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.

Maternal obesity programs risk for development of non-alcoholic fatty liver disease (NAFLD) in offspring. Maternal exercise is a potential intervention to prevent developmentally programmed phenotypes. We hypothesized that maternal exercise would protect from progression of NAFLD in offspring previously exposed to maternal obesogenic diet. Female mice were fed chow (CON) or HFFC and bred with lean males. A subset had an exercise wheel introduced 4 weeks after starting diet to allow for voluntary exercise. The offspring were weaned to HFFC diet for 7 weeks to induce NAFLD. Serum, adipose, and liver tissue were collected for metabolic, histologic, and gene expression analyses. Cecal contents were collected for 16S sequencing. Global metabolomics was performed on liver. Female mice fed HFFC diet had increased body weight prior to adding an exercise wheel. Female mice fed HFFC diet had an increase in exercise distance relative to CON during the pre-conception period. Exercise distance was similar between groups during pregnancy and lactation. CON-Active and HFFC-Active offspring exhibited decreased inflammation compared to offspring from sedentary dams. Fibrosis increased in offspring from HFFC-sedentary dams compared to CON-sedentary. Offspring from exercised HFFC dams exhibited less fibrosis than offspring from sedentary HFFC dams. While maternal diet significantly affected the microbiome of offspring, the effect of maternal exercise was minimal. Metabolomics analysis revealed shifts in multiple metabolites including several involved in bile acid, one-carbon, histidine, and acylcarnitine metabolism. This study provides pre-clinical evidence that maternal exercise is a potential approach to prevent developmentally programmed liver disease progression in offspring.

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