Understanding the physiological functions of the host xenobiotic-sensing nuclear receptors PXR and CAR on the gut microbiome using genetically modified mice  

作　　者：Mallory Little Moumita Dutta Hao Li Adam Matson Xiaojian Shi Gabby Mascarinas Bruk Molla Kris Weigel Haiwei Gu Sridhar Mani Julia Yue Cui 

机构地区：[1]Department of Environmental and Occupational Health Sciences,University of Washington,Seattle,WA 98105,USA [2]Department of Medicine,Molecular Pharmacology and Genetics,Albert Einstein College of Medicine,Bronx,NY 10461,USA [3]University of Connecticut,Hartford,CT 06106,USA [4]Arizona Metabolomics Laboratory,College of Health Solutions,Arizona State University,Phoenix,AZ 85004,USA

出　　处：《Acta Pharmaceutica Sinica B》2022年第2期801-820,共20页药学学报（英文版）

基　　金：supported by National Institutes of Health(NIH,USA)grant ES025708,ES030197,GM111381,ES031098;the University of Washington Center for Exposures,Diseases,Genomics,and Environment,USA[P30 ES0007033];the Murphy Endowment,USA;The Peer Reviewed Medical Research Program-Investigator Initiated Research Award under Award No.W81XWH-17-1-0479;NIH grants(CA 222469,USA)。

摘　　要：Pharmacological activation of the xenobiotic-sensing nuclear receptors pregnane X receptor(PXR) and constitutive androstane receptor(CAR) is well-known to increase drug metabolism and reduce inflammation. Little is known regarding their physiological functions on the gut microbiome. In this study, we discovered bivalent hormetic functions of PXR/CAR modulating the richness of the gut microbiome using genetically engineered mice. The absence of PXR or CAR increased microbial richness, and absence of both receptors synergistically increased microbial richness. PXR and CAR deficiency increased the pro-inflammatory bacteria Helicobacteraceae and Helicobacter. Deficiency in both PXR and CAR increased the relative abundance of Lactobacillus, which has bile salt hydrolase activity, corresponding to decreased primary taurine-conjugated bile acids(BAs) in feces, which may lead to higher internal burden of taurine and unconjugated BAs, both of which are linked to inflammation, oxidative stress, and cytotoxicity. The basal effect of PXR/CAR on the gut microbiome was distinct from pharmacological and toxicological activation of these receptors. Common PXR/CAR-targeted bacteria were identified, the majority of which were suppressed by these receptors. h PXR-TG mice had a distinct microbial profile as compared to wild-type mice. This study is the first to unveil the basal functions of PXR and CAR on the gut microbiome.

关 键 词：PXR CAR Gut microbiome Bile acids Inflammation Mice Nuclear receptor FECES 

分 类 号：R96[医药卫生—药理学]