Mechanisms of Altered Bile Acid Homeostasis in Offspring Exposed to Maternal Obesogenic Diet

Abstract

BackgroundNon‐alcoholic fatty liver disease (NAFLD) affects approximately one‐quarter of the global population with increasing prevalence in the pediatric population. There is currently no standard medical therapy and no diagnostic study capable of predicting which patients will develop severe disease. Recent evidence in both humans and animal models show that maternal obesity is a risk factor for the development of NAFLD and progression to NASH. We have shown in a murine model of maternal obesity the offspring develop periportal fibrosis and inflammation with associated changes in bile acid (BA) homeostasis. In this study we define the mechanisms of changes in BA homeostasis.MethodsFemale C57Bl6 mice were fed chow (CON) or HF/HS diet for 6 weeks to induce obesity and bred with lean males. Offspring were fed chow diet from the time of weaning until tissue collection. BA pool size and levels of specific intrahepatic bile acid species were measured. RT‐PCR was performed to evaluate gene expression of factors involved in bile acid metabolism and signaling. 16S sequencing was performed for evaluation of offspring microbiome. Levels of stool BAs were quantified and timed BA excretion performed.ResultsOffspring from the maternal HF/HS (mHF/HS) lineage exhibited an increase in total BA pool size with associated changes in expression of genes involved in bile acid metabolism (increased Cyp7a1, Cyp27a1). Measurement of specific bile acids in liver showed a shift in the intrahepatic BA pool composition (decreased deoxycholic acid, increased muricholic acid) in offspring from the mHF/HS lineage. Decreased BA excretion was observed in mHF/HS lineage offspring. Fecal microbiome analysis showed a decrease in alpha diversity and shifts in the abundance of particular phyla (increased Bacteroidetes, decreased Proteobacteria) and genera (increased Barnesiella, decreased Clostridium). Measurement of cecal BA levels showed an increase in abundance of muricholic acid (FXR antagonist) and a decrease in abundance of deoxycholic acid (FXR agonist) in mHF/HS lineage offspring.ConclusionsMaternal HF/HS diet exposure leads to pathologic changes in the offspring including periportal fibrosis and inflammation, which is associated with changes in BA homeostasis. Several factors are involved in the BA homeostasis changes including BA metabolism and excretion. Vertical transmission of gut dysbiosis may be a primary factor in driving changes in BA homeostasis in offspring exposed to maternal obesogenic diet.