Elevated Maternal Cholesterol is Linked to a Co-expression Network of Neonatal Indole Metabolism and Birth Weight

The Developmental Origins of Health and Disease (DOHaD) hypothesis links intrauterine exposure to sub-optimal fetal development and later-life cardiometabolic health. In 56 mother-newborn pairs, we quantified 389 newborn cord-blood metabolites by LC-MS/MS and recorded 24 clinical variables. With weighted co-expression 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% CI: -0.51, -0.01] SD lower 3^rd-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 hypercholesterolaemia (MSPH; 3^rd-trimester total cholesterol ≥280 mg/dL), higher maternal age and higher 1^st-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 1^st-trimester cholesterol (P = 0.038). Separately, each 1-tertile higher IPA was linked to 192.22 [55.44, 329.00] gram higher newborn weight (P = 0.008). Both 1^st- and 3^rd-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.