Hans Demmelmair

Physical activity (PA) supports health across the life course, yet the biological pathways linking habitual PA to long-term health remain incompletely understood. Metabolomics provides a powerful tool to study PA-related metabolic adaptations, but how habitual PA shapes the metabolome in childhood remains poorly characterized. Addressing this gap, we examined cross-sectional associations between accelerometer-measured habitual PA and the plasma metabolome in 515 children aged 5.5 to 11 years from the European Childhood Obesity Project (CHOP) and additionally determined whether associations differed between sexes and across the body mass index (BMI) range. Using targeted metabolomics, we quantified 315 metabolites and derived 91 metabolite sums and ratios. Associations with PA were assessed using linear mixed-effects models. Replication was performed in an independent pediatric cohort. Among the 406 metabolite variables, 73 were associated (p < 0.05) with at least one PA variable, of which 12 replicated, including lysophosphatidylcholine (LPC) a C14:0 and LPCs/phosphatidylcholines (PCs) with higher levels in more active children, and PC aa C40:6, monounsaturated PCs/saturated PCs, and valine/LPC a C18:1 with lower levels in more active children. At the metabolite-class level, intensity-dependent association patterns emerged. Amino acids and acylcarnitines were lower in more active children predominantly for time spent in higher-intensity PA, whereas LPCs were higher mainly with more total PA (80% light PA) and less sedentary time. Associations were more pronounced at older ages and differed (p < 0.05) by BMI for 42 metabolite variables and by sex for 45 variables in the interaction analyses. These findings provide insights into PA-related metabolic adaptations early in life and may help elucidate biological pathways linking childhood PA to long-term health.

Background/Objectives: As birth weight is related to later obesity risk, its associations with maternal pre-pregnancy body mass index (BMI) and leptin values in serum during pregnancy are of interest for obesity prevention. This study aimed to describe the association of leptin levels in maternal circulation and cord blood as well as pre-pregnancy BMI (pBMI) with infant anthropometry at birth and until the age of four months. Methods: Data on maternal pBMI, at delivery and four months after birth, and on infant weight and length at delivery and at age four months were collected in an observational study in Bangkok, Thailand. In a subgroup of 38 mother–infant dyads, leptin was measured in maternal blood serum at delivery and infant age 4 months and in cord and infant serum at 4 months. Associations were tested with correlation and multiple linear regression analyses in this explorative study. Results: The maternal serum leptin was 32.4 ± 17.8 ng/mL at delivery and 11.1 ± 8.9 ng/mL at four months (p < 0.001 for difference) and correlated (r = 0.45). Cord serum leptin was significantly higher in female than male infants (17.5 ± 9.8 ng/mL vs. 7.7 ± 4.9 ng/mL, p < 0.05) and not related to infant leptin at age four months. There was no significant association between maternal and cord serum leptin levels. Birth weight was strongly associated with pBMI (standardized β = 0.77, p < 0.001) and inversely related to maternal delivery leptin levels (standardized β = −0.44, p = 0.008), while the association with cord serum leptin was not significant. Conclusions: Our findings indicate that pBMI is strongly related to birth weight, while higher maternal leptin concentrations were independently associated with lower birth weight after accounting for pBMI. Cord serum leptin did not significantly correlate with maternal leptin levels and only tended to be positively associated with birth weight.

Context: Accurately assessing dietary intake in children and adolescents is challenging due to the limitations of traditional self-reported methods. Metabolomics has emerged as a valuable tool for assessing the body’s biochemical response to specific foods, food groups, or dietary patterns, thereby improving the evaluation of diet–health relationships. However, evidence on how diet influences metabolomic profiles in pediatric populations remains limited. Objective: To evaluate the evidence on the relationship between nutritional interventions or habitual dietary intake and metabolites measured in blood or urine among children and adolescents. Data Sources: A systematic search was conducted in PubMed, Cochrane, and Embase databases up to September 2024 Data Extraction: This systematic review was conducted in accordance with the principles of the Cochrane Collaboration, and PRISMA guidelines were followed. Randomized clinical trials and observational studies in children and adolescents were included. Data Analysis: From 659 records, 8 studies met the inclusion criteria, involving 5992 participants across 12 countries. The included studies reported associations across 3 dietary categories: dietary patterns, food groups, and specific food ingredients. Both targeted and untargeted metabolomic analyses were used to identify diet-related biomarkers in blood and urine. Positive associations were observed between higher adherence to the Mediterranean diet and greater fruit and vegetable consumption with metabolites such as hippurate, trigonelline, and proline betaine. In contrast, higher intake of ultra-processed foods and adherence to vegan diets were inversely associated with branched-chain amino acids and aromatic amino acids such as tyrosine and docosahexaenoic acid. Conclusion: This review identifies several metabolites consistently associated with specific dietary components across different studies in children and adolescents. These findings support the potential of metabolomics for validating dietary biomarkers and improving the accuracy of dietary assessment in pediatric populations. Although metabolomic markers reflect actual dietary intake, their implications for health outcomes remain to be explored. Systematic Review Registration: PROSPERO registration no. CRD42024506437.

Background: Fatty acid status during the perinatal period is important for optimal offspring growth and development. Objectives: We aimed to test the association between maternal fatty acid (FA) intake during the third trimester of pregnancy and the FA composition of placental phospholipids, a marker of maternal fatty acid status. Methods: This cohort study was performed on 54 mothers participating in the PREOBE study. Maternal dietary intake was assessed with prospective 7-day food diaries at 34 weeks of gestation. Placenta samples were collected immediately after delivery and phospholipid FA was quantified with established methods. Data were analyzed with Pearson correlations and linear regression models, with adjustment for confounding factors. Results: Total energy intake was 2019 ± 527 kcal/d (mean ± SD) and total fat intake of the mothers was 87 ± 35 g/day. Myristic, stearic, oleic, and α-linolenic acid intakes were modestly correlated with placental percentages, with r-values ≤ 0.33. Only docosahexaenoic (DHA) acid intake (%-energy, %-fat, and g/d) showed r-values > 0.4 for the correlation with placenta phospholipids. Intake of other fatty acids, including arachidonic acid, was not associated with the placenta percentage. Linear regression models considering confounders showed only dietary DHA intake significant associations. Total fat intake did not interfere with the association of DHA intake with placental incorporation. Conclusions: DHA and arachidonic acid are enriched in the placenta, but only placental DHA content seems modifiable by maternal dietary DHA intake.

Lack of maternal milk commonly leads to Asian elephant calves’ death in captivity. Currently, available supplements seem inefficient. Hence, we aimed at characterizing the composition of Asian elephant milk to provide information on calves’ nutritional needs. Seventy milk samples from 22 Asian elephants living in semi-captivity in their natural environment in Myanmar were collected. Samples were analysed through various techniques including liquid chromatography tandem mass spectrometry, gas chromatography-flame ionization detector, and bicinchoninic acid assay to determine total protein content and various metabolites. Associations with lactation stage (months postpartum) were investigated through repeated measure mixed models. We identified 160 compounds: 22 amino acids, 12 organic acids of the tricarboxylic acid cycle, 27 fatty acids, 15 acyl-carnitines and 84 phospholipids. The milk contained substantial amounts of free glutamate (median: 1727.9, interquartile range (IQR): 1278.4 µmol l−1) and free glycine (2541.7, IQR: 1704.1 µmol l−1). The fatty acid profile was mostly constituted by saturated fatty acids, particularly capric acid (40.1, IQR: 67.3 g l−1). Milk samples also contained high amounts of carnitines, phospholipids and organic acids. The wide array of metabolites identified and quantified, some of which present high concentrations in the milk from this species as opposed to other species, suggests underpinning physiological functions that might be crucial for the survival of Asian elephant calves.

Context: Milk protein contains high concentrations of branched-chain amino acids (BCAA) that play a critical role in anabolism and are implicated in the onset of obesity and chronic disease. Characterizing BCAA catabolism in the postprandial phase could elucidate the impact of protein intake on obesity risk established in the “early protein hypothesis.” Objective: To examine the acute effects of protein content of young child formulas as test meals on BCAA catabolism, observing postprandial plasma concentrations of BCAA in relation to their degradation products. Methods: The TOMI Add-On Study is a randomized, double-blind crossover study in which 27 healthy adults consumed 2 isocaloric young child formulas with alternating higher (HP) and lower (LP) protein and fat content as test meals during separate interventions, while 9 blood samples were obtained over 5 hours. BCAA, branched-chain α-keto acids (BCKA), and acylcarnitines were analyzed using a fully targeted HPLC-ESI-MS/MS approach. Results: Mean concentrations of BCAA, BCKA, and acylcarnitines were significantly higher after HP than LP over the 5 postprandial hours, except for the BCKA α-ketoisovalerate (KIVA). The latter metabolite showed higher postprandial concentrations after LP. With increasing mean concentrations of BCAA, concentrations of corresponding BCKA, acylcarnitines, and urea increased until a breakpoint was reached, after which concentrations of degradation products decreased (for all metabolites except valine and KIVA and Carn C4:0-iso). Conclusion: BCAA catabolism is markedly influenced by protein content of the test meal. We present novel evidence for the apparent saturation of the BCAA degradation pathway in the acute postprandial phase up to 5 hours after consumption.

Introduction Atopic dermatitis (AD) is a chronic, inflammatory skin condition significantly affecting quality of life. A small randomised trial showed an approximately one-third lower incidence of AD in goat milk formula-fed compared with cow milk formula-fed infants. However, due to limited statistical power, AD incidence difference was not found to be significant. This study aims to explore a potential risk reduction of AD by feeding a formula based on whole goat milk (as a source of protein and fat) compared with a formula based on cow milk proteins and vegetable oils. Methods and analysis This two-arm (1:1 allocation), parallel, randomised, double-blind, controlled nutritional trial shall enrol up to 2296 healthy term-born infants until 3 months of age, if parents choose to start formula feeding. Ten study centres in Spain and Poland are participating. Randomised infants receive investigational infant and follow-on formulas either based on whole goat milk or on cow milk until the age of 12 months. The goat milk formula has a whey:casein ratio of 20:80 and about 50% of the lipids are milk fat from whole goat milk, whereas the cow milk formula, used as control, has a whey:casein ratio of 60:40 and 100% of the lipids are from vegetable oils. The energy and nutrient levels in both goat and cow milk formulas are the same. The primary endpoint is the cumulative incidence of AD until the age of 12 months diagnosed by study personnel based on the UK Working Party Diagnostic Criteria. The secondary endpoints include reported AD diagnosis, measures of AD, blood and stool markers, child growth, sleep, nutrition and quality of life. Participating children are followed until the age of 5 years. Ethics and dissemination Ethical approval was obtained from the ethical committees of all participating institutions. Trial registration number NCT04599946.

Fetal tobacco exposure has persistent effects on growth and metabolism. The underlying mechanisms of these relationships are yet unknown. We investigated the associations of fetal exposure to maternal smoking with neonatal metabolite profiles. In a population-based cohort study among 828 mother-infant pairs, we assessed maternal tobacco use by questionnaire. Metabolite concentrations of amino acids, non-esterified fatty acids, phospholipids and carnitines were determined by using LC-MS/MS in cord blood samples. Metabolite ratios reflecting metabolic pathways were computed. Compared to non-exposed neonates, those exposed to first trimester only tobacco smoking had lower neonatal mono-unsaturated acyl-alkyl-phosphatidylcholines (PC.ae) and alkyl-lysophosphatidylcholines (Lyso.PC.e) 18:0 concentrations. Neonates exposed to continued tobacco smoking during pregnancy had lower neonatal mono-unsaturated acyl-lysophosphatidylcholines (Lyso.PC.a), Lyso.PC.e.16:0 and Lyso.PC.e.18:1 concentration (False discovery rate (FDR) p-values < 0.05). Dose-response associations showed the strongest effect estimates in neonates whose mothers continued smoking ≥5 cigarettes per day (FDR p-values < 0.05). Furthermore, smoking during the first trimester only was associated with altered neonatal metabolite ratios involved in the Krebs cycle and oxidative stress, whereas continued smoking during pregnancy was associated with inflammatory, transsulfuration, and insulin resistance markers (p-value < 0.05). Thus, fetal tobacco exposure seems associated with neonatal metabolite profile adaptations. Whether these changes relate to later life metabolic health should be studied further.

Fatty acids exert a range of different biological activities that could be relevant in the development of atopic dermatitis (AD). This study investigated the association of glycerophospholipid fatty acids (GPL-FA) with AD, and their interactions with single nucleotide polymorphisms (SNP) of the FADS1-3 gene cluster. Among 390 infants of the Indonesian ISADI study, GPL-FA were measured in umbilical plasma (P-0y) and in buccal cells at birth (B-0y), and again in buccal cells at AD onset or one year (B-1y). Prospective and cross-sectional associations with AD were assessed by logistic regression. Interactions of GPL-FA with 14 SNP were tested assuming an additive model. AD was diagnosed in 15.4% of participants. In B-1y, C18:2n-6 was inversely associated with AD; and positive associations were observed for C18:1n-9, C20:4n-6, C22:6n-3 and C20:4n-6/C18:2n-6. There were no prospective associations with AD, however, a significant interaction between the SNP rs174449 and B-0y C14:0 (myristic acid) was observed. This study indicates that Indonesian infants with AD have increased rates of endogenous long-chain polyunsaturated fatty acid production, as well as higher C18:1n-9 levels. GPL-FA measured at birth do not predict later AD incidence; however, genotype interactions reveal novel effects of myristic acid, which are modified by a FADS3 variant.