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Common dysglycemia measurements including fasting plasma glucose (FPG), oral glucose tolerance test (OGTT)-derived 2 h plasma glucose, and hemoglobin A1c (HbA1c) have limitations for children. Dynamic OGTT glucose and insulin responses may better reflect underlying physiology. This analysis assessed glucose and insulin curve shapes utilizing classifications-biphasic, monophasic, or monotonically increasing-and functional principal components (FPCs) to predict future dysglycemia. The prospective cohort included 671 participants with no previous diabetes diagnosis (BMI percentile ≥ 85th, 8-18 years old); 193 returned for follow-up (median 14.5 months). Blood was collected every 30 min during the 2 h OGTT. Functional data analysis was performed on curves summarizing glucose and insulin responses. FPCs described variation in curve height (FPC1), time of peak (FPC2), and oscillation (FPC3). At baseline, both glucose and insulin FPC1 were significantly correlated with BMI percentile (Spearman correlation r = 0.22 and 0.48), triglycerides (r = 0.30 and 0.39), and HbA1c (r = 0.25 and 0.17). In longitudinal logistic regression analyses, glucose and insulin FPCs predicted future dysglycemia (AUC = 0.80) better than shape classifications (AUC = 0.69), HbA1c (AUC = 0.72), or FPG (AUC = 0.50). Further research should evaluate the utility of FPCs to predict metabolic diseases.
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Liquid chromatography-high-resolution mass spectrometry (LC-HRMS), as applied to untargeted metabolomics, enables the simultaneous detection of thousands of small molecules, generating complex datasets. Alignment is a crucial step in data processing pipelines, whereby LC-MS features derived from common ions are assembled into a unified matrix amenable to further analysis. Variability in the analytical factors that influence liquid chromatography separations complicates data alignment. This is prominent when aligning data acquired in different laboratories, generated using non-identical instruments, or between batches from large-scale studies. Previously, we developed metabCombiner for aligning disparately acquired LC-MS metabolomics datasets. Here, we report significant upgrades to metabCombiner that enable the stepwise alignment of multiple untargeted LC-MS metabolomics datasets, facilitating inter-laboratory reproducibility studies. To accomplish this, a "primary" feature list is used as a template for matching compounds in "target" feature lists. We demonstrate this workflow by aligning four lipidomics datasets from core laboratories generated using each institution's in-house LC-MS instrumentation and methods. We also introduce batchCombine, an application of the metabCombiner framework for aligning experiments composed of multiple batches. metabCombiner is available as an R package on Github and Bioconductor, along with a new online version implemented as an R Shiny App.
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The gut microbiota is vital for human body development and function. Its development in early life is influenced by various environmental factors. In this randomized controlled trial, the gut microbiota was obtained as a secondary outcome measure in a study on the effects of one hour of daily skin-to-skin contact (SSC) for five weeks in healthy full-term infants. Specifically, we studied the effects on alpha/beta diversity, volatility, microbiota maturation, and bacterial and gut-brain-axis-related functional abundances in microbiota assessed thrice in the first year. Pregnant Dutch women (n = 116) were randomly assigned to the SSC or care-as-usual groups. The SSC group participants engaged in one hour of daily SSC from birth to five weeks of age. Stool samples were collected at two, five, and 52 weeks and the V4 region was sequenced. We observed significant differences in the microbiota composition, bacterial abundances, and predicted functional pathways between the groups. The SSC group exhibited lower microbiota volatility during early infancy. Microbiota maturation was slower in the SSC group during the first year and our results suggested that breastfeeding duration may have partially mediated this relation. Our findings provide evidence that postpartum SSC may influence microbiota development. Replication is necessary to validate and generalize these results. Future studies should include direct stress measurements and extend microbiota sampling beyond the first year to investigate stress as a mechanism and research SSC's impact on long-term microbiota maturation trajectories.
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Microbioma Gastrointestinal , Método Madre-Canguro , Femenino , Humanos , Lactante , Embarazo , Eje Cerebro-Intestino , Lactancia Materna , EtnicidadRESUMEN
OBJECTIVE: Individuals with higher intrinsic cardiorespiratory fitness (CRF) experience decreased rates of cardiometabolic disease and mortality, and high CRF is associated with increased utilization of fatty acids (FAs) for energy. Studies suggest a complex relationship between CRF, diet, and sex with health outcomes, but this interaction is understudied. We hypothesized that FA utilization differences by fitness and sex could be detected in the plasma metabolome when rats or humans were fed a high carbohydrate (HC) or high fat (HF) diet. METHODS: Male and female rats selectively bred for low (LCR) and high (HCR) CRF were fed a chow diet or a sucrose-free HF (45 % fat) or HC (10 % fat) diet. Plasma samples were collected at days 0, 3, and 14. Human plasma data was collected from male and female participants who were randomized into a HC or HF diet for 21 days. Samples were analyzed using liquid chromatography-mass spectrometry and regression statistics were used to quantify the effect of diet, CRF, and sex on the lipidome. RESULTS: In rats, the baseline lipidome is more significantly influenced by sex than by CRF, especially as elevated diglycerides, triglycerides, phosphatidylcholines, and lysophosphatidylcholines in males. A dynamic response to diet was observed 3 days after diet, but after 14 days of either diet, the lipidome was modulated by sex with a larger effect size than by diet. Data from the human study also suggests a sex-dependent response to diet with opposite directionality of affect compared to rats, highlighting species-dependent responses to dietary intervention.
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Capacidad Cardiovascular , Ratas , Humanos , Masculino , Femenino , Animales , Lipidómica , Dieta Alta en Grasa/efectos adversos , TriglicéridosRESUMEN
Obesity and metabolic diseases are rising among women of reproductive age, increasing offspring metabolic risk. Maternal nutritional interventions during lactation present an opportunity to modify offspring outcomes. We previously demonstrated in mice that adult male offspring have metabolic impairments and increased adipose tissue macrophages (ATM) when dams are fed high fat diet (HFD) during the postnatal lactation window (HFD PN). We sought to understand the effect of HFD during lactation on early-life inflammation. HFD PN offspring were evaluated at postnatal day 16 to 19 for tissue weight and gene expression. Profiling of adipose tissue and bone marrow immune cells was conducted through lipidomics, in vitro myeloid colony forming unit assays, and flow cytometry. HFD PN mice had more visceral gonadal white adipose tissue (GWAT) and subcutaneous fat. Adipose tissue RNA sequencing demonstrated enrichment of inflammation, chemotaxis, and fatty acid metabolism and concordant changes in GWAT lipidomics. Bone marrow (BM) of both HFD PN male and female offspring had increased monocytes (CD45+Ly6G-CD11b+CD115+) and B cells (CD45+Ly6G-CD11b-CD19+). Similarly, serum from HFD PN offspring enhanced in vitro BM myeloid colonies in a toll-like receptor 4-dependent manner. We identified that male HFD PN offspring had increased GWAT pro-inflammatory CD11c+ ATMs (CD45+CD64+). Maternal exposure to HFD alters milk lipids enhancing adiposity and myeloid inflammation even in early life. Future studies are needed to understand the mechanisms driving this pro-inflammatory state of both BM and ATMs, the causes of the sexually dimorphic phenotypes, and the feasibility of intervening in this window to improve metabolic health.
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Dieta Alta en Grasa , Obesidad , Femenino , Masculino , Ratones , Animales , Humanos , Dieta Alta en Grasa/efectos adversos , Obesidad/etiología , Lactancia , Inflamación , Exposición Materna , Fenómenos Fisiologicos Nutricionales MaternosRESUMEN
Systematic and random errors based on self-reported diet may bias estimates of dietary intake. The objective of this pilot study was to describe errors in self-reported dietary intake by comparing 24 h dietary recalls to provided menu items in a controlled feeding study. This feeding study was a parallel randomized block design consisting of a standard diet (STD; 15% protein, 50% carbohydrate, 35% fat) followed by either a high-fat (HF; 15% protein, 25% carbohydrate, 60% fat) or a high-carbohydrate (HC; 15% protein, 75% carbohydrate, 10% fat) diet. During the intervention, participants reported dietary intake in 24 h recalls. Participants included 12 males (seven HC, five HF) and 12 females (six HC, six HF). The Nutrition Data System for Research was utilized to quantify energy, macronutrients, and serving size of food groups. Statistical analyses assessed differences in 24 h dietary recalls vs. provided menu items, considering intervention type (STD vs. HF vs. HC) (Student's t-test). Caloric intake was consistent between self-reported intake and provided meals. Participants in the HF diet underreported energy-adjusted dietary fat and participants in the HC diet underreported energy-adjusted dietary carbohydrates. Energy-adjusted protein intake was overreported in each dietary intervention, specifically overreporting beef and poultry. Classifying misreported dietary components can lead to strategies to mitigate self-report errors for accurate dietary assessment.
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INTRODUCTION: Test performance screening measures for dysglycemia have not been evaluated prospectively in youth. This study evaluated the prospective test performance of random glucose (RG), 1-h nonfasting glucose challenge test (1-h GCT), hemoglobin A1c (HbA1c), fructosamine (FA), and 1,5-anhydroglucitol (1,5-AG) for identifying dysglycemia. METHODS: Youth ages 8-17 years with overweight or obesity (body mass index, BMI, ≥85th percentile) without known diabetes completed nonfasting tests at baseline (n = 176) and returned an average of 1.1 years later for two formal fasting 2-h oral glucose tolerance tests. Outcomes included glucose-defined dysglycemia (fasting plasma glucose ≥100 mg/dL or 2-h plasma glucose ≥140 mg/dL) or elevated HbA1c (≥5.7%). Longitudinal test performance was evaluated using receiver-operating characteristic (ROC) curves and calculation of area under the curve (AUC). RESULTS: Glucose-defined dysglycemia, elevated HbA1c, and either dysglycemia or elevated HbA1c were present in 15 (8.5%), 11 (6.3%), and 23 (13.1%) participants at baseline, and 16 (9.1%), 18 (10.3%), and 28 (15.9%) participants at follow-up. For prediction of glucose-defined dysglycemia at follow-up, RG, 1-h GCT, and HbA1c had similar performance (0.68 (95% CI: 0.55-0.80), 0.76 (95% CI: 0.64-0.89), and 0.70 (95% CI: 0.56-0.84)), while FA and 1,5-AG performed poorly. For prediction of HbA1c at follow-up, baseline HbA1c had strong performance (AUC 0.93 [95% CI: 0.88-0.98]), RG had moderate performance (AUC 0.67 [95% CI: 0.54-0.79]), while 1-h GCT, FA, and 1,5-AG performed poorly. CONCLUSION: HbA1c and nonfasting glucose tests had reasonable longitudinal discrimination identifying adolescents at risk for dysglycemia, but performance depended on outcome definition.
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Glucemia , Estado Prediabético , Humanos , Adolescente , Niño , Hemoglobina Glucada , Estudios Prospectivos , BiomarcadoresRESUMEN
Untargeted liquid chromatography-mass spectrometry metabolomics studies are typically performed under roughly identical experimental settings. Measurements acquired with different LC-MS protocols or following extended time intervals harbor significant variation in retention times and spectral abundances due to altered chromatographic, spectrometric, and other factors, raising many data analysis challenges. We developed a computational workflow for merging and harmonizing metabolomics data acquired under disparate LC-MS conditions. Plasma metabolite profiles were collected from two sets of maternal subjects three years apart using distinct instruments and LC-MS procedures. Metabolomics features were aligned using metabCombiner to generate lists of compounds detected across all experimental batches. We applied data set-specific normalization methods to remove interbatch and interexperimental variation in spectral intensities, enabling statistical analysis on the assembled data matrix. Bioinformatics analyses revealed large-scale metabolic changes in maternal plasma between the first and third trimesters of pregnancy and between maternal plasma and umbilical cord blood. We observed increases in steroid hormones and free fatty acids from the first trimester to term of gestation, along with decreases in amino acids coupled to increased levels in cord blood. This work demonstrates the viability of integrating nonidentically acquired LC-MS metabolomics data and its utility in unconventional metabolomics study designs.
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Aminoácidos , Metabolómica , Embarazo , Femenino , Humanos , Metabolómica/métodos , Cromatografía Liquida , Espectrometría de Masas/métodos , Aminoácidos/metabolismo , Plasma/metabolismoRESUMEN
Bariatric surgery is associated with weight loss attributed to reduced caloric intake, mechanical changes, and alterations in gut hormones. However, some studies have suggested a heightened incidence of colorectal cancer (CRC) has been associated with bariatric surgery, emphasizing the importance of identifying mechanisms of risk. The objective of this study was to determine if bariatric surgery is associated with decreases in fecal short-chain fatty acids (SCFA), a group of bacterial metabolites of fiber. Fecal samples (n = 22) were collected pre- (~6 weeks) and post-bariatric surgery (~4 months) in patients undergoing Roux-en-Y gastric bypass and sleeve gastrectomy. SCFA levels were quantified using liquid chromatography/mass spectrometry. Dietary intake was quantified using 24-h dietary recalls. Using an aggregate variable, straight SCFAs significantly decreased by 27% from pre- to post-surgery, specifically acetate, propionate, butyrate, and valerate. Pre-surgery weight was inversely associated with butyrate, with no association remaining post-surgery. Multiple food groups were positively (sugars, milk, and red and orange vegetables) and inversely (animal protein) associated with SCFA levels. Our results suggest a potential mechanism linking dietary intake and SCFA levels with CRC risk post-bariatric surgery with implications for interventions to increase SCFA levels.
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Cirugía Bariátrica , Derivación Gástrica , Obesidad Mórbida , Animales , Propionatos , Pérdida de Peso , Ácidos Grasos Volátiles/metabolismo , Derivación Gástrica/métodos , Acetatos , Ingestión de Alimentos , Butiratos , Valeratos , Azúcares , Hormonas , Obesidad Mórbida/cirugíaRESUMEN
BACKGROUND: Prenatal phthalates exposures have been related to adiposity in peripuberty in a sex-specific fashion. Untargeted metabolomics analysis to assess circulating metabolites offers the potential to characterize biochemical pathways by which early life exposures influence the development of cardiometabolic risk during childhood and adolescence, prior to becoming evident in clinical markers. METHODS: Among mother-child dyads from the Early Life Exposure in Mexico to ENvironmental Toxicants (ELEMENT) birth cohort, we measured 9 phthalate metabolites and bisphenol A in maternal spot urine samples obtained during each trimester of pregnancy, corrected for urinary specific gravity and natural log-transformed. In 110 boys and 124 girls aged 8-14 years, we used a mass-spectrometry based untargeted metabolomics platform to measure fasting serum metabolites, yielding 572 annotated metabolites. We estimated the associations between trimester-specific urinary toxicants and each serum metabolite, among all children or stratified by sex and adjusting for child age, BMI z-score, and pubertal onset. We accounted for multiple comparisons using a 10% false discovery rate (q<0.1). RESULTS: Associations between exposures and metabolites were observed among all children and in sex-stratified analyses (q<0.1). First trimester MEP, MiBP, and MCPP were associated with decreased 2-deoxy-D-glucose among all children. Among girls, third trimester concentrations of MECPP, MEHHP, MEHP, and MCPP were associated with 15, 13, 1, and 10 metabolites, respectively, including decreased choline and increased acylcarnitines and saturated FAs (FA). Among boys, third trimester MIBP was positively associated with 9 features including long chain saturated FAs, and second trimester MBzP was inversely associated with thyroxine. CONCLUSIONS: Metabolomics biomarkers may reflect sex- and exposure timing-specific responses to prenatal phthalate exposures manifesting in childhood that may not be detected using standard clinical markers of cardiometabolic risk.
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Enfermedades Cardiovasculares , Contaminantes Ambientales , Ácidos Ftálicos , Adolescente , Biomarcadores , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Contaminantes Ambientales/análisis , Femenino , Humanos , Masculino , Ácidos Ftálicos/orina , EmbarazoRESUMEN
BACKGROUND: Alterations in body composition (BC) during adolescence relates to future metabolic risk, yet underlying mechanisms remain unclear. OBJECTIVES: To assess the association between the metabolome with changes in adiposity (body mass index [BMI], waist circumference [WC], triceps skinfold [TS], fat percentage [BF%]) and muscle mass (MM). METHODS: In Mexican adolescents (n = 352), untargeted serum metabolomics was profiled at baseline. and data were reduced by pairing hierarchical clustering with confirmatory factor analysis, yielding 30 clusters with 51 singleton metabolites. At the baseline and follow-up visits (1.6-3.5 years apart), anthropometry was collected to identify associations between baseline metabolite clusters and change in BC (∆) using seemingly unrelated and linear regression. RESULTS: Between visits, MM increased in boys and adiposity increased in girls. Sex differences were observed between metabolite clusters and changes in BC. In boys, aromatic amino acids (AAA), branched chain amino acids (BCAA) and fatty acid oxidation metabolites were associated with increases in ∆BMI, and ∆BF%. Phospholipids were associated with decreases in ∆TS and ∆MM. Negative associations were observed for ∆MM in boys with a cluster including AAA and BCAA, whereas positive associations were found for a cluster containing tryptophan metabolites. Few associations were observed between metabolites and BC change in girls, with one cluster comprising methionine, proline and lipids associated with decreases in ∆BMI, ∆WC and ∆MM. CONCLUSION: Sex-specific associations between the metabolome and change in BC were observed, highlighting metabolic pathways underlying adolescent physical growth.