Mice exposed in gestation to maternal high fat/high sucrose (HF/HS) diet develop altered bile acid (BA) homeostasis. We hypothesized that these reflect an altered microbiome and asked if microbiota transplanted from HF/HS offspring change hepatic BA and lipid metabolism to determine the directionality of effect. Female mice were fed HF/HS or chow (CON) for 6 weeks and bred with lean males. 16S sequencing was performed to compare taxa in offspring. Cecal microbiome transplantation (CMT) was performed from HF/HS or CON offspring into antibiotic treated mice fed chow or high fructose. BA, lipid metabolic, and gene expression analyses performed in recipient mice. Gut microbiomes from HF/HS offspring segregated from CON offspring, with increased Firmicutes to Bacteriodetes ratios and Verrucomicrobial abundance. Following CMT, HF/HS recipient mice had larger BA pools, and increased intrahepatic muricholic acid and decreased deoxycholic acid species. HF/HS recipient mice exhibited downregulated hepatic Mrp2, increased hepatic Oatp1b2, and decreased ileal Asbt mRNA expression. HF/HS recipient mice exhibited decreased cecal butyrate and increased hepatic expression of Il6. HF/HS recipient mice had larger livers, and increased intrahepatic triglyceride versus CON recipient mice after fructose feeding, with increased hepatic mRNA expression of lipogenic genes including Srebf1, Fabp1, Mogat1, and Mogat2. CMT from HF/HS offspring increased BA pool and shifted the composition of the intrahepatic BA pool. CMT from HF/HS donor offspring increased fructose-induced liver triglyceride accumulation. These findings support a causal role for vertical transfer of an altered microbiome in hepatic BA and lipid metabolism in HF/HS offspring.

Background Non‐alcoholic fatty liver disease (NAFLD) affects approximately one‐quarter of the global population, with up to 20–25% developing progressive liver 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 altered bile acid homeostasis and a varied response to a western diet which is passed by female offspring across generations. In this study we tested the hypothesis that male offspring exposed to maternal obesogenic diet pass an altered bile acid homeostasis phenotype and susceptibility to western diet induced liver disease to their offspring. Methods Female C57Bl6 mice were fed chow (CON) or HF/HS diet for 6 weeks to induce obesity and bred with lean males. Male F1 offspring were then bred with lean females to create a paternal second generation (PF2C from maternal CON lineage, PF2H from maternal HF/HS lineage). Tissues were collected from PF2 offspring to measure bile acid pool size and hepatic bile acid species profile. Additional PF2 offspring were fed high trans‐fat, cholesterol, fructose (HTFC) diet for 16 weeks to induce progressive NAFLD. Metabolic and histopathologic analyses were performed. Results In chow fed PF2 offspring from the maternal HF/HS (mHF/HS) lineage, total BA pool size was increased. No change in intrahepatic BA composition was observed. After HTFC diet, PF2H offspring showed decreased liver weight and liver weight to body weight ratio compared to PF2C offspring. PF2H offspring exhibited lower levels of intrahepatic triglyceride and free fatty acids. Conversely, PF2H offspring liver showed increased Sirius red staining. Conclusions Male offspring exposed to maternal obesogenic diet transmit a phenotype of altered BA homeostasis to their offspring. After exposure to a western diet, PF2H offspring exhibited worse fibrosis despite having less steatosis. Passage of these phenotypes through male offspring would suggest an epigenetic phenomenon as a mechanistic etiology. Future studies will evaluate the mechanism for transmission of maternal obesity driven changes in the liver across generations in the male lineage.