Maternal obesity and the human milk metabolome: associations with infant body composition and postnatal weight gain.

BACKGROUND: Maternal obesity is a risk factor for childhood obesity; this is a major public health concern given that ∼40% of pregnant women are either overweight or obese. Whether differences in milk composition in lean compared with obese women contribute to childhood obesity is unclear. OBJECTIVES: We aimed to analyze relationships between maternal obesity and human milk metabolites, infant body composition, and postnatal weight gain. METHODS: This was a prospective study in which mothers intending to breastfeed exclusively, and their newborn infants, were enrolled at delivery (n = 35 mother-infant pairs). We excluded mothers with diabetes, other medical conditions, or pregnancy complications. Participants were grouped by maternal prepregnancy BMI <25 (lean) or ≥25 kg/m2 (overweight/obese). We analyzed infant body composition by dual-energy X-ray absorptiometry and used untargeted liquid chromatography-gas chromatography-mass spectrometry to measure the milk content of 275 metabolites at 1 and 6 mo postpartum. RESULTS: At 1 mo postpartum, 10 metabolites differed between overweight/obese and lean groups with nominal P < 0.05, but none was altered with a false discovery rate <0.25. Many differentially abundant metabolites belonged to the same chemical class; e.g., 4/10 metabolites were nucleotide derivatives, and 3/10 were human milk oligosaccharides. Milk adenine correlated positively with both continuously distributed maternal BMI and with infant adiposity and fat accrual. Analysis of milk composition at 6 mo postpartum revealed 20 differentially abundant metabolites (P < 0.05) in overweight/obese compared with lean women, including 6 metabolites with a false discovery rate of <0.25. At both 1 and 6 mo, human milk abundance of 1,5-anhydroglucitol, which has not previously been described in milk, was positively associated with maternal BMI. CONCLUSIONS: Maternal obesity is associated with changes in the human milk metabolome. While only a subset of metabolites correlated with both maternal and infant weight, these point to potential milk-dependent mechanisms for mother-child transmission of obesity. This trial was registered at www.clinicaltrials.gov as NCT02535637.

Attenuated Effects of Bile Acids on Glucose Metabolism and Insulin Sensitivity in a Male Mouse Model of Prenatal Undernutrition.

Prenatal undernutrition and low birth weight are associated with risk of type 2 diabetes and obesity. Prenatal caloric restriction results in low birth weight, glucose intolerance, obesity, and reduced plasma bile acids (BAs) in offspring mice. Because BAs can regulate systemic metabolism and glucose homeostasis, we hypothesized that BA supplementation could prevent diet-induced obesity and glucose intolerance in this model of developmental programming. Pregnant dams were food restricted by 50% from gestational days 12.5 to 18.5. Offspring of both undernourished (UN) and control (C) dams given unrestricted diets were weaned to high-fat diets with or without supplementation with 0.25% w/w ursodeoxycholic acid (UDCA), yielding four experimental groups: C, UN, C + UDCA, and UN + UDCA. Glucose homeostasis, BA composition, liver and intestinal gene expression, and microbiota composition were analyzed in the four groups. Although UDCA supplementation ameliorated diet-induced obesity in C mice, there was no effect in UN mice. UDCA similarly lowered fasting insulin, and improved glucose tolerance, pyruvate tolerance, and liver steatosis in C, but not UN, animals. BA composition differed significantly, and liver and ileal expression of genes involved in BA metabolism (Cyp7b1, Shp) were differentially induced by UDCA in C vs UN animals. Bacterial taxa in fecal microbiota correlated with treatment groups and metabolic parameters. In conclusion, prenatal undernutrition alters responsiveness to the metabolic benefits of BA supplementation, with resistance to the weight-lowering and insulin-sensitizing effects of UDCA supplementation. Our findings suggest that BA metabolism may be a previously unrecognized contributor to developmentally programmed diabetes risk.