Maternal diet-induced hypercholanemia alters gut microbiota and metabolome in adult female Western diet-fed offspring

Children of mothers with intrahepatic cholestasis of pregnancy (ICP) are more likely to develop metabolic disease later in life. Using a mouse model of gestational cholestasis, we previously found that 18-week-old offspring had metabolic alterations that were exacerbated in female offspring when challenged with a Western diet (WD). Microbiota manipulation is emerging as a potential mechanism for developmental programming, and the maternal gut microbiota is known to be altered in pregnancy and in ICP. We hypothesized that, in our model, the offspring gut microbiota is altered by maternal gestational disease, potentially impacting future offspring metabolic health. Female mice were fed a cholic acid (CA)-supplemented diet for one week preceding and throughout pregnancy to mimic gestational hypercholanemia. Offspring were challenged with a WD from 12-18 weeks of age and cecal contents were collected for metataxonomics and metabolomic profiling. Female WD-fed offspring of CA-fed mothers had a >2-fold reduction in CA and dehydrocholic acid levels compared to those from NC-fed mothers. WD feeding altered more cecal lipid species in offspring from CA-fed mothers compared to NC-fed mothers. This observational mouse study has shown that exposure to maternal hypercholanemia can significantly impact the effects of an obesogenic diet on offspring intestinal bile acid metabolism and gut microbiota, likely increasing their vulnerability to metabolic dysfunction when exposed to the ‘second hit’ of an unhealthy postnatal environment.