Neurodevelopment and Metabolism in the Maternal-Placental-Fetal Unit.

Importance: Disturbances in maternal, placental, and fetal metabolism are associated with developmental outcomes. Associations of maternal, placental, and fetal metabolism with subsequent neurodevelopmental outcomes in the child are understudied. Objective: To investigate the metabolic associations within the maternal-placental-fetal unit and subsequent neurodevelopmental outcomes in younger siblings of children with autism spectrum disorder (ASD). Design, Setting, and Participants: This cohort study was conducted within a subset of the Markers of Autism Risk in Babies, Learning Early Signs (MARBLES) cohort. MARBLES is a prospective birth cohort of younger siblings of children with ASD assessed for neurodevelopmental outcomes at approximately age 36 months. Participants in MARBLES were recruited through the UC Davis MIND Institute. This subset of the MARBLES cohort included younger siblings born between 2009 and 2015. Maternal third trimester serum, placental tissue, and umbilical cord serum samples were collected from participants. Only pregnancies with at least 2 of these sample types were included in this analysis. Data analysis was conducted from March 1, 2023, to March 15, 2024. Exposures: Quantitative metabolomics analysis was conducted on maternal third trimester serum, as well as placental tissue and umbilical cord serum collected at delivery. Main Outcomes and Measures: Using the Autism Diagnostic Observation Schedule and Mullen Scales of Early Learning, outcomes were classified as ASD, other nontypical development (non-TD), and typical development (TD). Results: This analysis included 100 maternal serum samples, 141 placental samples, and 124 umbilical cord serum samples from 152 pregnancies (median [IQR] maternal age, 34.6 [30.8-38.3] years; median [IQR] gestational age, 39.0 [38.6-39.7] weeks; 87 [57.2%] male infants). There was no evidence that the maternal third trimester serum metabolome was significantly associated with the other metabolomes. The placental and cord serum metabolomes were highly correlated (first latent variate pair: R2 = 0.75; P < .001) and the variate scores for each tissue were significantly associated with reduced risk of non-TD (placenta: relative risk [RR], 0.13; 95% CI, 0.02-0.71; cord: RR, 0.13; 95% CI, 0.03-0.70) but not ASD (placenta: RR, 1.09; 95% CI, 0.42-2.81; cord: RR, 0.63; 95% CI, 0.23-1.73) compared with the TD reference group. Conclusions and Relevance: In this cohort study of children with high familial risk of ASD, placental and cord serum metabolism at delivery were highly correlated. Furthermore, placental and cord serum metabolic profiles were associated with risk of non-TD.

Associations Between Prenatal Vitamin D and Placental Gene Expression.

Background: Vitamin D is a hormone regulating gene transcription. Prenatal vitamin D has been linked to immune and vascular function in the placenta, a key organ of pregnancy. To date, studies of vitamin D and placental gene expression have focused on a limited number of candidate genes. Transcriptome-wide RNA sequencing can provide a more complete representation of the placental effects of vitamin D. Objective: We investigated the association between prenatal vitamin D levels and placental gene expression in a large, prospective pregnancy cohort. Methods: Participants were recruited in Shelby County, Tennessee in the Conditions Affecting Neurocognitive Development and Learning in Early childhood (CANDLE) study. Vitamin D level (plasma total 25-hydroxyvitatmin D, [25(OH)D]) was measured at mid-pregnancy (16-28 weeks' gestation) and delivery. Placenta samples were collected at birth. RNA was isolated and sequenced. We identified differentially expressed genes (DEGs) using adjusted linear regression models. We also conducted weighted gene co-expression network analysis (WGCNA). Results: The median 25(OH)D of participants was 21.8 ng/mL at mid-pregnancy (N=774, IQR: 15.4-26.5 ng/mL) and 23.6 ng/mL at delivery (N=753, IQR: 16.8-29.1 ng/mL). Placental expression of 25 DEGs was associated with 25(OH)D at mid-pregnancy, but no DEG was associated with 25(OH)D at delivery. DEGs were related to energy metabolism, cytoskeletal function, and RNA transcription. Using WGCNA, we identified 2 gene modules whose expression was associated with 25(OH)D at mid-pregnancy and 1 module associated with 25(OH)D at delivery. These modules were enriched for genes related to mitochondrial and cytoskeletal function, and were regulated by transcription factors including ARNT2, BHLHE40, FOSL2, JUND, and NFKB1. Conclusions: Our results indicate that 25(OH)D during mid-pregnancy, but not at delivery, is associated with placental gene expression at birth. Future research is needed to investigate a potential role of vitamin D in programming placental mitochondrial metabolism, intracellular transport, and transcriptional regulation during pregnancy.

Antibiotics augment the impact of iron deficiency on metabolism in a piglet model.

Infancy and childhood represent a high-risk period for developing iron deficiency (ID) and is a period of increased susceptibility to infectious disease. Antibiotic use is high in children from low-, middle-, and high-income countries, and thus we sought to determine the impact of antibiotics in the context of ID. In this study, a piglet model was used to assess the impact of ID and antibiotics on systemic metabolism. ID was induced by withholding a ferrous sulfate injection after birth to piglets in the ID group and providing an iron deficient diet upon weaning on postnatal day (PD) 25. Antibiotics (gentamicin and spectinomycin) were administered on PD34-36 to a set of control (Con*+Abx) and ID piglets (ID+Abx) after weaning. Blood was analyzed on PD30 (before antibiotic administration) and PD43 (7 days after antibiotic administration). All ID piglets exhibited growth faltering and had lower hemoglobin and hematocrit compared to control (Con) and Con*+Abx throughout. The metabolome of ID piglets at weaning and sacrifice exhibited elevated markers of oxidative stress, ketosis, and ureagenesis compared to Con. The impact of antibiotics on Con*+Abx piglets did not result in significant changes to the serum metabolome 7-days after treatment; however, the impact of antibiotics on ID+Abx piglets resulted in the same metabolic changes observed in ID piglets, but with a greater magnitude when compared to Con. These results suggest that antibiotic administration in the context of ID exacerbates the negative metabolic impacts of ID and may have long lasting impacts on development.

Maternal Serum and Placental Metabolomes in Association with Prenatal Phthalate Exposure and Neurodevelopmental Outcomes in the MARBLES Cohort.

Prenatal exposure to phthalates, a family of endocrine-disrupting plasticizers, is associated with disruption of maternal metabolism and impaired neurodevelopment. We investigated associations between prenatal phthalate exposure and alterations of both the maternal third trimester serum metabolome and the placental metabolome at birth, and associations of these with child neurodevelopmental outcomes using data and samples from the Markers of Autism Risk in Babies Learning Early Signs (MARBLES) cohort. The third trimester serum (n = 106) and placental (n = 132) metabolomes were investigated using 1H nuclear magnetic resonance spectroscopy. Children were assessed clinically for autism spectrum disorder (ASD) and cognitive development. Although none of the urinary phthalate metabolite concentrations were associated with maternal serum metabolites after adjustment for covariates, mixture analysis using quantile g-computation revealed alterations in placental metabolites with increasing concentrations of phthalate metabolites that included reduced concentrations of 2-hydoxybutyrate, carnitine, O-acetylcarnitine, glucitol, and N-acetylneuraminate. Child neurodevelopmental outcome was not associated with the third trimester serum metabolome, but it was correlated with the placental metabolome in male children only. Maternal phthalate exposure during pregnancy is associated with differences in the placental metabolome at delivery, and the placental metabolome is associated with neurodevelopmental outcomes in males in a cohort with high familial ASD risk.

Metabolomic changes in severe acute malnutrition suggest hepatic oxidative stress: a secondary analysis.

Severe acute malnutrition (SAM), due to poor energy and/or protein intake, is associated with poor growth, depressed immune function, and long-term impacts on metabolic function. As the liver is a major metabolic organ and malnutrition poses metabolic stress, we hypothesize that SAM will be associated with alterations in the hepatic metabolome reflective of oxidative stress, gluconeogenesis, and ketogenesis. Thus, the purpose of this secondary analysis was to understand how SAM alters hepatic metabolism using a piglet model. Weanling piglets were feed either a reference (REF) or protein-energy deficient diet (MAL) for 5 weeks. After dietary treatment MAL piglets were severely underweight (weight-for-age Z-score of -3.29, Welch's t test, P = .0007), moderately wasted (weight-for-length Z-score of-2.49, Welch's t test, P = .003), and tended toward higher hepatic triglyceride content (Welch's t test, P = .07). Hematologic and blood biochemical measurements were assessed at baseline and after dietary treatment. The hepatic metabolome was investigated using 1H-NMR spectroscopy. Hepatic concentrations of betaine, cysteine, and glutathione tended to be lower in MAL (Welch's t test with FDR correction, P < .1), while inosine, lactate, and methionine sulfoxide concentrations were higher in MAL (inosine: P = .0448, lactate: P = .0258, methionine sulfoxide: P = .0337). These changes suggest that SAM is associated with elevated hepatic oxidative stress, increased gluconeogenesis, and alterations in 1-carbon metabolism.

A Pilot Study Comparing the Effects of Consuming 100% Orange Juice or Sucrose-Sweetened Beverage on Risk Factors for Cardiometabolic Disease in Women.

Overconsumption of sugar-sweetened beverages increases risk factors associated with cardiometabolic disease, in part due to hepatic fructose overload. However, it is not clear whether consumption of beverages containing fructose as naturally occurring sugar produces equivalent metabolic dysregulation as beverages containing added sugars. We compared the effects of consuming naturally-sweetened orange juice (OJ) or sucrose-sweetened beverages (sucrose-SB) for two weeks on risk factors for cardiometabolic disease. Healthy, overweight women (n = 20) were assigned to consume either 3 servings of 100% orange juice or sucrose-SB/day. We conducted 16-hour serial blood collections and 3-h oral glucose tolerance tests during a 30-h inpatient visit at baseline and after the 2-week diet intervention. The 16-h area under the curve (AUC) for uric acid increased in subjects consuming sucrose-SB compared with subjects consuming OJ. Unlike sucrose-SB, OJ did not significantly increase fasting or postprandial lipoproteins. Consumption of both beverages resulted in reductions in the Matsuda insulin sensitivity index (OJ: -0.40 ± 0.18, p = 0.04 within group; sucrose-SB: -1.0 ± 0.38, p = 0.006 within group; p = 0.53 between groups). Findings from this pilot study suggest that consumption of OJ at levels above the current dietary guidelines for sugar intake does not increase plasma uric acid concentrations compared with sucrose-SB, but appears to lead to comparable decreases of insulin sensitivity.

Publisher Correction: Metabolic phenotype of breast-fed infants, and infants fed standard formula or bovine MFGM supplemented formula: a randomized controlled trial.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Fecal microbiome and metabolome of infants fed bovine MFGM supplemented formula or standard formula with breast-fed infants as reference: a randomized controlled trial.

Human milk delivers an array of bioactive components that safeguard infant growth and development and maintain healthy gut microbiota. Milk fat globule membrane (MFGM) is a biologically functional fraction of milk increasingly linked to beneficial outcomes in infants through protection from pathogens, modulation of the immune system and improved neurodevelopment. In the present study, we characterized the fecal microbiome and metabolome of infants fed a bovine MFGM supplemented experimental formula (EF) and compared to infants fed standard formula (SF) and a breast-fed reference group. The impact of MFGM on the fecal microbiome was moderate; however, the fecal metabolome of EF-fed infants showed a significant reduction of several metabolites including lactate, succinate, amino acids and their derivatives from that of infants fed SF. Introduction of weaning food with either human milk or infant formula reduces the distinct characteristics of breast-fed- or formula-fed- like infant fecal microbiome and metabolome profiles. Our findings support the hypothesis that higher levels of protein in infant formula and the lack of human milk oligosaccharides promote a shift toward amino acid fermentation in the gut. MFGM may play a role in shaping gut microbial activity and function.

Metabolic phenotype of breast-fed infants, and infants fed standard formula or bovine MFGM supplemented formula: a randomized controlled trial.

Formula-fed (FF) infants exhibit a different metabolic profile than breast-fed (BF) infants. Two potential mechanisms are the higher protein level in formula compared with breast milk and the removal of the milk fat and associated milk fat globule membranes (MFGM) during production of infant formula. To determine whether MFGM may impact metabolism, formula-fed infants were randomly assigned to receive either an MFGM isolate-supplemented experimental formula (EF) or a standard formula (SF) from 2 until 6 months and compared with a BF reference group. Infants consuming EF had higher levels of fatty acid oxidation products compared to infants consuming SF. Although the protein level in the study formula was approximately 12 g/L (lower than most commercial formulas), a metabolic difference between FF and BF remained such that FF infants had higher levels of amino acid catabolism by-products and a low efficiency of amino acid clearance (preference for protein metabolism). BF infants had higher levels of fatty acid oxidation products (preference for fat metabolism). These unique, energy substrate-driven metabolic outcomes did not persist after diet was shifted to weaning foods and appeared to be disrupted by complementary feeding. Our results suggest that MFGM may have a role in directing infant metabolism.

Compositional Dynamics of the Milk Fat Globule and Its Role in Infant Development.

Human milk is uniquely optimized for the needs of the developing infant. Its composition is complex and dynamic, driven primarily by maternal genetics, and to a lesser extent by diet and environment. One important component that is gaining attention is the milk fat globule (MFG). The MFG is composed of a triglyceride-rich core surrounded by a tri-layer membrane, also known as the milk fat globule membrane (MFGM) that originates from mammary gland epithelia. The MFGM is enriched with glycerophospholipids, sphingolipids, cholesterol, and proteins, some of which are glycosylated, and are known to exert numerous biological roles. Mounting evidence suggests that the structure of the MFG and bioactive components of the MFGM may benefit the infant by aiding in the structural and functional maturation of the gut through the provision of essential nutrients and/or regulating various cellular events during infant growth and immune education. Further, antimicrobial peptides and surface carbohydrate moieties surrounding the MFG might have a pivotal role in shaping gut microbial populations, which in turn may promote protection against immune and inflammatory diseases early in life. This review seeks to: (1) understand the components of the MFG, as well as maternal factors including genetic and lifestyle factors that influence its characteristics; (2) examine the potential role of this milk component on the intestinal immune system; and (3) delineate the mechanistic roles of the MFG in infant intestinal maturation and establishment of the microbiota in the alimentary canal.

Descentralización y equidad en salud: estudio sobre la utilización de servicios de salud de la Ciudad de Buenos Aires por parte de usuarios pobres del Conurbano Bonaerense / Equity and decentralisation: accessibility of poor families from Buenos Aires province to health public services of Buenos Aires city

Este estudio describe y analiza las características de los usuarios de servicios de salud de la Ciudad de Buenos Aires residentes en el conurbano bonaerense y rastrea los motivos invocados por éstos para realizar este desplazamiento en busca de atención. El objetivo es analizar la posible relación entre esta estrategia de cuidado de la salud y el proceso de descentralización a nivel nacional y local, enmarcándolo en el concepto de equidad en el acceso a servicios de salud. Metodología: se trabajó con una metodología de articulación entre niveles de análisis y con técnicas de producción de datos cuantitativas y cualitativas. Para las conclusiones se realizó una triangulación de las técnicas. Principales conclusiones: Acudir a los Hospitales de la Ciudad de Buenos Aires es parte de una estrategia compleja que incluye también a los servicios de su zona de residencia. El primer motivo de elección refiere a distintos aspectos de calidad de la atención.

Aproximación al análisis de la accesibilidad al sector salud de los ciudadanos del conurbano bonaerense: monitoreando derechos de ciudadanos con necesidades básicas insatisfechas / An approximation to the analysis of the accesibility to the health sector by the Buenos Aires Province residents: monitoring the poor population rights

Objetivo: Analizar la accesibilidad al sector salud de los ciudadanos del Conurbano Bonaerense en el contexto de los procesos de descentralización y el debate mundial sobre derecho a la salud. Metodología: Procesamiento cuantitativo de estadísticas del AMBA, revisión documental de normativas, administración de un cuestionario. Conclusiones: 1. El conurbano bonaerense presenta indicadores sociales heterogéneos pero en el segundo cordón se concentran los mayores niveles de pobreza. 2. La capacidad instalada de Servicios de Salud del Conurbano es deficitaria comparada con el promedio nacional del Subsector Estatal. 3. Las normativas rastreadas, facilitarían la posibilidad de acceso de ciudadanos bonaerenses a los centros asistenciales de la Ciudad de Buenos Aires. 4. Los usuarios de servicios de salud, habitantes del conurbano, encuentran mas barreras de accesibilidad en su área de residencia que en la Ciudad de Buenos Aires, contradiciendo la lógica con la que fueron concebidos los procesos de descentralización.