The gut-liver axis mechanism of increased susceptibility to non-alcoholic fat disease in female adult offspring rats with prenatal caffeine exposure

Accumulating studies suggest that the adverse environment during pregnancy may contribute to the disease susceptibility of offspring by affecting their gut microbiota. Caffeine intake during pregnancy is common but may adversely affect offspring health, but its effect on offspring gut microbiota composition and the relationship with multi-disease susceptibility remain unclear. This study aimed to confirm the effects of prenatal caffeine exposure (PCE)on the gut microbiota and its metabolites in female adult offspring rats, elucidate the mechanism of the gut-liver axis mediating susceptibility to NAFLD, with the purpose of providing intervention targets. The results showed that the gut microbiota of PCE female adult offspring rats was significantly changed with depletion of butyric acid-producing bacteria, accompanied by reduced butyric acid levels. PCE female adult offspring rats were susceptible to NAFLD induced by a postnatal high-fat diet (HFD), which is mainly related to the enhancement of hepatic TG synthesis function. By exploring the mechanism,we found that an HFD further reduced the butyric acid levels of PCE female offspring, which was significantly negatively correlated with hepatic TG level and SREBP-1c/FASN mRNA expression. The in vivo and in vitro experiments confirmed that the decreased expression of MCT1/GPR109A induced by the low butyric acid might mediate the low AMPK phosphorylation level in PCE offspring, thus promoting the liver TG synthesis function and causing NAFLD susceptibility. Sodium butyrate (NaB) supplementation could reduce lipid accumulation through MCT1/GPR109A-AMPK, thereby effectively alleviating NAFLD susceptibility of PCE female adult offspring rats.