Potential role of gut microbiota-LCA-INSR axis in high fat-diet-induced non-alcoholic fatty liver dysfunction: From perspective of radiation variation

Non-alcoholic fatty liver disease (NAFLD) is a progressive disease of the liver covering a range of conditions from hepatic steatosis to liver fibrosis. NAFLD could be induced by High-fat-diet(HFD). Ionizing radiation is widely used in medical diagnosis and therapy as well as is a common risk factor in occupational environment. Whether the exposure of various dose of radiation has effects on HFD-induced NAFLD remains unclear. Here, we reported that radiation exposure promoted HFD-induced NAFLD in a dose-response manner. Furthermore, the gut microbiota composition had significant difference among mice with or without radiation treatment. Specifically, the Bacteroidetes/Firmicutes ratio, the abundance of A. muciniphila, Butyricococcus, and Clostridiaceae decreased significantly in the mice with co-exposure of high dose of radiation and HFD treatment. A fecal transplantation trial (FMT) further verified the role of gut microbiota in the regulation of the liver response to co-exposure of high dose of radiation and HFD treatment. Notably, the gut microbiome analysis showed plasma lithocholic acid (LCA) level increased in the mice with co-exposure of high dose of radiation and HFD treatment. Following antibiotic and probiotic treatments there was a significantly decreased LCA bile acid concentration and subsequent promotion of INSR/PI3K/Akt insulin signaling in the liver tissues. Our results demonstrate that the co-exposure of radiation and HFD aggravates the HFD-induced NAFLD through gut microbiota-LCA-INSR axis. Probiotics supplementation is a potential way to protect against co-exposure of radiation and HFD-induced liver damage. Meanwhile, our study provide a new insight that population with potential HFD-induced damage should pay more attention on preventing from liver damage while exposing radiation.