Pregnane X receptor (PXR) is a drug receptor with novel functions in promoting non-alcoholic fatty liver disease (NAFLD). We hypothesize that PXR worsens NAFLD accompanied by gut dysbiosis. Wild-type and PXR-knockout mice were fed control or high fat diet (HFD) for 16-weeks. Serum parameters, liver histopathology, transcriptomic profiling, 16S-rDNA sequencing, and bile acid (BA) metabolomics were performed. PXR enhanced HFD-induced weight gain, hepatic steatosis and inflammation especially in

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... les, accompanied by male-specific and PXR-dependent up-regulation in pro-inflammatory cytokines and microbial response-related genes in liver, an increase in intestinal Firmicutes/Bacteroides ratio (hallmark of obesity) and the pro-inflammatory Lactobacillus, and a decrease in the anti-obese Allobaculum and the anti-inflammatory Bifidobacterum. The gut dysbiosis was associated with a reduction of hepatic beneficial BAs in males. In conclusion, PXR exacerbates hepatic steatosis and inflammation accompanied by obesity- and inflammation-prone gut microbiome signature, suggesting that gut microbiome may contribute to PXR-mediated exacerbation of NAFLD.