Elevated maternal cholesterol is linked to a coexpression network of neonatal indole metabolism and birth weight

The developmental origins of health and disease (DOHaD) hypothesis links intrauterine exposure to suboptimal fetal development and later-life cardiometabolic health. In 56 mother-newborn pairs, we quantified 389 newborn cord blood metabolites by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and recorded 24 clinical variables. With weighted coexpression network analysis, we identified module 05, comprising birth weight and metabolites enriched for the "gut-liver indole metabolism" pathway (indole, indole-3-pyruvic acid, and indole-3-lactic acid). Multivariable regression revealed that each 1-SD higher module 05 expression score was associated with -0.26 [95% confidence interval (CI): -0.51, -0.01]-SD lower 3rd-trimester total cholesterol (P = 0.039), adjusting for newborn and maternal covariates. This supports a coordinated newborn pattern of lower birth weight and lower cord blood indole metabolite abundance in pregnancy cases with higher late-pregnancy total cholesterol. Stratified analyses further suggested that, among pregnancies with maternal supraphysiological hypercholesterolemia (MSPH; 3rd-trimester total cholesterol ≥ 280 mg/dL), higher maternal age and higher 1st-trimester systolic blood pressure were accompanied by lower module 05 score, whereas these associations were not observed in non-MSPH pregnancies. Complementary regression analysis associated each tertile higher cord blood indole-3-propionic acid (IPA) with -9.09 [-17.45, -0.72]-mg/dL lower 1st-trimester cholesterol (P = 0.038). Separately, each 1-tertile higher IPA was linked to 192.22 [55.44, 329.00]-g higher newborn weight (P = 0.008). Both 1st- and 3rd-trimester total cholesterols were positively associated with higher cord blood oxidative stress (8-hydroxy-2'-deoxyguanosine, 8-OHdG). In conclusion, maternal cholesterol level varies with cord blood indole metabolites and birth weight, suggesting a potential shared metabolic axis modifiable by maternal cholesterol level in mother-newborn pairs.NEW & NOTEWORTHY This study identifies a coexpression network module connecting birth weight with cord blood indole metabolites, highlighting an integrated neonatal growth-metabolism signature. Maternal lipid status tracks with this signature, adding molecular resolution to the developmental origins of health and disease (DOHaD) paradigm by implicating growth-linked biochemical perturbations in gut-derived indole metabolites. Given the established relevance of indole metabolites to cardiovascular health, our preliminary results motivate future studies aimed at targeting neonatal metabolism as an early window for cardiovascular health intervention.