetics and metabolic health. Physiological Genomics. 56(2):145-157. https://doi.org/10.1152/physiolgenomics.00045.2023.
Karl, K.R., Schall, P.Z., Clark, Z.L., Ruebel, M., Cibelli, J., Tempelman, R., Latham, K.E., Ireland, J.J. 2023. Ovarian stimulation with excessive FSH doses causes cumulus cell and oocyte dysfunction in small ovarian reserve heifers. Molecular Human Reproduction. 29(10). Article gaad033. https://doi.org/10.1093/molehr/gaad033.
Adepu, K.K., Anishkin, A., Adams, S.H., Chintapalli, S.V. 2024. A versatile delivery vehicle for cellular oxygen and fuels, or metabolic sensor? – A review and perspective on the functions of myoglobin. Physiological Reviews. https://doi.org/10.1152/physrev.00031.2023.
Li, Z., Gurung, M., Rodrigues, R.R., Padiadpu, J., Newman, N.K., Manes, N.P., Pederson, J.W., Greer, R.L., Morgun, A., Shulzhenko, N. 2022. Microbiota and adipocyte mitochondrial damage in type 2 diabetes are linked by Mmp12+ macrophages. Journal of Experimental Medicine. 219(7):e20220017. https://doi.org/10.1084/jem.20220017.
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