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 micro-biome 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,corre-sponding 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 pharma-cological and toxicological activation of these receptors.Common PXR/CAR-targeted bacteria were identified,the majority of which were suppressed by these receptors.hPXR-TG mice had a distinct mi-crobial 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.