Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease due to the current epidemics of obesity and diabetes. The pregnane X receptor (PXR) is a xenobiotic-sensing nuclear receptor known for trans-activating liver genes involved in drug metabolism and transport, and more recently implicated in energy metabolism. The gut microbiota can modulate the host xenobiotic biotransformation and contribute to the development of obesity. While the male sex confers a higher risk for NAFLD than women before menopause, the mechanism remains unknown. We hypothesized that the presence of PXR promotes obesity by modifying the gut-liver axis in a sex-specific manner. Male and female C57BL/6 (wild-type/WT) and PXR-knockout (PXR-KO) 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 males, accompanied by PXR-dependent up-regulation in hepatic genes involved in microbial response, inflammation, oxidative stress, and cancer; PXR-dependent increase in intestinal Firmicutes/Bacteroides ratio (hallmark of obesity) and the pro-inflammatory Lactobacillus, as well as a decrease in the anti-obese Allobaculum and the anti-inflammatory Bifidobacterum, with a PXR-dependent reduction of beneficial BAs in liver. The resistance to NAFLD in females may be explained by PXR-dependent decrease in pro-inflammatory bacteria (Ruminococcus gnavus and Peptococcaceae). 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.
Highlights
non-alcoholic fatty liver disease (NAFLD) is a progressive disease associated with obesity, usually accompanied by steatosis and inflammation, potentially degenerating to non-alcoholic steatohepatitis (NASH) and liver cancer [1]
Our study demonstrated that Pregnane X receptor (PXR) is necessary in modulating the gut microbiome-liver axis to impact the susceptibility to high fat diet (HFD)-induced obesity in a sex-specific manner, and gut microbiome is likely a mechanistic component in augmenting the liver steatosis and inflammation in PXR-carriers
The PXR is necessary for the distinct separation of microbiome signatures driven by HFD, increased F/B ratio, decreased anti-obesity taxon Allobaculum, decreased anti-inflammatory taxa Bifidobacterium, and increased Lactobacillus taxa, which are anti-inflammatory for probiotic use [40, 41], but it is shown to be pro-inflammatory endogenously [42, 43]
Summary
NAFLD is a progressive disease associated with obesity, usually accompanied by steatosis and inflammation, potentially degenerating to non-alcoholic steatohepatitis (NASH) and liver cancer [1]. Obesity and NAFLD have been linked with dysregulation of the gut microbiome [2, 3], including an increase in the Firmicutes/Bacteroidetes (F/B) ratio, which is a well-established obesity biomarker [4, 5]. The gut microbiome is an important modifier of host xenobiotic biotransformation. Besides its wellcharacterized role in xenobiotic biotransformation, PXR plays novel roles in lipid and glucose metabolism [6]. Human PXR gene variants are associated with disease severity in NAFLD [7], potentially leading to liver steatosis [8].
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