Maternal obesogenic diet regulates offspring bile acid homeostasis and hepatic lipid metabolism via the gut microbiome in mice.

ABSTRACT

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 wk 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 were performed in recipient mice. Gut microbiomes from HF/HS offspring segregated from CON offspring, with increased Firmicutes to Bacteriodetes ratios and Verrucomicrobial abundance. After CMT was performed, HF/HS-recipient mice had larger BA pools, 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.NEW & NOTEWORTHY We utilized a mouse model of maternal obesogenic diet exposure to evaluate the effect on offspring microbiome and bile acid homeostasis. We identified shifts in the offspring microbiome associated with changes in cecal bile acid levels. Transfer of the microbiome from maternal obesogenic diet-exposed offspring to microbiome-depleted mice altered bile acid homeostasis and increased fructose-induced hepatic steatosis.