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

## TL;DR

Mothers with high bile acid levels during pregnancy can alter their offspring's gut bacteria and bile acid metabolism, increasing their risk of metabolic disease when exposed to a Western diet.

## Contribution

This study shows maternal hypercholanemia alters offspring gut microbiota and bile acid metabolism in response to a Western diet.

## Key findings

- Maternal CA supplementation led to a 387-fold increase in cecal sulfated bile acid species in offspring.
- WD-fed offspring of CA-supplemented mothers had a >2-fold reduction in CA and dehydrocholic acid levels.
- Maternal diet caused distinct microbiota profiles in WD-fed, but not NC-fed, offspring.

## Abstract

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 changes are 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 1 week preceding and throughout pregnancy to mimic gestational hypercholanemia. Female offspring were challenged with a WD from 12 to 18 weeks of age and cecal contents were collected for metataxonomics and metabolomic profiling. Maternal CA dietary supplementation was associated with markedly increased cecal sulfated bile acid species (up to 387-fold increase). Whilst WD-feeding of offspring was associated with a greater proportion of primary to secondary bile acids, and more tauro-conjugated bile acids than for offspring fed a normal diet, this adaptation to WD-feeding was not evident for those whose mothers were fed a CA-supplemented diet. Indeed, WD-fed offspring of CA-supplemented mothers had a >2-fold reduction in CA and dehydrocholic acid levels compared to those from NC-fed mothers. This corresponded with an altered profile of cecal microbiota, with clear separation of microbiotal profiles according to maternal diet in the WD-fed, but not NC-fed, offspring. 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.