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 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 obesogenic diet enhances cholestatic liver disease in offspring

“…An altered offspring microbiome has been described in the setting of maternal obesogenic diet exposure and is a potential mechanism for enhanced cholestatic liver injury observed in the offspring ( 22 , 23 ). We previously reported shifts in the offspring microbiome after maternal HF/HS exposure ( 24 ). Principal component analysis of microbial 16S sequences demonstrated that CON and HF/HS offspring fed DDC diverged in community content, though this was not statistically significant ( P = 0.07) ( Fig.…”

Epigenetic programming mediates abnormal gut microbiota and disease susceptibility in offspring with prenatal dexamethasone exposure

“…It has been reported that abnormal gut microbiota contributes to disease susceptibility in offspring prenatally exposed to adverse environmental factors. 7 , 55 A possible explanation is that the altered gut microbiota participates in host physiology and even pathology by regulating metabolic processes, such as bile acid conversion. Accumulation of hydrophobic bile acids in hepatocytes can lead to liver injury by inducing mitochondrial oxidative damage or endoplasmic reticulum stress.…”

Liver’s influence on the brain through the action of bile acids

“…The stimulation of the neuronal and astrocyte-localized LCA receptor VDR with physiological levels of an active metabolite of Vitamin D reduces calcium channel expression and protects hippocampal neurons against excitotoxicity ( Brewer et al, 2001 ). Interestingly, maternal intrahepatic cholestasis or overnutrition is associated with altered metabolism and hepatic function in the offspring ( Papacleovoulou et al, 2013 ; Thompson et al, 2022 ), with an increased risk of developing cognitive deficits and neuropsychiatric disorders ( Sullivan et al, 2012 ; Wolfrum and Peleg-Raibstein, 2019 ). S1PR signaling is implicated in neuronal differentiation ( Lee et al, 2011 ), neurite outgrowth during development ( Yang et al, 2020 ), and the determination of neuronal properties ( Li et al, 2015 ).…”