Endocrine Abstracts (2019) 65 P209 | DOI: 10.1530/endoabs.65.P209

Maternal diet-induced cholestasis programmes murine offspring metabolic impairment on feeding a Western diet, with altered intestinal metabolites and microbiota in the female offspring

Caroline Ovadia1, Konstantina Spagou2, Alvaro Perdones-Montero2, Ann Smith3, Georgia Papacleovoulou1, Peter Dixon1, Elaine Holmes2, Julian Marchesi2,3 & Catherine Williamson1

1King’s College London, London, UK; 2Imperial College London, London, UK; 3Cardiff University, Cardiff, UK

Background: The 16-year-old children of mothers with intrahepatic cholestasis of pregnancy demonstrate increased adiposity, dyslipidaemia, and males have raised fasting insulin. Similarly, the offspring of cholestatic pregnant mice have impaired glucose tolerance and dyslipidaemia when challenged with a Western diet. Female offspring have a more marked phenotype than males. Bile influences microbial growth, thus intestinal bile acid exposure in pregnancy may contribute to metabolic impairments observed. We hypothesise that the offspring of cholestatic pregnancies develop an abnormal gut bacterial and metabolite composition, contributing to the offspring’s phenotype.

Methods: C57BL/6 female mice were fed normal chow or 0.5% cholic acid-supplemented diets and mated. Their offspring were fed normal chow or Western diets. Ultra-performance liquid chromatography – mass spectrometry was used to assess the caecal metabonome. Metataxonomics was performed to determine the caecal microbiota. Results were compared using OPLS-DA, PCA, NMDS, and T-tests with Benjamini–Hochberg correction for multiple measures.

Results: The offspring microbiota was significantly affected by maternal and neonatal diet, with a sex difference in bacterial composition revealed in the pups of mothers fed cholic acid, when fed a Western diet. The female offspring of cholic acid-fed mothers had a higher abundance of Alistipes, a bile acid-resistant member of the Bacteroidetes phylum, than males. This group had lower caecal bile acids (P=0.036) (particularly deoxycholic acid, cholic acid and ω-muricholic acid) than offspring of normal chow-fed mothers when challenged with a Western diet.

Conclusions: Maternal cholic acid feeding results in increases in bile-resistant bacteria in the caecum of female offspring. A gender difference in the microbiome and bile acid content of the caecum is revealed by a Western diet. Together, these findings demonstrate how the establishment of the offspring gut microbiome, and associated metabonome, is influenced by an altered maternal environment, contributing to increased long-term risk of metabolic impairment.