Prebiotics partially protect offspring from maternal antibiotic-induced obesity risk by altering maternal milk microbiota and gut colonization in Sprague-Dawley rats.

Maternal antibiotic use can increase obesity risk in offspring. Co-administering prebiotics mitigates the risk in rats. How prebiotics and antibiotics interact to affect obesity risk is unknown, but could involve altered milk microbiota that influences offspring gut colonization. Sprague-Dawley rat dams were exposed to antibiotics (low-dose penicillin) and/or prebiotics (oligofructose) during gestation and lactation. Gut and milk microbiota were measured using 16S rRNA sequencing, and metabolic measurements were taken for dams and offspring at weaning (day 21) and 10 days postweaning (day 31). Germ-free mice were transplanted with maternal cecal microbiota to assess the causal role of vertically transmitted microbiota. Offspring maternally exposed to antibiotics showed relatively accelerated taxonomic maturation in the gut pre- and postweaning. Milk composition (fat, protein, hormone, microRNA, and cytokines) was unchanged, but milk-derived bacteria differed between maternal treatments and contributed to offspring gut microbial structure. Male offspring were especially affected by maternal antibiotic exposure and had increased body weight, fat mass, caloric intake, and hepatic triglycerides by day 31. All but hepatic triglycerides were attenuated with maternal prebiotic coconsumption. fecal microbiota transplants of maternal cecal matter into germ-free mice replicated male offspring body weight and hepatic outcomes. Untargeted hepatic lipidomics and network analysis revealed strong connections between several bacteria and lipid species potentially of bacterial origin that were enriched in prebiotic offspring microbiota and livers. These data confirm the role of milk microbiota in seeding offspring microbiota and implicate maternal antibiotic-associated gut microbiota as causally implicated in compromising early-life offspring hepatic metabolism that may lead to later metabolic disorders.